TYPE Original Research PUBLISHED 24 February 2023 DOI 10.3389/fimmu.2023.1125030 Outcome of COVID-19 in OPEN ACCESS allogeneic stem cell transplant EDITED BY David Allan, Ottawa Hospital Research Institute (OHRI), recipients: Results from the Canada REVIEWED BY EPICOVIDEHA registry Guillermo José Ruiz-Argüelles, Clı´nica Ruiz, Mexico Muhammad Bilal Abid, Alessandro Busca 1†, Jon Salmanton-Garcı́a 2,3*†, Medical College of Wisconsin, United States Francesco Marchesi 4, Francesca Farina 5, *CORRESPONDENCE Guldane Cengiz Seval 6, Jaap Van Doesum 7, Jon Salmanton-Garcı´a Nick De Jonge 8, Nathan C. Bahr 9, Johan Maertens 10,11, jon.salmanton-garcia@uk-koeln.de † Joseph Meletiadis 12, Nicola S. Fracchiolla 13, These authors share first authorship Barbora Weinbergerová 14, Luisa Verga 15,16, SPECIALTY SECTION This article was submitted to Zdeněk Ráčil 17, Moraima Jiménez 18,19, Alloimmunity and Transplantation, a section of the journal Andreas Glenthøj 20, Ola Blennow 21, Alina Daniela Tanase 22, Frontiers in Immunology Martin Schönlein 23, Lucia Prezioso 24, Nina Khanna 25, RECEIVED 15 December 2022 Rafael F. Duarte 26, Pavel Žák 27, Marcio Nucci 28, ACCEPTED 01 February 2023 PUBLISHED 24 February 2023 Marina Machado 29, Austin Kulasekararaj 30,31, CITATION Ildefonso Espigado 32, Elizabeth De Kort 33, Busca A, Salmanton-Garcı´a J, Marchesi F, José-Marı́a Ribera-Santa Susana 34, Monia Marchetti 35, Farina F, Seval GC, Van Doesum J, De Jonge N, Bahr NC, Maertens J, Gabriele Magliano 36, Iker Falces-Romero 37, Meletiadis J, Fracchiolla NS, Weinbergerová B, Verga L, Ráčil Z, Osman Ilhan 6, Emanuele Ammatuna 7, Sofia Zompi 1, Jiménez M, Glenthøj A, Blennow O, Panagiotis Tsirigotis 12, Anastasia Antoniadou 12, Tanase AD, Schönlein M, Prezioso L, Khanna N, Duarte RF, Žák P, Nucci M, Giovanni Paolo Maria Zambrotta 15,16, Anna Nordlander 21, Machado M, Kulasekararaj A, Espigado I, De Kort E, Ribera-Santa Susana JM, Linda Katharina Karlsson 20, Michaela Hanakova 17, Marchetti M, Magliano G, Falces-Romero I, Giulia Dragonetti 38, Alba Cabirta 18, Ilhan O, Ammatuna E, Zompi S, Tsirigotis P, Antoniadou A, Zambrotta GPM, Caroline Berg Venemyr 20, Stefanie Gräfe 2,3, Nordlander A, Karlsson LK, Hanakova M, Dragonetti G, Cabirta A, Berg Venemyr C, Jens Van Praet 39, Athanasios Tragiannidis 40, Gräfe S, Van Praet J, Tragiannidis A, Verena Petzer 41, Alberto López-Garcı́a 42, Federico Itri 43, Petzer V, López-Garcı´a A, Itri F, Groh A, Gavriilaki E, Dargenio M, Rahimli L, Ana Groh 44, Eleni Gavriilaki 45, Michelina Dargenio 46, Cornely OA, Pagano L and EPICOVIDEHA Consortium (2023) Outcome of COVID-19 Laman Rahimli 2,3, Oliver A. Cornely 2,3,47,48,49, in allogeneic stem cell transplant Livio Pagano 50 and EPICOVIDEHA Consortium recipients: Results from the EPICOVIDEHA registry. 1 Stem Cell Transplant Center, AOU Citta’ della Salute e della Scienza, Turin, Italy, 2 University of Cologne, Front. Immunol. 14:1125030. Faculty of Medicine and University Hospital Cologne, Translational Research, Cologne Excellence doi: 10.3389/fimmu.2023.1125030 Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany, 3 University of Cologne, Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD) and Excellence Center for Medical Mycology (ECMM), Cologne, Germany, 4 Hematology and Stem Cell Transplant Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy, 5 IRCCS Ospedale San Raffaele, Milan, Italy, 6 Ankara University, Ankara, Türkiye, 7 University Medical Center Groningen, Groningen, Netherlands, 8 Amsterdam UMC, Amsterdam, Netherlands, 9 University of Kansas Medical Center, Kansas, KS, United States, 10 Department of Microbiology, Immunology, and Transplantation, KULeuven, Leuven, Belgium, 11 Department of Hematology, UZ Leuven, Leuven, Belgium, 12 Clinical Microbiology Laboratory, Medical School, “Attikon” University General Hospital, National and Kapodistrian University of Athens, Athens, Greece, 13 Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy, 