Skip to main content
Top

Open Access 25-04-2024 | Post-COVID Syndrome | Original Article

Clinical-based phenotypes in children with pediatric post-COVID-19 condition

Authors: Lieke C. E. Noij, Jelle M. Blankestijn, Coen R. Lap, Marlies A. van Houten, Giske Biesbroek, Anke-Hilse Maitland-van der Zee, Mahmoud I. Abdel-Aziz, Johannes B. van Goudoever, Mattijs W. Alsem, Caroline L. H. Brackel, Kim J. Oostrom, Simone Hashimoto, Suzanne W. J. Terheggen-Lagro

Published in: World Journal of Pediatrics

Login to get access

Abstract

Background

Pediatric post coronavirus disease 2019 (COVID-19) condition (PPCC) is a heterogeneous syndrome, which can significantly affect the daily lives of children. This study aimed to identify clinically meaningful phenotypes in children with PPCC, to better characterize and treat this condition.

Methods

Participants were children with physician-diagnosed PPCC, referred to the academic hospital Amsterdam UMC in the Netherlands between November 2021 and March 2023. Demographic factors and information on post-COVID symptoms, comorbidities, and impact on daily life were collected. Clinical clusters were identified using an unsupervised and unbiased approach for mixed data types.

Results

Analysis of 111 patients (aged 3–18 years) revealed three distinct clusters within PPCC. Cluster 1 (n = 62, median age = 15 years) predominantly consisted of girls (74.2%). These patients suffered relatively more from exercise intolerance, dyspnea, and smell disorders. Cluster 2 (n = 33, median age = 13 years) contained patients with an even gender distribution (51.5% girls). They suffered from relatively more sleep problems, memory loss, gastrointestinal symptoms, and arthralgia. Cluster 3 (n = 16, median age = 11 years) had a higher proportion of boys (75.0%), suffered relatively more from fever, had significantly fewer symptoms (median age of 5 years compared to 8 and 10 years for clusters 1 and 2 respectively), and experienced a lower impact on daily life.

Conclusions

This study identified three distinct clinical PPCC phenotypes, with variations in sex, age, symptom patterns, and impact on daily life. These findings highlight the need for further research to understand the potentially diverse underlying mechanisms contributing to post-COVID symptoms in children.

