Risk factors for a severe disease course in children with SARS-COV-2 infection following hematopoietic cell transplantation in the pre-Omicron period: a prospective multinational Infectious Disease Working Party from the European Society for Blood and Marrow Transplantation group (EBMT) and the Spanish Group of Hematopoietic Stem Cell Transplantation (GETH) study

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Abstract

Risk factors for severe SARS-Cov-2 infection course are poorly described in children following hematopoietic cell transplantation (HCT). In this international study, we analyzed factors associated with a severe course (intensive care unit (ICU) admission and/or mortality) in post-HCT children. Eighty-nine children (58% male; median age 9 years (min-max 1–18)) who received an allogeneic (85; 96%) or an autologous (4; 4%) HCT were reported from 28 centers (18 countries). Median time from HCT to SARS-Cov-2 infection was 7 months (min-max 0–181). The most common clinical manifestations included fever (37; 42%) and cough (26; 29%); 37 (42%) were asymptomatic. Nine (10%) children following allo-HCT required ICU care. Seven children (8%) following allo-HCT, died at a median of 22 days after SARS-Cov-2 diagnosis. In a univariate analysis, the probability of a severe disease course was higher in allo-HCT children with chronic GVHD, non-malignant disease, immune suppressive treatment (specifically, mycophenolate), moderate immunodeficiency score, low Lansky score, fever, cough, coinfection, pulmonary radiological findings, and high C-reactive protein. In conclusion, SARS-Cov-2 infection in children following HCT was frequently asymptomatic. Despite this, 10% needed ICU admission and 8% died in our cohort. Certain HCT, underlying disease, and SARS-Cov-2 related factors were associated with a severe disease course.

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COVID-19 in children and adolescents in Europe: a multinational, multicentre cohort study

Florian Götzinger, Begoña Santiago-Garcia, Antoni Noguera-Julian … (2020)

Summary Background To date, few data on paediatric COVID-19 have been published, and most reports originate from China. This study aimed to capture key data on children and adolescents with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection across Europe to inform physicians and health-care service planning during the ongoing pandemic. Methods This multicentre cohort study involved 82 participating health-care institutions across 25 European countries, using a well established research network—the Paediatric Tuberculosis Network European Trials Group (ptbnet)—that mainly comprises paediatric infectious diseases specialists and paediatric pulmonologists. We included all individuals aged 18 years or younger with confirmed SARS-CoV-2 infection, detected at any anatomical site by RT-PCR, between April 1 and April 24, 2020, during the initial peak of the European COVID-19 pandemic. We explored factors associated with need for intensive care unit (ICU) admission and initiation of drug treatment for COVID-19 using univariable analysis, and applied multivariable logistic regression with backwards stepwise analysis to further explore those factors significantly associated with ICU admission. Findings 582 individuals with PCR-confirmed SARS-CoV-2 infection were included, with a median age of 5·0 years (IQR 0·5–12·0) and a sex ratio of 1·15 males per female. 145 (25%) had pre-existing medical conditions. 363 (62%) individuals were admitted to hospital. 48 (8%) individuals required ICU admission, 25 (4%) mechanical ventilation (median duration 7 days, IQR 2–11, range 1–34), 19 (3%) inotropic support, and one (<1%) extracorporeal membrane oxygenation. Significant risk factors for requiring ICU admission in multivariable analyses were being younger than 1 month (odds ratio 5·06, 95% CI 1·72–14·87; p=0·0035), male sex (2·12, 1·06–4·21; p=0·033), pre-existing medical conditions (3·27, 1·67–6·42; p=0·0015), and presence of lower respiratory tract infection signs or symptoms at presentation (10·46, 5·16–21·23; p<0·0001). The most frequently used drug with antiviral activity was hydroxychloroquine (40 [7%] patients), followed by remdesivir (17 [3%] patients), lopinavir–ritonavir (six [1%] patients), and oseltamivir (three [1%] patients). Immunomodulatory medication used included corticosteroids (22 [4%] patients), intravenous immunoglobulin (seven [1%] patients), tocilizumab (four [1%] patients), anakinra (three [1%] patients), and siltuximab (one [<1%] patient). Four children died (case-fatality rate 0·69%, 95% CI 0·20–1·82); at study end, the remaining 578 were alive and only 25 (4%) were still symptomatic or requiring respiratory support. Interpretation COVID-19 is generally a mild disease in children, including infants. However, a small proportion develop severe disease requiring ICU admission and prolonged ventilation, although fatal outcome is overall rare. The data also reflect the current uncertainties regarding specific treatment options, highlighting that additional data on antiviral and immunomodulatory drugs are urgently needed. Funding ptbnet is supported by Deutsche Gesellschaft für Internationale Zusammenarbeit.

