key: cord-0914675-zindm6tf
authors: Fernández-Ruiz, Mario; Aguado, José María
title: Severe acute respiratory syndrome coronavirus 2 infection in the stem cell transplant recipient − clinical spectrum and outcome
date: 2021-09-16
journal: Curr Opin Infect Dis
DOI: 10.1097/qco.0000000000000790
sha: 5f831bd2f87945b0691a042666938387285ca3f2
doc_id: 914675
cord_uid: zindm6tf

PURPOSE OF REVIEW: Focusing on large multicenter cohorts reported over the last months, this review aims at summarizing the available evidence by July 2021 on the impact of coronavirus disease 2019 (COVID-19) on hematopoietic stem cell transplant (HSCT) recipients in terms of epidemiology, clinical features, and outcome. RECENT FINDINGS: The incidence of COVID-19 in institutional cohorts varied according to different regions and study periods from 0.4% to 8.3%. Clinical presentation was overall comparable to other immunocompromised hosts and the general population. Microbiologically confirmed superinfection occurred in 13–25% of recipients, with most episodes due to hospital-acquired bacteria and few reported cases of COVID-19-associated aspergillosis. Prolonged nasopharyngeal severe acute respiratory syndrome coronavirus 2 shedding has been demonstrated for as long as 210 days. Mortality rates were similar across studies (14.8–28.4%) and did not markedly differ from those observed in nontransplant hematological patients during the first wave. Older age and shorter time from transplantation were associated with mortality, as well as underlying disease status and amount of immunosuppression. No outcome differences were found in most studies between allogeneic and autologous procedures. SUMMARY: Considerable advances have been achieved in the characterization of COVID-19 in the HSCT population, although uncertainties remain in the optimal therapeutic management.

The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID- 19) , has profoundly affected the care of hematopoietic stem cell transplant (HSCT) recipients. In view of the serious manifestations associated with other respiratory viral infections -such as influenza or respiratory syncytial virus (RSV) -in this and other groups of immunocompromised hosts [1] , it was early clear that HSCT should be considered as a risk factor for severe course of SARS-CoV-2 infection [2] . Indeed, it has been shown that patients with hematological malignancies and COVID-19 have poorer outcomes than the general population [3, 4] . Ongoing immunosuppression and treatment-related toxicities resulting in immune dysregulation, mucositis or graft-versus-host disease (GvHD) would further contribute to increase the risk of complications among HCST patients. On the other hand, the overwhelming of healthcare resources and travel restrictions imposed in most Western countries during the first months of the pandemic negatively impacted HSCT activity, particularly for allogeneic procedures [5] . A report from a large donor registry from six countries revealed a decline by around 15% in the total number of stem cell products provided (particularly for bone marrow products) and by 38% in the number of newly registered donors from March to June 2020 in comparison with the preceding months [6] . In addition, initial uncertainties on the potential transmissibility of SARS-CoV-2 through stem cell products implied that exposed donors, as well as those recovering from COVID-19, should be deferred for various weeks, thus compromising the ability to perform live-saving procedures at the appropriate time [7] .

More than 18 months into the pandemic, a large amount of literature has been generated on the epidemiology, clinical manifestations and determinants of outcome of COVID-19 among HSCT recipients. The present review is aimed at critically summarizing the evidence available on this issue by July 2021 as well as proposing future research avenues according to identified gaps in the current knowledge. Therapeutic strategies (either based on antiviral or immunomodulatory agents) and COVID-19 vaccines safety and effectiveness in this population will be not covered.

Since the early small, single-center case series reported during the first months of the pandemic [8, 9] , various large multinational cohort studies involving tens to hundreds of patients have been published over the past months [10 && -13 && ,14] (summarized in Table 1 ), providing a comprehensive description of SARS-CoV-2 infection in both allogeneic and autologous HSCT.

Only a few studies have attempted to estimate the incidence of COVID-19 in the corresponding institutional cohorts, although reported rates greatly varied across regions and study periods ( 

The clinical manifestations of COVID-19 in the HSCT setting seem not to meaningfully differ from those reported for other immunocompromised hosts such as solid organ transplant (SOT) recipients, as confirmed by a recent meta-analysis [16] 

The incidence of coronavirus disease 2019 (COVID- 19) across institutional hematopoietic stem cell transplant (HSCT) cohorts vary according to regions and study periods (from 0.4% to 8.3%), although it is still unclear whether these patients face a higher risk of developing symptomatic infection as compared to the general population.