14 Department of Internal Medicine - Hematology and Oncology, Masaryk University Hospital Brno, Brno, Czechia, 15 Azienda Ospedaliera San Gerardo - Monza, Monza, Italy, 16 Università Milano-Bicocca, Milan, Italy, 17 Institute of Hematology and Blood Transfusion, Frontiers in Immunology 01 frontiersin.org Busca et al. 10.3389/fimmu.2023.1125030 Prague, Czechia, 18 Department of Hematology, Vall d’Hebron Hospital Universitari, Experimental Hematology, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona Hospital, Barcelona, Spain, 19 Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain, 20 Department of Hematology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark, 21 Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden, 22 Fundeni Clinical Institute, University of Medicine and Pharmacy Carol Davila, Bucharest, Romania, 23 Department of Oncology, Hematology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, 24 Hospital University of Parma - Hematology and Bone Marrow Unit, Parma, Italy, 25 Division of Infectious Diseases and Hospital Epidemiology, and Department of Clinical Research, University and University Hospital of Basel, Basel, Switzerland, 26 Hospital Universitario Puerta de Hierro, Majadahonda, Spain, 27 University Hospital Hradec Králové, Hradec Králové, Czechia, 28 Federal University of Rio de Janeiro, Rio de Janeiro, Brazil, 29 Clinical Microbiology and Infectious Diseases Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain, 30 King’s College Hospital, London, United Kingdom, 31 King’s College London, London, United Kingdom, 32 Department of Hematology, University Hospital Virgen Macarena - University Hospital Virgen del Rocı´o, Instituto de Biomedicina de Sevilla (IBIS/CSIC), Universidad de Sevilla (Departamento de Medicina), Seville, Spain, 33 Radboudumc, Nijmegen, Netherlands, 34 Clinical Hematology Department, ICO-Hospital germans Trias i Pujol, Josep Carreras Research Institute, Badalona, Spain, 35 Azienda Ospedaliera Nazionale SS. Antonio e Biagio e Cesare Arrigo, Alessandria, Italy, 36 ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy, 37 La Paz University Hospital, Madrid, Spain, 38 Hematology Unit, Fondazione Policlinico Universitario Agostino Gemelli - IRCCS, Rome, Italy, 39 Department of Nephrology and Infectious diseases, AZ Sint-Jan Brugge- Oostende AV, Brugge, Belgium, 40 Aristotle University of Thessaloniki, Thessaloniki, Greece, 41 Department of Hematology and Oncology, Medical University of Innsbruck, Innsbruck, Austria, 42 Fundacion Jimenez Diaz University Hospital, Health Research Institute IIS-FJD, Madrid, Spain, 43 San Luigi Gonzaga Hospital - Orbassano, Orbassano, Italy, 44 Infektiologie, Universitätsklinikum Frankfurt am Main, Frankfurt am Main, Germany, 45 General Hospital of Thessaloniki “George Papanikolaou”, Thessaloniki, Greece, 46 Hematology and Stem Cell Transplant Unit, Vito Fazzi, Lecce, Italy, 47 University of Cologne, Faculty of Medicine and University Hospital Cologne, Clinical Trials Centre Cologne (ZKS Köln), Cologne, Germany, 48 University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Molecular Medicine Cologne (CMMC), Cologne, Germany, 49 German Centre for Infection Research (DZIF) , Cologne, Germany, 50 Hematology Unit, Università Cattolica del Sacro Cuore, Rome, Italy Background: The outcome of COVID-19 in allogeneic hematopoietic stem cell transplantation (HSCT) recipients is almost uniformely considered poor. The aim of present study was to retrospectively analyse the outcome and risk factors for mortality in a large series of patients who developed COVID-19 infection after an allogeneic HSCT. Methods: This multicenter retrospective study promoted by the European Hematology Association – Infections in Hematology Study Working Group, included 326 adult HSCT patients who had COVID-19 between January 2020 and March 2022. Results: The median time from HSCT to the diagnosis of COVID-19 was 268 days (IQR 86-713; range 0-185 days). COVID-19 severity was mild in 21% of the patients, severe in 39% and critical in 16% of the patients. In multivariable analysis factors associated with a higher risk of mortality were, age above 50 years, presence of 3 or more comorbidities, active hematologic disease at time of COVID-19 infection, development of COVID-19 within 12 months of HSCT, and severe/critical infections. Overall mortality rate was 21% (n=68): COVID-19 was the main or secondary cause of death in 16% of the patients (n=53). Conclusions: Mortality in HSCT recipients who develop COVID-19 is high and largely dependent on age, comorbidities, active hematologic disease, timing from transplant and severity of the infection. KEYWORDS allogeneic HSCT, COVID-19 infection, immunocompromised patients, SARS-CoV-2, hematological malignances Frontiers in Immunology 02 frontiersin.org Busca et al. 10.3389/fimmu.2023.1125030 Introduction diagnosis of COVID-19, immunosuppression within 6 months of COVID-19 diagnosis, conditioning intensity (myeloablative vs Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reduced intensity), GVHD prophylaxis, time to engraftment, was recognized in late 2019 and developed into a pandemic with life- development of acute or chronic GVHD before COVID-19 threatening disease documented in high-risk groups (1). Allogeneic diagnosis and immunodeficiency scoring index (ISI) at the time of hematopoietic stem cell transplantation (HSCT) has been increasingly COVID-19 infection. Clinically significant outcomes (hospital adopted as a curative treatment option for a great variety of admission and intensive care unit [ICU] admission, vital status) hematologic malignancies, however HSCT recipients are vulnerable were also evaluated. We did not collect information on treatment to viral infections due to neutropenia, immunosuppressive treatments, strategies of COVID-19. graft-versus-host disease (GVHD) and incomplete immune reconstitution occurring in the post-transplant period. In this respect, efforts have been made not to postpone transplantation during the Definitions pandemic (2). To date, scattered case series of HSCT recipients with coronavirus disease 2019 (COVID-19) have been reported (3–11). Confirmed cases of COVID-19 were defined by a positive reverse Overall, the prognosis of HSCT recipients has been uniformly transcription polymerase chain reaction (RT-PCR) assay of a reported dismal with COVID-19-related mortality ranging between specimen collected on a nasopharyngeal swab. 20 and 39% (5, 6, 12–16), much higher than in the general population. The severity of COVID-19 at admission is graded according to the Advanced age, presence of active GVHD and a short time interval from China Center for Disease Control and Prevention definitions (17). HSCT to COVID-19 were identified as predictors of adverse outcome Disease status at the time of SARS-CoV-2 detection was defined (3, 5, 14). These findings may be discouraging the treating physicians, according to each specific disease’s revised criteria for leukemia, fearing for the high fatality rate of HSCT recipients. On the other hand, myeloproliferative neoplasm, multiple myeloma, and lymphoma. the use of immunosuppressive agents may potentially mitigate the The ISI was calculated as previously described (4). deleterious systemic inflammatory syndrome secondary to the cytokine storm unleashed by SARS-Cov-2 leading to multiorgan dysfunction and eventually death. According to this observation some studies have Endpoints and statistical analysis reported a lower mortality rate of allogeneic HSCT recipients as compared to non-stem cell transplant patients (18% vs 31%) (3). The primary outcome of this analysis was overall survival 30 days Hence, aim of our retrospective study was to address the outcome after COVID-19 diagnosis. and risk factors for mortality in a large series of patients who developed Categorical variables were summarised in