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Characteristics and Outcomes of Children With Coronavirus Disease 2019 (COVID-19) Infection Admitted to US and Canadian Pediatric Intensive Care Units

Lara Shekerdemian, Nabihah R. Mahmood, Katie Wolfe … (2020)

The recent and ongoing coronavirus disease 2019 (COVID-19) pandemic has taken an unprecedented toll on adults critically ill with COVID-19 infection. While there is evidence that the burden of COVID-19 infection in hospitalized children is lesser than in their adult counterparts, to date, there are only limited reports describing COVID-19 in pediatric intensive care units (PICUs).

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Clinical characteristics and outcomes of COVID-19 in haematopoietic stem-cell transplantation recipients: an observational cohort study

Akshay Sharma, Neel S. Bhatt, Andrew St Martin … (2021)

Background Haematopoietic stem-cell transplantation (HSCT) recipients are considered at high risk of poor outcomes after COVID-19 on the basis of their immunosuppressed status, but data from large studies in HSCT recipients are lacking. This study describes the characteristics and outcomes of HSCT recipients after developing COVID-19. Methods In response to the pandemic, the Center for International Blood and Marrow Transplant Research (CIBMTR) implemented a special form for COVID-19-related data capture on March 27, 2020. All patients—irrespective of age, diagnosis, donor type, graft source, or conditioning regimens—were included in the analysis with data cutoff of Aug 12, 2020. The main outcome was overall survival 30 days after a COVID-19 diagnosis. Overall survival probabilities were calculated using Kaplan-Meier estimator. Factors associated with mortality after COVID-19 diagnosis were examined using Cox proportional hazard models. Findings 318 HSCT recipients diagnosed with COVID-19 were reported to the CIBMTR. The median time from HSCT to COVID-19 diagnosis was 17 months (IQR 8–46) for allogeneic HSCT recipients and 23 months (8–51) for autologous HSCT recipients. The median follow-up of survivors was 21 days (IQR 8–41) for allogeneic HSCT recipients and 25 days (12–35) for autologous HSCT recipients. 34 (18%) of 184 allogeneic HSCT recipients were receiving immunosuppression within 6 months of COVID-19 diagnosis. Disease severity was mild in 155 (49%) of 318 patients, while severe disease requiring mechanical ventilation occurred in 45 (14%) of 318 patients—ie, 28 (15%) of 184 allogeneic HSCT recipients and 17 (13%) of 134 autologous HSCT recipients. At 30 days after the diagnosis of COVID-19, overall survival was 68% (95% CI 58–77) for recipients of allogeneic HSCT and 67% (55–78) for recipients of autologous HSCT. Age 50 years or older (hazard ratio 2·53, 95% CI 1·16–5·52; p=0·020); male sex (3·53; 1·44–8·67; p=0·006), and development of COVID-19 within 12 months of transplantation (2·67, 1·33–5·36; p=0·005) were associated with a higher risk of mortality among allogeneic HSCT recipients, and a disease indication of lymphoma was associated with a higher risk of mortality compared with plasma cell disorder or myeloma (2·41, [1·08–5·38]; p=0·033) in autologous HSCT recipients. Interpretation Recipients of autologous and allogeneic HSCT who develop COVID-19 have poor overall survival. These data emphasise the need for stringent surveillance and aggressive treatment measures in HSCT recipients who develop COVID-19. Funding American Society of Hematology; Leukemia and Lymphoma Society; National Cancer Institute; National Heart, Lung and Blood Institute; National Institute of Allergy and Infectious Diseases; National Institutes of Health; National Cancer Institute; Health Resources and Services Administration; Office of Naval Research.