The clinical manifestations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection after HSCT are similar to those seen in other immunocompromised hosts, with fever, cough, upper respiratory tract symptoms, diarrhea and vomiting as the most common symptoms at presentation.

The kinetics of SARS-CoV-2 in HSCT recipients are characterized by a more prolonged nasopharyngeal viral shedding than immunocompetent patients.

Mortality rates are overall comparable across studies (ranging between 14.8% and 28.4%), and seem not to significantly differ from those reported for nontransplant hematological patients that required hospitalization during the first pandemic wave Older recipient age, shorter time interval between transplantation and COVID-19 diagnosis, status of the underlying hematological disease and amount of immunosuppression are risk factors for mortality, whereas differences in outcomes between allogeneic and autologous procedures have been observed in most studies. data, with higher rates of pneumonia and oxygen support requirement in the former group [11 && ,15]. The proportion of asymptomatic patients in these cohorts largely varied from 8.9% [10 && ] to 14.8% [17 & ] depending on the study period (first vs. second pandemic waves) and design (retrospective vs. prospective). Nevertheless, it cannot be ruled out the existence of some degree of reporting bias in studies performed during the first wave, which would have skewed the sample towards the more severe cases because of limited diagnostic capabilities in many countries.

It has been suggested the existence of pathogenic similarities between the cytokine release syndrome (CRS) that complicates the course of severe COVID-19 and that observed in allo-HSCT recipients with acute GvHD. In fact, the term CRS was originally coined for the latter situation [20] . Indeed, a primary proinflammatory trigger -SARS-CoV-2 infection in COVID-19 or the complex interplay between conditioning regimen toxicity, engraftment syndrome and secondary infections in the allo-HSCT setting -leads in both cases to a chain of inflammatory responses mediated through damage-associated molecular patterns. This uncontrolled process disrupts the homeostasis of the immune system and ultimately results in the production of stress cytokines such as interleukin (IL)-6, lymphopenia, and events of immune dysregulation (hemophagocytic lymphohistiocytosis [HLH]) and endothelial cell damage (thrombotic microangiopathy [TMA]) [21 & ]. In an attempt to counter-balance this proinflammatory status, the frequency of CD14 þ HLA-DR low/neg monocytic-myeloid derived suppressor cells in peripheral blood is increased in both allo-HSCT [22] and COVID-19 [23] , although the associated immunosuppression may facilitate in turn the occurrence of bacterial or fungal superinfection or herpesviruses reactivation [21 & ].

Only a few studies have provided detailed information on serum IL-6 kinetics in HSCT recipients with COVID-19 [ ] found that IL-6 levels >50 pg/ml -present in 42.5% of evaluable patients -was associated with increased infection severity and mortality at the univariate (but not multivariate) analysis. Peak median IL-6 level in seven patients in which this cytokine was measured was 147.4 pg/ml in other cohort [17 & ]. Shah et al. [19] reported peak values of 108.5 and 49.5 pg/ml for 15 allo-HSCT and 13 auto-HSCT recipients, respectively. Although clearly increased in comparison to healthy subjects, these levels are far beyond those observed in critical patients with sepsis or in the setting of chimeric antigen receptor T-cell therapy, which has led some authors to question the use of the term CRS in COVID-19 [24 & ].

The combined effect of ongoing immunosuppression, SARS-CoV-2-induced immune dysregulation, prolonged hospital and intensive care unit (ICU) stay and immunomodulatory therapies -such as dexamethasone or anti-IL-6 agents -may contribute to the development of infectious complications, either as co-infection at presentation or most commonly during the disease course. The incidence rates of microbiologically confirmed superimposed infections range from 13% to 25% [15,17 & ,19] . Most reported episodes were bacterial, with predominance of hospitalacquired pathogens such as methicillin-resistant Staphylococcus aureus or nonfermenting Gram-negative bacilli. Reactivation of latent viral infections (mainly Epstein-Barr virus) may also occur [19] . Some studies have observed higher serum procalcitonin levels in recipients with co-infection as compared to those free from this complication [17 & ]. The diagnosis of COVID-19-associated pulmonary aspergillosis (CAPA) has been only occasionally reported [15,17 & , 25, 26] , and HSCT recipients are marginally represented in case series of CAPA [27, 28] . There have been also an anecdotal report of an aseptic meningitis with negative reverse transcription polymerase chain reaction (RT-PCR) testing for SARS-CoV-2 in the cerebrospinal fluid after initial clinical recovery from COVID-19, suggesting a potential pathogenic role for molecular mimicry [29] .