frequencies and COVID-19 infection after an allogeneic HSCT. percentages and continuous variables with median, interquartile range (IQR) and absolute range. Additionally, to determine which factors were associated to mortality in our sample, we performed a Patients and methods Cox regression, with the backwards Wald method. Those variables with a p value <0.1 in the univariable model were included into the Study population multivariable analysis. A p<0.05 was considered significant. Overall survival probability has been plotted in a Kaplan-Meier survival This is retrospective multicenter cohort study promoted by the curve. SPSSv25.0 was employed for statistical analyses (SPSS, IBM European Hematology Association – Infections in Hematology Study Corp., Chicago, IL, United States). Working Group (EHA-IDWP; EPICOVIDEHA survey, https:// pubmed.ncbi.nlm.nih.gov/34235404/). Data have been collected on all consecutive adult patients who received an allogeneic HSCT and Results had COVID-19 in more than 150 European centers between January 2020 and March 2022. Only patients for whom allogeneic HSCT Demographics represented the last treatment performed were included into the study. Each institutional review board independently approved Between January 2020 and March 2022, 326 patients receiving an the study. allogeneic HSCT were diagnosed with COVID-19 infection and registered in EPICOVIDEHA. Baseline transplant characteristics are shown in Table 1. The Data collection median age at the time of COVID-19 diagnosis was 51 years (IQR 38- 61; range 18-75), 132 patients (41%) were female, and 194 patients Researchers at each center collected data using an online (59%) were male. Acute leukemia and myelodysplastic syndromes questionnaire hosted at www.clinicalsurveys.net, EPICOVIDEHA is (MDS) (n=257, 79%) were the most common indications for registered at http://www.clinicaltrials.gov, with the identifier NCT allogeneic HSCT. Overall, 232 patients (71%) received grafts from 04733729. Only de-identified data have been analyzed. alternative donors, including matched unrelated donors in 158 cases Data collected included: age at transplantation (dichotomized as (48%) and haploidentical donors in 74 cases (23%). For GVHD <50 years and ≥50 years), sex (male vs female), time from HSCT to the prophylaxis, 114 patients (35%) received calcineurin inhibitors- Frontiers in Immunology 03 frontiersin.org Busca et al. 10.3389/fimmu.2023.1125030 based immunosuppression and 71 patients (22%) received post- Clinical characteristics transplantation cyclophosphamide (PT/Cy). The majority of the patients (297 out of 326 patients, 91%) were not vaccinated at the The median time from HSCT to the diagnosis of COVID-19 was time of HSCT. 268 days (IQR 86-713; range 0.185 days). Collectively, 45 patients (14%) received post-HSCT vaccination before COVID-19 diagnosis: 6 patients received one dose, 18 patients two doses, 19 patients three doses and 2 patients four doses. TABLE 1 Characteristics of HSCT patients with COVID-19 diagnosis. At the time of COVID-19 diagnosis, active grade II-IV acute No. patients 326 GVHD (aGVHD) was present in 15 patients (5%), and 32 patients (10%) had evidence of moderate to severe chronic GVHD (cGVHD). Age, median (range), years 51 (18-75) Overall, 199 patients (61%) were on systemic immunosuppressive Sex male/female 194 (60%) / 132 (40%) treatments during the last 6 months before COVID-19 diagnosis. Diagnosis Only a minority of patients was neutropenic (ANC ≤500/mm3) or lymphocytopenic (ALC ≤200/mm3) at the time of COVID-19 AML/MDS 196 (60%) ALL 61 (19%) diagnosis (6% and 10% respectively). Lymphomas 36 (11%) COVID-19 severity was mild in 21% of the patients, severe in 39% Multiple myeloma 5 (2%) and critical in 16% of the patients; 79 patients (24%) had Chronic myeloproliferative malignancies 17 (5%) other 11 (3%) asymptomatic infection. Among the 184 patients who were hospitalized, 51 patients (28%) Disease