COVID-19 in Children Following Hematopoietic Cell Transplantation: A Multinational Study of the European Bone Marrow Transplantation Society (EBMT) and the Spanish Group of Hematopoietic Stem Cell Transplantation (GETH)
Authors: Averbuch Diana , De La Camara Rafael , Corbacioglu Selim , Mikulska Malgorzata , Piñana Sanchez Jose Luis , Tridello Gloria , Knelange Nina Simone , Kulagin Aleksandr D. , Ayas Mouhab , Perez-Martinez Antonio , Hamidieh Amir Ali , Sundin Mikael , Martino Rodrigo , Sedlacek Petr , Cesaro Simone , Paillard Catherine , Gibson Brenda , Lawson Sarah , Kroeger Nicolaus , Styczynski Jan , Ljungman Per 
Published: November 2021

Abstract
Introduction
COVID-19 is usually a mild disease in immunocompetent children, with ~1% requiring intensive care unit (ICU) admission and &lt;0.1% mortality. Data on its course in children following hematopoietic cell transplantation (HCT) is limited.
Methods
Data on children following HCT who developed COVID-19 (diagnosed by positive SARS-CoV-2 PCR on respiratory tract samples) during 3.2020-4.2021 were prospectively collected by EBMT and GETH, including demography, HCT data, COVID-related manifestations, ICU admission and mortality. Factors associated with worse outcomes (ICU admission or mortality) were characterized.
Results
Sixty-two children (34 boys; median age 9; min-max; 0.7-17 years) were reported from 27 centers, 16 countries; 57 (92%) following allogeneic and 5 (8%) following autologous HCT. Underlying diseases were acute leukemia (23; 37%), inherited disorders (9; 15%), hemoglobinopathies (7; 11%), solid tumor (6; 10%), bone marrow failure (5; 8%), other malignant (8; 13%) and non-malignant (4; 6%) diseases. Five (8%) children had high blood pressure; 6 (10%) had underlying lung pathology. The median time from the most recent HCT to COVID was 5 months (min-max; 0-169). The stem cell source was bone marrow (33); peripheral (22) or cord blood (1). Among the patients with information available, 34 (62%) underwent in-vivo T cell depletion, 20 (33%) received corticosteroids, and 36 (60%) other immunosuppressant drugs(s) within two months prior to and after the COVID-19 episode. The presence of acute grade 2-4 or chronic graft versus host disease (GVHD) was reported in 12/54 (23%) and 8/51 (16%) children, respectively. Clinical presentation (n=57) included fever (28; 49%), cough (18; 32%), diarrhea (8; 14%), upper respiratory tract disease (as rhinorrhea, sinusitis, otitis, or pharyngitis; 12; 21%); six (10%) required oxygen to maintain oxygen saturation above 92%; 20 children (35%) were asymptomatic. The median time from symptoms onset to COVID diagnosis was 1 day (-43-40). Sixty-three percent of patients were hospitalized; 43% due to COVID. The proportion of children with neutropenia or lymphocytopenia (&lt;500 cells/mm 3) was 75% and 73%, respectively. Sixteen children (26%) had evidence of viral (n=10), bacterial (n=6) or fungal (n=2) coinfections. The median time from COVID diagnosis to the last follow-up in alive patients was 69 days (min-max; 2 - 294).
Six (10%) children who developed COVID at a median 6.5 (min-max; 2- 16) months following allo-HCT (median age 6 years; 5 boys) required ICU care within a median 6 (min-max; -5-15) days after diagnosis. All of them were neutropenic, received steroids, and other immunosuppressive drugs at COVID diagnosis; 5 had undergone in-vivo T cell depletion; 5 were lymphocytopenic, 5 had GVHD (2 acute and 3 chronic); 3 received non-invasive and 2 invasive ventilation. Three children had viral or bacterial coinfections. Three children died.
Six (10%) children (5 boys, median age 10.5 years; min-max; 4-13) who developed COVID at median 2 (min-max; 0-147) months following allo-HCT died within median 35 days (min-max; 5-54) after diagnosis. One had high blood pressure, and none suffered from underlying lung pathology. At the time of COVID, 3 were neutropenic, 2 lymphocytopenic; 4 had GVHD (2 acute, 2 chronic); 3 received steroids and 4 immunosuppressive drugs. Two had viral or bacterial coinfections. Five had positive SARS-CoV-2 PCR at the time of death. In 3, COVID was the primary cause of death.
We compared nine children with the worse outcomes to 53 children with benign course. Among patients alive at 100-day post HCT, the probability of worse outcomes was higher in patients with vs. without chronic GVHD (Figure). No other significant differences were observed in demographic, underlying disease, and HCT-related characteristics.
Compared to adults following HCT (Ljungman, Leukemia 2021), children had:
- Shorter median time from HCT to COVID diagnosis, 5 vs 18 months;
- Higher proportion of asymptomatic infections, 35% vs 9%;
- Lower proportion of those who required oxygen, 10% vs 35%;
- Lower all-cause mortality, 10% vs 29%.
Conclusions
Children following HCT with COVID-19 have a higher risk of ICU admission and mortality compared to immune competent children. The presence of chronic GVHD at COVID diagnosis was associated with worse outcomes. COVID course following HCT is milder in children compared to adults.
Figure 1 Figure 1.

Disclosures
Averbuch: Takeda: Consultancy; Pfizer: Consultancy; GSK: Speakers Bureau. De La Camara: Roche: Consultancy; IQONE: Consultancy. Corbacioglu: Gentium/Jazz Pharmaceuticals: Consultancy, Honoraria. Mikulska: Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Speakers Bureau; MSD: Speakers Bureau; Janssen: Speakers Bureau; Biotest: Speakers Bureau. Kulagin: Roche: Speakers Bureau; Sanofi: Speakers Bureau; Generium: Speakers Bureau; Biocad: Research Funding; Apellis: Research Funding; Alexion: Research Funding; X4 Pharmaceuticals: Research Funding; Novartis: Speakers Bureau; Johnson & Johnson: Speakers Bureau; Pfizer: Speakers Bureau. Cesaro: Sobi: Membership on an entity's Board of Directors or advisory committees; Gilead: Speakers Bureau. Lawson: Alexion: Honoraria. Kroeger: Neovii: Honoraria, Research Funding; Sanofi: Honoraria; Jazz: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Riemser: Honoraria, Research Funding; Gilead/Kite: Honoraria; AOP Pharma: Honoraria; Novartis: Honoraria. Styczynski: MSD, Pfizer, Giled, TEVA, Jazz, Novartis: Honoraria, Speakers Bureau. Ljungman: Takeda: Consultancy, Other: Endpoint committee, speaker; Enanta: Other: DSMB; Janssen: Other: Investigator; OctaPharma: Other: DSMB; Merck: Other: Investigator, speaker; AiCuris: Consultancy.