Graphical abstract

Appendix
Available only for authorised users
Literature
2.
go back to reference To KK, Sridhar S, Chiu KH, Hung DL, Li X, Hung IF, et al. Lessons learned 1 year after SARS-CoV-2 emergence leading to COVID-19 pandemic. Emerg Microbes Infect. 2021;10:507–3510.CrossRefPubMedPubMedCentral To KK, Sridhar S, Chiu KH, Hung DL, Li X, Hung IF, et al. Lessons learned 1 year after SARS-CoV-2 emergence leading to COVID-19 pandemic. Emerg Microbes Infect. 2021;10:507–3510.CrossRefPubMedPubMedCentral
4.
go back to reference Lopez-Leon S, Wegman-Ostrosky T, Ayuzo Del Valle NC, Perelman C, Sepulveda R, Rebolledo PA, et al. Long-COVID in children and adolescents: a systematic review and meta-analyses. Sci Rep. 2022;12:9950.CrossRefPubMedPubMedCentral Lopez-Leon S, Wegman-Ostrosky T, Ayuzo Del Valle NC, Perelman C, Sepulveda R, Rebolledo PA, et al. Long-COVID in children and adolescents: a systematic review and meta-analyses. Sci Rep. 2022;12:9950.CrossRefPubMedPubMedCentral
5.
go back to reference Brackel CLH, Lap CR, Buddingh EP, van Houten MA, van der Sande L, Langereis EJ, et al. Pediatric long-COVID: An overlooked phenomenon? Pediatr Pulmonol. 2021;56:2495–502.CrossRefPubMedPubMedCentral Brackel CLH, Lap CR, Buddingh EP, van Houten MA, van der Sande L, Langereis EJ, et al. Pediatric long-COVID: An overlooked phenomenon? Pediatr Pulmonol. 2021;56:2495–502.CrossRefPubMedPubMedCentral
7.
go back to reference Zheng YB, Zeng N, Yuan K, Tian SS, Yang YB, Gao N, et al. Prevalence and risk factor for long COVID in children and adolescents: a meta-analysis and systematic review. J Infect Public Health. 2023;16:660–7210.CrossRefPubMedPubMedCentral Zheng YB, Zeng N, Yuan K, Tian SS, Yang YB, Gao N, et al. Prevalence and risk factor for long COVID in children and adolescents: a meta-analysis and systematic review. J Infect Public Health. 2023;16:660–7210.CrossRefPubMedPubMedCentral
8.
go back to reference Pellegrino R, Chiappini E, Licari A, Galli L, Marseglia GL. Prevalence and clinical presentation of long COVID in children: a systematic review. Eur J Pediatr. 2022;181:3995–4009.CrossRefPubMedPubMedCentral Pellegrino R, Chiappini E, Licari A, Galli L, Marseglia GL. Prevalence and clinical presentation of long COVID in children: a systematic review. Eur J Pediatr. 2022;181:3995–4009.CrossRefPubMedPubMedCentral
9.
go back to reference Buonsenso D, Munblit D, De Rose C, Sinatti D, Ricchiuto A, Carfi A, et al. Preliminary evidence on long COVID in children. Acta Paediatr. 2021;110:2208–11. CrossRefPubMedPubMedCentral Buonsenso D, Munblit D, De Rose C, Sinatti D, Ricchiuto A, Carfi A, et al. Preliminary evidence on long COVID in children. Acta Paediatr. 2021;110:2208–11. CrossRefPubMedPubMedCentral
10.
go back to reference Behnood S, Newlands F, O’Mahoney L, Haghighat Ghahfarokhi M, Muhid MZ, Dudley J, et al. Persistent symptoms are associated with long term effects of COVID-19 among children and young people: results from a systematic review and meta-analysis of controlled studies. PLoS ONE. 2023;18:e0293600.CrossRefPubMedPubMedCentral Behnood S, Newlands F, O’Mahoney L, Haghighat Ghahfarokhi M, Muhid MZ, Dudley J, et al. Persistent symptoms are associated with long term effects of COVID-19 among children and young people: results from a systematic review and meta-analysis of controlled studies. PLoS ONE. 2023;18:e0293600.CrossRefPubMedPubMedCentral
11.
go back to reference Wacks M, Wortley E, Gregorowski A, Segal TY, Whittaker E. Fifteen-minute consultation: managing post-COVID-19 syndrome (long COVID) in children and young people. Arch Dis Child Educ Pract Ed. 2024;109:29–34.CrossRef Wacks M, Wortley E, Gregorowski A, Segal TY, Whittaker E. Fifteen-minute consultation: managing post-COVID-19 syndrome (long COVID) in children and young people. Arch Dis Child Educ Pract Ed. 2024;109:29–34.CrossRef
12.
go back to reference Morello R, Mariani F, Mastrantoni L, De Rose C, Zampino G, Munblit D, et al. Risk factors for post-COVID-19 condition (Long Covid) in children: a prospective cohort study. EClinicalMedicine. 2023;59:101961.CrossRefPubMedPubMedCentral Morello R, Mariani F, Mastrantoni L, De Rose C, Zampino G, Munblit D, et al. Risk factors for post-COVID-19 condition (Long Covid) in children: a prospective cohort study. EClinicalMedicine. 2023;59:101961.CrossRefPubMedPubMedCentral