status at HSCT were admitted to ICU, and 34 patients required mechanical ventilation. CR/partial remission 289 (89%) Patient characteristics at the time of COVID-19 diagnosis are stable disease 14 (4%) summarized in Table 2. R/R disease 15 (5%) unknown 11 (2%) Conditioning intensity Factors associated with mortality and myeloablative 224 (69%) outcome of COVID-19 infection RIC 30 (9%) unknown 72 (22%) The results of Cox regression analysis for factors associated with Donor mortality after COVID-19 diagnosis in allogeneic HSCT recipients matched sibling donor 88 (27%) are shown in Table 3. MUD 158 (48%) In multivariable analysis factors associated with a higher risk of Haploidentical 74 (23%) mortality were, age 50 years or older, presence of 3 or more unknown 6 (2%) comorbidities, active hematologic disease at time of COVID-19 Graft source 28 (9%) infection, development of COVID-19 within 12 months of HSCT, BM 287 (88%) PBSC 4 (1%) and severe/critical infections. The type of HSCT, the intensity of CB 7 (2%) preparative regimen, the presence of aGVHD and cGVHD before unknown COVID-19 infection and ISI group were not associated with GVHD prophylaxis increased mortality. Vaccination and the number of doses (one, two or more doses) CI plus other 114 (35%) PT/Cy 71 (22%) administered did not have an impact on the outcome of the patients. other 86 (26%) At the time of last follow-up, 258 patients (79%) are alive: from unknown 55 (17%) the diagnosis of COVID-19, the median follow of survivors was 126 Vaccination before HSCT days (IQR 32-339; range 0-643 days). The Kaplan-Meier overall survival estimate is shown in Figure 1. Overall, 68 patients (21%) no 297 (91%) 1 dose 3 (1%) had died after a median follow-up post COVID-19 of 26 days (IQR 2 doses 25 (8%) 12-56; range 0-379 days). Causes of death were COVID-19 infection 3 doses 1 (0.3% in 42 cases (13%), COVID-19 in parallel to recurrence of the Comorbidities at HSCT* underlying hematologic malignancy in 11 cases (3%), and hematologic malignancy +/- other reasons in 15 cases (5%). 1 comorbidity 95 (29%) 2 comorbidities 41 (12%) 3 comorbidities 21 (6%) HSCT, hematopoietic stem cell transplantation; AML, acute myeloid leukemia; MDS Discussion myelodysplastic syndrome; ALL, acute lymphoblastic leukemia; CR, complete remission; R/R relapse/refractory; RIC, reduced intensity conditioning; MUD, matched unrelated donor; BM, bone marrow; PBSC, peripheral blood stem cell; CB, cord blood; CI, calcineurin inhibitors; PT/ Cy, post-transplant cyclophosphamide. To our knowledge, the present study includes the largest series of *Comorbidities included diabetes, liver disease, renal impairment, smoking history. allogeneic HSCT recipients with COVID-19. The aim of our analysis Frontiers in Immunology 04 frontiersin.org Busca et al. 10.3389/fimmu.2023.1125030 TABLE 2 Patient Characteristics at diagnosis of COVID-19. 1st and 2nd COVID-19 wave. In fact, it should be recognized that one third of the patients had COVID-19 infection diagnosed during the No. patients according to the time of COVID-19 diagnosis 3rd wave. 1st wave (February-June 2020) 65 (20%) Our study demonstrated that COVID-19 infection is a severe 2nd wave (September-December 2020) 138 (42%) complication in allogeneic HSCT recipients with an attributable 3rd wave (January-March 2022) 123 (38%) mortality of 16%. Our results are roughly superimposable to those Median time form HSCT to COVID-19, days 268 reported from other recent studies. The CIBMTR reported a COVID- Disease status at COVID-19 diagnosis 19-related mortality rate of 20% in 184 allogeneic HSCT recipients (14), Piñana et al. analyzed the outcome of COVID-19 in 65 CR/partial remission 289 (89%) allogeneic HSCT patients and reported a mortality of 18% (3). An stable disease 14 (4%) EBMT (European Society for Blood and Marrow Transplantation) active disease 18 (5%) and GETH (Spanish Group of Hematopoietic Stem Cell unknown 5 (2%) Transplantation) prospective