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Author and article information

Contributors

Dina Averbuch:

ORCID: http://orcid.org/0000-0001-9614-7274

adiana@hadassah.org.il

Journal

Journal ID (nlm-ta): Bone Marrow Transplant

Journal ID (iso-abbrev): Bone Marrow Transplant

Title: Bone Marrow Transplantation

Publisher: Nature Publishing Group UK (London )

ISSN (Print): 0268-3369

ISSN (Electronic): 1476-5365

Publication date (Electronic): 27 February 2023

Pages: 1-9

Affiliations

[1 ]GRID grid.17788.31, ISNI 0000 0001 2221 2926, Faculty of Medicine, Hebrew University of Jerusalem, , Pediatric Infectious Diseases, Hadassah Medical Center, ; Jerusalem, Israel

[2 ]GRID grid.411251.2, ISNI 0000 0004 1767 647X, Hematology Department, , Hospital Universitario de La Princesa, ; Madrid, Spain

[3 ]GRID grid.411475.2, ISNI 0000 0004 1756 948X, Pediatric Hematology Oncology, Department of Mother and Child, , Azienda Ospedaliera Universitaria Integrata, ; Verona, Italy

[4 ]GRID grid.476306.0, EBMT - Leiden Study Unit, ; Leiden, Netherlands

[5 ]GRID grid.412460.5, RM Gorbacheva Research Institute, , Pavlov University, ; St. Petersburg, Russia

[6 ]GRID grid.4973.9, ISNI 0000 0004 0646 7373, Department of Children and Adolescents Medicine, Stem Cell Transplant Unit, Rigshospitalet, , Copenhagen University Hospital, ; Copenhagen, Denmark

[7 ]GRID grid.7634.6, ISNI 0000000109409708, Department of Pediatric Hematology and Oncology, , Comenius University, ; Bratislava, Slovakia

[8 ]Bone Marrow Transplantation Unit, National Institute of Children’s Diseases, Bratislava, Slovakia

[9 ]GRID grid.415310.2, ISNI 0000 0001 2191 4301, Pediatric Hematology/Oncology, , King Faisal Specialist Hospital and Research Centre, ; Riyadh, Saudi Arabia

[10 ]GRID grid.411705.6, ISNI 0000 0001 0166 0922, Pediatric Cell and Gene Therapy Research Center, Gene, Cell & Tissue Research Institute, , Tehran University of Medical Sciences, ; Tehran, Iran

[11 ]GRID grid.22937.3d, ISNI 0000 0000 9259 8492, Department of Pediatric Hematology and Oncology, St. Anna Children’s Hospital, Department of Pediatrics and Adolescent Medicine, , Medical University of Vienna, ; Vienna, Austria

[12 ]GRID grid.81821.32, ISNI 0000 0000 8970 9163, Department of Pediatric Hematology and Oncology, , Hospital Universitario La Paz, ; Madrid, Spain

[13 ]GRID grid.24381.3c, ISNI 0000 0000 9241 5705, Section of Pediatric Hematology, Immunology and HCT, , Astrid Lindgren Children’s Hospital, Karolinska University Hospital and Division of Pediatrics, CLINTEC, Karolinska Institutet, ; Stockholm, Sweden

[14 ]GRID grid.7080.f, ISNI 0000 0001 2296 0625, Pediatric BMT Unit, Hospital Santa Creu i Sant Pau, , Universitat Autonoma de Barcelona, ; Barcelona, Spain

[15 ]GRID grid.411088.4, ISNI 0000 0004 0578 8220, Universitaetsklinikum Frankfurt Goethe-Universitaet, ; Frankfurt Main, Germany

[16 ]GRID grid.1649.a, ISNI 000000009445082X, Sahlgrenska University Hospital, ; Goeteborg, Sweden

[17 ]GRID grid.415172.4, ISNI 0000 0004 0399 4960, BMT Unit, , Bristol Royal Hospital for Children, ; Bristol, UK