13.
go back to reference Jiang L, Li X, Nie J, Tang K, Bhutta Z. A systematic review of persistent clinical features after SARS-CoV-2 in the pediatric population. Pediatrics. 2023;152:2.CrossRef Jiang L, Li X, Nie J, Tang K, Bhutta Z. A systematic review of persistent clinical features after SARS-CoV-2 in the pediatric population. Pediatrics. 2023;152:2.CrossRef
15.
16.
go back to reference Buonsenso D, Espuny Pujol F, Munblit D, Pata D, McFarland S, Simpson FK. Clinical characteristics, activity levels and mental health problems in children with long coronavirus disease: a survey of 510 children. Future Microbiol. 2022;17:577–88.CrossRefPubMedPubMedCentral Buonsenso D, Espuny Pujol F, Munblit D, Pata D, McFarland S, Simpson FK. Clinical characteristics, activity levels and mental health problems in children with long coronavirus disease: a survey of 510 children. Future Microbiol. 2022;17:577–88.CrossRefPubMedPubMedCentral
17.
go back to reference Kenny G, McCann K, O’Brien C, Savinelli S, Tinago W, Yousif O, et al. Identification of Distinct Long COVID Clinical Phenotypes Through Cluster Analysis of Self-Reported Symptoms. Open Forum Infect Dis. 2022;9:ofac060.CrossRefPubMedPubMedCentral Kenny G, McCann K, O’Brien C, Savinelli S, Tinago W, Yousif O, et al. Identification of Distinct Long COVID Clinical Phenotypes Through Cluster Analysis of Self-Reported Symptoms. Open Forum Infect Dis. 2022;9:ofac060.CrossRefPubMedPubMedCentral
18.
go back to reference Gentilotti E, Gorska A, Tami A, Gusinow R, Mirandola M, Rodriguez Bano J, et al. Clinical phenotypes and quality of life to define post-COVID-19 syndrome: a cluster analysis of the multinational, prospective ORCHESTRA cohort. EClinicalMedicine. 2023;62:102–7.CrossRef Gentilotti E, Gorska A, Tami A, Gusinow R, Mirandola M, Rodriguez Bano J, et al. Clinical phenotypes and quality of life to define post-COVID-19 syndrome: a cluster analysis of the multinational, prospective ORCHESTRA cohort. EClinicalMedicine. 2023;62:102–7.CrossRef
22.
go back to reference Peersmann SHM, Luijten MAJ, Haverman L, Terwee CB, Grootenhuis MA, van Litsenburg RRL. Psychometric properties and CAT performance of the PROMIS pediatric sleep disturbance, sleep-related impairment, and fatigue item banks in Dutch children and adolescents. Psychol Assess. 2022;34:860–9.CrossRefPubMed Peersmann SHM, Luijten MAJ, Haverman L, Terwee CB, Grootenhuis MA, van Litsenburg RRL. Psychometric properties and CAT performance of the PROMIS pediatric sleep disturbance, sleep-related impairment, and fatigue item banks in Dutch children and adolescents. Psychol Assess. 2022;34:860–9.CrossRefPubMed
23.
go back to reference Terwee CB, Peipert JD, Chapman R, Lai JS, Terluin B, Cella D, et al. Minimal important change (MIC): a conceptual clarification and systematic review of MIC estimates of PROMIS measures. Qual Life Res. 2021;30:2729–54.CrossRefPubMedPubMedCentral Terwee CB, Peipert JD, Chapman R, Lai JS, Terluin B, Cella D, et al. Minimal important change (MIC): a conceptual clarification and systematic review of MIC estimates of PROMIS measures. Qual Life Res. 2021;30:2729–54.CrossRefPubMedPubMedCentral
25.
go back to reference van Buuren S, Groothuis-Oudshoorn K. mice: Multivariate imputation by chained equations in R. J Stat Softw. 2011;45:1–67.CrossRef van Buuren S, Groothuis-Oudshoorn K. mice: Multivariate imputation by chained equations in R. J Stat Softw. 2011;45:1–67.CrossRef
26.
go back to reference Dunn JC. A fuzzy relative of the ISODATA process and itsuse in detecting compact well-separated clusters. J Cybernet. 1973;3:32–57.CrossRef Dunn JC. A fuzzy relative of the ISODATA process and itsuse in detecting compact well-separated clusters. J Cybernet. 1973;3:32–57.CrossRef
29.
go back to reference Fischer A, Badier N, Zhang L, Elbeji A, Wilmes P, Oustric P, et al. Long COVID classification: findings from a clustering analysis in the Predi-COVID Cohort Study. Int J Environ Res Public Health. 2022;19:16018. CrossRefPubMedPubMedCentral Fischer A, Badier N, Zhang L, Elbeji A, Wilmes P, Oustric P, et al. Long COVID classification: findings from a clustering analysis in the Predi-COVID Cohort Study. Int J Environ Res Public Health. 2022;19:16018. CrossRefPubMedPubMedCentral