study reported an overall mortality rate of 28% among 236 allogeneic HSCT recipients (12). Other Acute GVHD grades II-IV 15 (5%) smaller series documented similar mortality rates ranging from 20 Chronic GVHD, moderate to severe 32 (10%) to 25% (5–7, 9). It is worthwhile recalling that mortality in the general Patients on systemic immunosuppressive agents 199 (61%) population declined over the 2nd and 3rd waves: this observation should be considered when we consider that only 20% of our patients Symptoms at COVID-19 onset were diagnosed with COVID-19 during the first wave. Pulmonary 110 (34%) Multivariable analysis showed that age, comorbidities, active Pulmonary and extrapulmonary 59 (18%) disease, and severe/critical infection have been associated with higher mortality, consistent with previous studies (3, 4, 12, 14). Extrapulmonary 74 (23%) Nevertheless, it should be noted that a consistent number of Screening, no symptoms 83 (25%) comorbidities and demographic characteristics (i.e. diabetes, BMI, Patients requiring hospital admission 184 (56%) race) potentially influencing the outcome of the patients were not available Similarly, time from HSCT to COVID-19 diagnosis of less Median duration, days 14 than 12 months was a factor significantly associated with fatal Patients requiring ICU admission 51 (16%) outcome. Surprisingly, GVHD at the time of COVID-19 diagnosis Median duration, days 15 did not impact on the outcome of our patients, however it should be underscored that only 5% of the patients had grade II-IV acute Immunity subset analysis GVHD and 10% had moderate/severe chronic GVHD; in addition, Neutrophils 20 (6%) data on the cumulative dose of steroids and the different ≤ 500/mm3 20 (6%) immunosuppressive agents used were not available. Likewise, mortality was not influenced by the use of 501-999/mm3 232 (71%) immunosuppressive drugs and steroids during the 6 months ≥ 1000/mm3 54 (17%) preceding COVID-19 diagnosis, notwithstanding the number of Unknown patients on treatment was extremely high. Whether the administration of two to three doses of vaccine in 20% of the Lymphocytes 34 (10%) patients might have contributed to dampen the severity of the disease ≤200/mm 3 43 (13%) as documented in some studies (18, 19), remains speculative. 201-499/mm 3 189 (58%) Regrettably, we do not have data on patient seroconversion and B- cell reconstitution underpinning the effectiveness of vaccination. ≥500/mm3 60 (19%) ISI did not result as an independent risk factor for poor outcome Unknown as shown by Ljungman et al, however several variables included in the HSCT, hematopoietic stem cell transplantation; CR, complete remission; GVHD, graft-versus- ISI (ANC and ALC, GVHD) were poorly represented in our study host disease; ICU, intensive care unit. group. Two studies including a small number of patients reported a favorable outcome of patients receiving PT/Cy as GVHD prophylaxis, was to evaluate the outcome of COVID-19 in a cohort of patients since cytokine release syndrome (CRS) associated with haploidentical particularly susceptible to infectious complications and to investigate HSCT and COVID-19 share similar pathophysiology (10, 11). It is risk factors that may impact on mortality. Patients were at high risk well known that a dysregulated, excessive immune response with for severe disease and adverse outcome from COVID-19: a large increased pro-inflammatory cytokines levels during the later phases of proportion of patients (70%) received HSCT from alternative donors, COVID-19 infection may lead to multiorgan failure (20). Cy is an 16% had critical infection and required ICU admission. Even more alkylating agent largely used in the setting of haploidentical HSCT importantly, the median time from HSCT to COVID-19 infection was due to its capacity of depleting rapidly proliferating T-cells while 268 days, remarkably shorter when compared to other reports (474- sparing regulatory-T cells (21). According to these observations, it has 790 days) (3, 4, 12, 14). This finding might mirror the adoption of less been postulated a potential effect of Cy in mitigating the COVID-19 stringent measures of stewardship among transplant centers after the infection (22), however in our cohort, we did not find any significant Frontiers in Immunology 05 frontiersin.org Busca et al. 10.3389/fimmu.2023.1125030 TABLE 3 Univariate and multivariate analysis for risk factors associated with COVID-19 mortality. Evaluable n Univariable Multivariable p value HR 95% CI p value HR 95% CI Lower Upper Lower Upper Age at HSCT <50 years 157 – – – – – – – ≥50 years 169 <0.001 3.880 2.185 6.890 <0.001 3.206 1.756 5.853 Time from HSCT to COVID-19 <12 months 194 – – – – – – – – ≥12 months 132 0.049 0.596 0.356 0.998 0.031 0.538 0.306 0.946 Underlying disease Acute leukemia (AML,ALL,MDS) 257 – – – – Lymphomas (NHL,HD) Other 36 0.622 0.794 0.317 1.987 37 0.317 1.435 0.708 2.910 Type of HSCT Matched sibling donor 88 – – – – Alternative (MUD, Haploidentical, Cord) Unknown 232 0.759 0.921 0.547 1.553 6 0.961 0.000 0.000 . Preparative regimen Non-myeloablative 54 – – – – RIC Myeloablative 30 0.819 1.107 0.464 2.644 Unknown 224 0.186 0.663 0.360 1.219 18 0.250 1.756 0.673 4.577 GVHD prophylaxis No 17 – – – – CI+MTX/MMF PT/Cy 114 0.858 1.116 0.336 3.703 Other 71 0.516 0.648 0.175 2.401 Unknown 86 0.519 1.487 0.445 4.974 38 0.828 1.156 0.312 4.274 Comorbidities before COVID-19 No comorbidities 169 – – – – – – – – 1-2 comorbidities 3 or more comorbidities 136 0.039 1.720 1.028 2.877 0.164 1.476 0.853 2.553 21 0.006 2.915 1.365 6.225 0.002 3.718 1.596 8.662 Disease status at COVID-19 diagnosis CR/Partial remission 289 – – – – – – – – Stable disease Active disease 14 0.534 1.382 0.499 3.821 0.475 1.474 0.508 4.275 Unknown 18 <0.001 4.255 2.092 8.652 <0.001 3.859 1.810 8.226 5 0.056 3.968 0.963 16.353 0.282 2.239 0.516 9.713 ISI group Low risk 149 – – – – Moderate/High risk 177 0.250 1.332 0.817 2.173 (Continued) Frontiers in Immunology 06 frontiersin.org Busca et al. 10.3389/fimmu.2023.1125030 TABLE 3 Continued Evaluable n Univariable Multivariable p value HR 95% CI p value HR 95% CI Lower Upper Lower Upper Acute GVHD before COVID-19 diagnosis 237 – – – – 0-I II-IV 74 0.766 1.092 0.611 1.951 Unknown 15 0.203 1.820 0.724 4.576 Chronic GVHD before COVID-19 diagnosis Absent-Mild 261 – – – – Moderate-Severe Unknown 48 0.797 1.089 0.570 2.080 17 0.141 0.227 0.031 1.639 COVID-19 severity Asymptomatic 79 – – – – – – – – Mild infection Severe infection 68 0.253 1.953 0.620 6.156 0.192 2.160 0.680 6.857 Critical infection 128 0.014 3.363 1.273 8.887 0.012 3.628 1.333 9.879 51 <0.001 15.27 5.954 39.157 <0.001 12.91 4.892 34.069 Drugs within 6 months of COVID-19 diagnosis None 66 – – – – Immunosuppressive/Corticosteroids Unknown 221 0.198 1.596 0.784 3.250 39 0.226 1.744 0.708 4.292 HSCT, hematopoietic stem cell transplantation; AML, acute myeloid leukemia; MDS myelodysplastic syndrome; ALL, acute lymphoblastic leukemia; NHL, Non-Hodgkin lymphoma; HD, Hodgkin lymphoma; MUD, matched unrelated donor; RIC, reduced intensity conditioning; GVHD, graft-versus-host disease; CI, calcineurin inhibitors; MTX, methotrexate; MMF, mycophenolate mofetil; PT/Cy, post-transplant cyclophosphamide; CR, complete remission; ISI, immunodeficiency scoring index. relationship between the type of GVHD prophylaxis and mortality, the patients among such a large number of centers. Our study presents including PT/Cy in 22% of the cases. ANC and ALC at the time of a significant heterogeneity in terms of different variants of concern, COVID-19 diagnosis did not result as significant factors for disease namely wild type, delta and omicron variants, each with distinctive severity as shown in other studies (3, 5), however a minority of our transmission rates and infection associated mortality. Information on patients were neutropenic or had low ALC. the treatment of COVID-19 were