Severe acute respiratory syndrome coronavirus 2 kinetics Prolonged viral shedding from nasopharyngeal swab specimens has been long described in HSCT and SOT recipients with other respiratory tract infections, in particular influenza [30] [31] [32] , The impact of host characteristics on viral kinetics has been also proven for COVID-19, with the subsequent consequences for guiding infection control practices and discontinuation of isolation [33, 34] . Persistent SARS-CoV-2 shedding for as much as 74 days was described in a 61-year-old Hodgkin lymphoma patient that had undergone auto-HSCT 6 months ago [35] . The median time to viral clearance among survivors with repeated RT-PCR testing in a large multicenter cohort was 24 days, with the longest being 210 days [10 && ]. Although RT-PCR positivity does not necessarily equate to ongoing infectivity, viable SARS-CoV-2 has been recovered in cell culture for more than 50 days from symptom onset in allo-HSCT recipients with low cycle thresholds (Ct) [36] . ] (14.8%) might be explained by the younger age of their cohort and the inclusion of outpatients with milder illness. These figures are not markedly different from those observed among nonimmunocompromised patients requiring hospital admission during the first pandemic wave [37, 38] . A meta-analysis concluded that hospitalized HSCT recipients with COVID-19 seem similar to the general Higher mortality for allo-HSCT than auto-HSCT (28% vs. 0%; P-value ¼ 0.007) population in terms of disease severity and outcomes, although data from the more recent cohorts were not pooled [16] . On the other hand, mortality reported for other groups of hematological patients hospitalized during the first wave was at least comparable or higher, with 27.3% for chronic lymphocytic leukemia [39] or 33.5% for multiple myeloma [40] . Transplant recipient status was not associated with the risk of death in a large population-based registry study performed in Madrid on 697 patients with hematologic malignancies [41] . In fact, Piñana et al. [11 && ] found that nontransplant patients with hematological disorders such as non-Hodgkin lymphoma, chronic myeloproliferative disease or acute leukemia had actually higher mortality rates compared to HSCT recipients (32.8% vs. 20.3%, respectively). The nature of underlying condition seems to exert a smaller impact than the disease status (relapsed or refractory vs. complete/partial response) at COVID-19 diagnosis, with only one study reporting higher attributable mortality in auto-HSCT due to lymphoma compared to plasma cell disorders [13 && ]. The presence and amount of immunosuppression -as assessed by the immunodeficiency scoring index (ISI) or the number of drugs -was also significantly correlated with higher mortality [10 &&

& ] or disease severity [15] in various cohorts.

The largest series reported to date was based on the collaborative effort of the European Group for Blood and Marrow Transplantation (EBMT) Infectious Diseases Working Party and the Spanish Hematopoietic Stem Cell Transplantation and Cell Therapy Group (GETH) and prospectively included 382 recipients from 22 European countries. The median age was 56.8 years and the median interval from the most recent HSCT to RT-PCR-confirmed diagnosis was 17.9 months. There was heterogeneity across countries in the proportion of patients aHR, adjusted hazard ratio; Allo-HSCT, allogeneic hematopoietic stem cell transplantation; aOR, adjusted odds ratio; auto-HSCT, autologous hematopoietic stem cell transplantation; CAR-T, chimeric antigen receptor T-cell; COVID-19, coronavirus disease 2019; CRP, C-reactive protein; ECOG, Eastern Cooperative Oncology Group; ICU, intensive care unit; IMV, invasive mechanical ventilation; ISI, immunodeficiency scoring index; LDH, lactate dehydrogenase; RRT, renal replacement therapy. a Includes five patients that received CAR-T therapy. b Disease severity defined as requiring nonrebreather or higher oxygen, or death at a lower level of oxygen. c Includes three patients that received CAR-T therapy. d Disease severity included moderate (evidence of lower respiratory disease/pneumonia with oxygen saturation <94% on room air), severe (oxygen saturation < 94% on room air, a ratio of arterial partial pressure of oxygen to fraction of inspired oxygen < 300 mmHg, respiratory rate > 30 breaths/min, or lung infiltrates > 50%), or critical (respiratory failure, septic shock, multiple organ dysfunction, and/or death) categories. e Includes one patient that received CAR-T therapy.