30.
go back to reference Reese JT, Blau H, Casiraghi E, Bergquist T, Loomba JJ, Callahan TJ, et al. Generalisable long COVID subtypes: findings from the NIH N3C and RECOVER programmes. EBioMedicine. 2023;87:104413.CrossRefPubMed Reese JT, Blau H, Casiraghi E, Bergquist T, Loomba JJ, Callahan TJ, et al. Generalisable long COVID subtypes: findings from the NIH N3C and RECOVER programmes. EBioMedicine. 2023;87:104413.CrossRefPubMed
31.
go back to reference Goldhaber NH, Kohn JN, Ogan WS, Sitapati A, Longhurst CA, Wang A, et al. Deep dive into the long haul: analysis of symptom clusters and risk factors for post-acute sequelae of COVID-19 to inform clinical care. Int J Environ Res Public Health. 2022;19:16841. CrossRefPubMedPubMedCentral Goldhaber NH, Kohn JN, Ogan WS, Sitapati A, Longhurst CA, Wang A, et al. Deep dive into the long haul: analysis of symptom clusters and risk factors for post-acute sequelae of COVID-19 to inform clinical care. Int J Environ Res Public Health. 2022;19:16841. CrossRefPubMedPubMedCentral
32.
go back to reference Izquierdo-Pujol J, Moron-Lopez S, Dalmau J, Gonzalez-Aumatell A, Carreras-Abad C, Mendez M, et al. Post COVID-19 condition in children and adolescents: an emerging problem. Front Pediatr. 2022;10:894204.CrossRefPubMedPubMedCentral Izquierdo-Pujol J, Moron-Lopez S, Dalmau J, Gonzalez-Aumatell A, Carreras-Abad C, Mendez M, et al. Post COVID-19 condition in children and adolescents: an emerging problem. Front Pediatr. 2022;10:894204.CrossRefPubMedPubMedCentral
33.
go back to reference Garai R, Krivacsy P, Herczeg V, Kovacs F, Tel B, Kelemen J, et al. Clinical assessment of children with long COVID syndrome. Pediatr Res. 2023;93:1616–25.CrossRefPubMed Garai R, Krivacsy P, Herczeg V, Kovacs F, Tel B, Kelemen J, et al. Clinical assessment of children with long COVID syndrome. Pediatr Res. 2023;93:1616–25.CrossRefPubMed
34.
go back to reference Glinianowicz M, Ciura D, Burnatowska E, Olszanecka-Glinianowicz M. Psychological effects of the COVID-19 pandemic - what do we know about them? Eur Rev Med Pharmacol Sci. 2023;27:6445–58.PubMed Glinianowicz M, Ciura D, Burnatowska E, Olszanecka-Glinianowicz M. Psychological effects of the COVID-19 pandemic - what do we know about them? Eur Rev Med Pharmacol Sci. 2023;27:6445–58.PubMed
36.
go back to reference Proal AD, VanElzakker MB, Aleman S, Bach K, Boribong BP, Buggert M, et al. SARS-CoV-2 reservoir in post-acute sequelae of COVID-19 (PASC). Nat Immunol. 2023;24:1616–27.CrossRefPubMed Proal AD, VanElzakker MB, Aleman S, Bach K, Boribong BP, Buggert M, et al. SARS-CoV-2 reservoir in post-acute sequelae of COVID-19 (PASC). Nat Immunol. 2023;24:1616–27.CrossRefPubMed
37.
go back to reference Paris D, Palomba L, Albertini MC, Tramice A, Motta L, Giammattei E, et al. The biomarkers’ landscape of post-COVID-19 patients can suggest selective clinical interventions. Sci Rep. 2023;13:22496.CrossRefPubMedPubMedCentral Paris D, Palomba L, Albertini MC, Tramice A, Motta L, Giammattei E, et al. The biomarkers’ landscape of post-COVID-19 patients can suggest selective clinical interventions. Sci Rep. 2023;13:22496.CrossRefPubMedPubMedCentral
40.
go back to reference Lorman V, Razzaghi H, Song X, Morse K, Utidjian L, Allen AJ, et al. A machine learning-based phenotype for long COVID in children: an EHR-based study from the RECOVER program. PLoS ONE. 2023;18:e0289774.CrossRefPubMedPubMedCentral Lorman V, Razzaghi H, Song X, Morse K, Utidjian L, Allen AJ, et al. A machine learning-based phenotype for long COVID in children: an EHR-based study from the RECOVER program. PLoS ONE. 2023;18:e0289774.CrossRefPubMedPubMedCentral
Metadata
Title
Clinical-based phenotypes in children with pediatric post-COVID-19 condition
Authors
Lieke C. E. Noij
Jelle M. Blankestijn
Coen R. Lap
Marlies A. van Houten
Giske Biesbroek
Anke-Hilse Maitland-van der Zee
Mahmoud I. Abdel-Aziz
Johannes B. van Goudoever
Mattijs W. Alsem
Caroline L. H. Brackel
Kim J. Oostrom
Simone Hashimoto
Suzanne W. J. Terheggen-Lagro
Publication date
25-04-2024
Publisher
Springer Nature Singapore
Published in
World Journal of Pediatrics
Print ISSN: 1708-8569
Electronic ISSN: 1867-0687
DOI
https://doi.org/10.1007/s12519-024-00805-2