not available and the management of We recognize limitations of our study inherent to the retrospective patients with COVID-19 across centers may differ profoundly, design. We cannot exclude a possible selection bias in the registration of potentially influencing clinical outcome. FIGURE 1 Kaplan-Meier overall survival curve after diagnosis of COVID-19 infection in 326 allogeneic HSCT recipients. Frontiers in Immunology 07 frontiersin.org Busca et al. 10.3389/fimmu.2023.1125030 Conclusion Author contributions Our study on a large number of patients who developed COVID- AB, JS-G, FM, OC and LiP contributed to study design, study 19 infection following HSCT, shows a high mortality rate compared supervision, and data interpretation and wrote the paper. AB, JS-G to the general population. In this respect, it is of upmost relevance to and LiP did the statistical plan. JS-G performed the analysis and AB, see whether vaccination of patients after HSCT and the availability of JS-G and LiP interpreted the data. All authors recruited participants pre- and post-exposure prophylactic measures effectively mitigates and collected and interpreted data, contributed to manuscript writing the severity of the disease in this vulnerable group of patients. and review of the manuscript, agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and Data availability statement resolved and have read and agreed to the published version of the manuscript. All authors have read and agreed to the published version The raw data supporting the conclusions of this article will be of the manuscript. made available by the authors, without undue reservation. Funding Ethics statement EPICOVIDEHA has received funds from Optics COMMITTM The studies involving human participants were reviewed and (COVID-19 Unmet Medical Needs and Associated Research approved by EPICOVIDEHA was approved by the local ethics Extension) COVID-19 RFP program by GILEAD Science, United committee of the Fondazione Policlinico Universitario Agostino States (Project 2020-8223). The funder of the study had no role in Gemelli - IRCCS, Università Cattolica del Sacro Cuore of Rome, study design, data analysis, interpretation, or writing of the report. All Italy (Study ID: 3226). The patients/participants provided their authors had full access to the data and had final responsibility for the written informed consent to participate in this study. decision to submit for publication. A list of EPICOVIDEHA Collaborators members Conflict of interest The authors declare that the research was conducted in the Juergen Prattes, Malgorzata Mikulska, Gustavo-Adolfo Méndez, absence of any commercial or financial relationships that could be Tobias Lahmer, Pavel Jindra, Anna Guidetti, Rita Fazzi, Maria Ilaria construed as a potential conflict of interest. Del Principe, Cristina De Ramón, Maria Calbacho, Zlate Stojanoski, Andrés Soto, Alexandra Serris, Irati Ormazabal-Vélez, Ali S. Omrani, Milan Navrátil, Sonia Martín-Pérez, Joyce Marques De Almeida, Sylvain Lamure, Martin Kolditz, Ozren Jaksic, Martin Hoenigl, Publisher’s note Carolina Garcia-Vidal, Noemí Fernández, Shaimaa El-Ashwah, Natasha Čolović, Martin Čerňan, Caterina Buquicchio, Valentina All claims expressed in this article are solely those of the authors Bonuomo, Josip Batinić, Murtadha Al-Khabori, Tatjana Adžić- and do not necessarily represent those of their affiliated Vukičević, Juan-Alberto Martín-González, Maria Vittoria Sacchi, organizations, or those of the publisher, the editors and the María-Josefa Jiménez-Lorenzo, Dominik Wolf, Maria Vehreschild, reviewers. Any product that may be evaluated in this article, or Raul Cordoba, Ramón García-Sanz, Toni Valković, Miloš claim that may be made by its manufacturer, is not guaranteed or Mladenović, Nicole García-Poutón, Ziad Emarah, Julio Dávila-Valls endorsed by the publisher. References 1. Zhang Y, Xu J, Li H, Cao B. 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