admitted to the ICU, which may be related to differences in available healthcare resources during the first pandemic wave. Overall, 107 patients died, yielding an all-cause mortality rate of 28.4%. The attributable mortality was slightly lower (25.2%) and the median time from confirmed infection to death was 18 days. The authors observed no significant differences in survival between autologous and allogeneic procedures, nor between recipients developing COVID-19 within the first 100 posttransplant days or beyond that point. In the multivariate analysis, older age and higher ISI acted as predictors of death, whereas better performance status exerted a protective effect. When the multivariate analysis was restricted to the allo-HSCT group, age and need for ICU admission remained associated with fatal outcome [10 && ]. Table 2 ) and previous experiences derived from the 2009 H1N1 influenza pandemic [42] . Although the amount of immunosuppression is usually higher in the allo-HSCT population due to the common use of myeloablative conditioning and the need of prophylaxis for GvHD, it is likely that the older age and more common presence of cardiovascular comorbidities among auto-HSCT recipients (Table 1 ) would act as strongest determinants of outcome, diluting potential differences between both groups.

Discrepant results, however, have been obtained from a recent single-center study on 55 HSCT recipients (32 allogeneic and 23 autologous) diagnosed with COVID-19 between March 2020 and May 2021. Most patients (62%) had undergone myeloablative conditioning. After a median follow-up of 6.1 months, all-cause mortality in the overall cohort was 16.3%, reaching 28.1% among allo-HSCT recipients. Prior grade II-IV acute GvHD, immunosuppression and allo-HSCT (compared to auto-HSCT or CAR-T therapy) were associated with the combined outcome of illness severity [15] .

As previously pointed, the studies only comprising hospitalized patients during the early months of the pandemic should be taken with some caution, since the sample may be skewed towards more severe cases that were more likely to seek for medical attention and to receive a RT-PCR-based diagnosis. A prospective cohort study carried out at a single Italian center with 254 allo-HSCT recipients that were subjected to a scheduled follow-up through in-person visits or telemedicine identified 24 patients with symptoms compatible with COVID-19 in the first wave. Only six of them tested positive for SARS-CoV-2 (overall incidence of 2.4%), four of which were affected by chronic GvHD and two were receiving ruxolitinib. Despite the presence of risk factors for unfavorable outcome (male gender, age >60 years, cardiovascular comorbidities), only three patients required hospitalization and all of them completely recovered. Acknowledging the small sample size, the authors suggested that allo-HSCT should not be necessarily considered a determinant of dismal prognosis in COVID-19 [9] .

Finally, the comparison of the clinical picture and outcome in allo-HSCT recipients infected with SARS-CoV-2 or seasonal human coronaviruses may be useful to contextualize the impact of COVID-19 in this population. A recent multicenter study with 402 allo-HSCT recipients included 449 episodes of upper or lower respiratory tract infection due to OC43 (37.8%), 229E (21.6%), NL63 (14.3%), and KHU1 (12.0%) coronaviruses. Hospital and ICU admission were required in only 17.8% and 2.8% of episodes, respectively. All-cause mortality was 6.9% for the overall cohort and 16.5% for those recipients with lower respiratory tract involvement [43 & ].

Although the available evidence is more limited, some experiences have been reported on the outcome of COVID-19 in pediatric allo-HSCT, with an overall incidence estimated at 3-4% [44,45 & ,46] . In the general population, children with SARS-CoV-2 infection show milder manifestations compared to adult patients [47] . A report from the Spanish Group of Pediatric HSCT identified 8 children (seven males) with a median age at diagnosis of 10 years old (range: 1-12) and leukemia or myelodysplasia as the most common underlying conditions. Clinical presentation included fever in five patients, respiratory symptoms in four, and diarrhea in the other two. Two children required ICU admission and IMV and one of them died, accounting for an overall mortality rate of 12.5%. Since primary immunodeficiencies were overrepresented in these series (more than a third of cases) as compared to the proportion of indications for pediatric allo-HSCT (about 10%), the authors suggested that impaired T-cell-mediated immunity due to the lack of thymus development may contribute to the severity of infection [45 & ]. A multicenter study from the United Kingdom reported the outcome of nine patients with a median age of 12 years (range: 6-16), all of them had achieved neutrophil engraftment. Clinical manifestations were variable, with fever being present in only four cases (associated to significant hypotension that required aggressive fluid resuscitation in one of them). Two patients were asymptomatic and tested as part of routine admission screening. Eight infants (88.9%) showed a mild disease course, whereas the remaining recipient developed CRS treated with tocilizumab, remdesivir and positive pressure respiratory support and latter evolved into secondary HLH, with full recovery. Of note, two patients experienced medium-term hematologic sequelae in form of pancytopenia (with hypocellular bone marrow aspirate) and transplant-associated TMA requiring defibrotide and eculizumab therapy [44] .