[18 ]GRID grid.412826.b, ISNI 0000 0004 0611 0905, HSCT Unit, Department of Paediatric Haematology and Oncology, , University Hospital Motol, ; Prague, Czech Republic

[19 ]GRID grid.11843.3f, ISNI 0000 0001 2157 9291, Pediatric Hematology Oncology, Hautepierre Hospital, , Strasbourg University, ; Strasbourg, France

[20 ]GRID grid.415571.3, ISNI 0000 0004 4685 794X, Department of Haematology, , Royal Hospital for Children, ; Glasgow, UK

[21 ]GRID grid.415246.0, ISNI 0000 0004 0399 7272, Department of Haematology, , Birmingham Children’s Hospital, ; Birmingham, UK

[22 ]GRID grid.13648.38, ISNI 0000 0001 2180 3484, Department of Stem Cell Transplantation, , University Hospital Eppendorf, ; Hamburg, Germany

[23 ]GRID grid.7727.5, ISNI 0000 0001 2190 5763, Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, , University of Regensburg, ; Regensburg, Germany

[24 ]GRID grid.5606.5, ISNI 0000 0001 2151 3065, Division of Infectious Diseases, , University of Genova, Ospedale Policlinco San Martino, ; Genova, Italy

[25 ]GRID grid.411308.f, Hospital Clinico Universitario de Valencia. Fundación de investigación INCLIVA, , Hospital Clinico Universitario de Valencia, ; Valencia, Spain

[26 ]GRID grid.5374.5, ISNI 0000 0001 0943 6490, Pediatric Hematology and Oncology, University Hospital, Collegium Medicum, , Nicolaus Copernicus University Torun, ; Bydgoszcz, Poland

[27 ]GRID grid.4714.6, ISNI 0000 0004 1937 0626, Department of Cellular Therapy and Allogeneic Stem Cell Transplantation, Karolinska Comprehensive Cancer Center, Karolinska University Hospital Huddinge, Division of Hematology, Department of Medicine Huddinge, , Karolinska Institutet, ; Stockholm, Sweden

Author information

Dina Averbuch http://orcid.org/0000-0001-9614-7274

Rafael de la Camara http://orcid.org/0000-0002-8189-5779

Tatiana A. Bykova http://orcid.org/0000-0002-4456-2369

Marianne Ifversen http://orcid.org/0000-0002-2558-1935

Mouhab Ayas http://orcid.org/0000-0002-5740-1302

Amir Ali Hamidieh http://orcid.org/0000-0002-8935-079X

Herbert Pichler http://orcid.org/0000-0001-5107-5123

Antonio Perez-Martinez http://orcid.org/0000-0002-6436-9195

Simone Cesaro http://orcid.org/0000-0002-8698-9547

Peter Bader http://orcid.org/0000-0003-4554-0265

Petr Sedlacek http://orcid.org/0000-0001-7895-2886

Nicolaus Kroeger http://orcid.org/0000-0001-5103-9966

Malgorzata Mikulska http://orcid.org/0000-0002-5535-4602

Jose Luis Piñana http://orcid.org/0000-0001-8533-2562

Jan Styczynski http://orcid.org/0000-0002-3158-119X

Per Ljungman http://orcid.org/0000-0002-8281-3245

Article

Publisher ID: 1941

DOI: 10.1038/s41409-023-01941-5

PMC ID: 9969031

PubMed ID: 36849806

SO-VID: 511a4453-a1aa-4910-aa79-36088a2bd52c

Copyright © © The Author(s), under exclusive licence to Springer Nature Limited 2023, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

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This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

History

Date received : 22 July 2022

Date revision received : 9 February 2023

Date accepted : 15 February 2023

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Most cited references 25

COVID-19 in children and adolescents in Europe: a multinational, multicentre cohort study

Characteristics and Outcomes of Children With Coronavirus Disease 2019 (COVID-19) Infection Admitted to US and Canadian Pediatric Intensive Care Units

Clinical characteristics and outcomes of COVID-19 in haematopoietic stem-cell transplantation recipients: an observational cohort study

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