Unprecedented efforts have been made over the last year and a half to characterize the clinical course and outcomes of SARS-CoV-2 infection and its differential features in selected groups of immunocompromised patients, with particular attention having been paid to HSCT recipients [48] . As a result, we now know that symptoms at presentation in this group are overall comparable to those reported for the general population, and that the high mortality observed during the first pandemic wave seems to be driven by factors common to nontransplant patients -mainly older age -and others transplant-specific -such as the amount of immunosuppression or the status of the underlying disease. The modality of transplantation (allogeneic or autologous), on the contrary, does not influence outcomes in most published cohorts. In addition, the duration of nasopharyngeal viral shedding has been shown to be longer than in immunocompetent hosts. Unfortunately, uncertainties still persist on some critical issues. No studies to date have ascertained whether the incidence of severe COVID-19 is actually different compared to non-HSCT patients matched for age and comorbidity burden. Increased individual susceptibility may be partially outweighed by a higher compliance with preventive measures or a more stringent surveillance at early stages of infection. Beyond the fact that ongoing immunosuppression acts as a risk factor for poor outcome, the optimal adjustment of baseline therapies such as corticosteroids or calcineurin inhibitors once SARS-CoV-2 infection is diagnosed remains unknown. A multicenter study found that the rapid discontinuation of the Janus kinase inhibitor ruxolitinib in patients with myeloproliferative neoplasms and COVID-19 increased the risk of death [49 & ]. Although no similar data is yet available for HSCT recipients, it could hypothesized that the enhancement of SARS-CoV-2-associated CRS following the abrupt suspension of immunosuppression would also occur in these patients. Finally, and although beyond the scope of the present review, the precise role of immunomodulatory (i.e. tocilizumab [50] ) or antiviral agents (i.e. remdesivir [51] ) in the HSCT population should be established by means of prospective collaborative efforts, as well as the strategies to improve the immunogenicity of mRNA-based vaccines [52, 53] .

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Facing COVID-19 in the hematopoietic cell transplant setting: a new challenge for transplantation physicians

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COVID-19 in bone marrow transplant recipients: reflecting on a single centre experience

COVID-19 in recipients of allogeneic stem cell transplantation: favorable outcome

COVID-19 and stem cell transplantation; results from an EBMT and GETH multicenter prospective survey

The largest series on HSCT recipients with COVID-19 published to date, with a detailed description of clinical spectrum and risk factors for mortality, ICU admission and resolution of infection

Risk factors and outcome of COVID-19 in patients with hematological malignancies

Multicenter retrospective study on 367 pediatric and adult patients with hematological malignancies, including auto-HSCT and allo-HSCT recipients

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

Large multicenter cohort of HSCT recipients with COVID-19 revealing that older age, male gender and development of COVID-19 within the first 12 months are associated with a higher risk of mortality

COVID-19 infection in hematopoietic cell transplantation: age, time from transplant and steroids matter

Impact of SARS-CoV-2 in hematopoietic stem cell transplantation and chimeric antigen receptor T cell therapy recipients

COVID-19 in immunocompromised patients: a systematic review of cancer, hematopoietic cell and solid organ transplant patients

Very detailed clinical description of a single-center cohort of HSCT recipients and patients treated with CAR-T therapy diagnosed

The clinical course of COVID-19 in hematopoietic stem cell transplantation (HSCT) recipients

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Interleukin-1 is a critical effector molecule during cytokine dysregulation in graft versus host disease to minor histocompatibility antigens

A comprehensive review of the common pathogenic mechanisms underlyng the cytokine release syndrome that occurs in the setting of COVID-19 and allo-HSCT

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A critical review on the magnitude of the cytokine response seen in COVID-19 patients and other clinical settings such as sepsis or CAR-T therapy

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One of the largest experiences describing the incidence and clinical presentation and outcomes of COVID-19 in pediatric HSCT recipients

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None.Financial support and sponsorship This work was supported by Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation (COVID-19 Research Call COV20/00181) -co-financed by European Development Regional Fund 'A way to achieve Europe'. M.F.R. holds a research contract 'Miguel Servet' (CP18/00073) from the Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation.

There are no conflicts of interest.

Papers of particular interest, published within the annual period of review, have been highlighted as: