Leukemia (2021) 35:2885–2894 https://doi.org/10.1038/s41375-021-01302-5 ARTICLE Infectious medicine, virology COVID-19 and stem cell transplantation; results from an EBMT and GETH multicenter prospective survey Per Ljungman 1,2 Rafael de la Camara 3 Malgorzata Mikulska 4 Gloria Tridello5 Beatriz Aguado3 ● ● ● ● ● Mohsen Al Zahrani 6 Jane Apperley7 Ana Berceanu8 Rodrigo Martino Bofarull9 Maria Calbacho10 ● ● ● ● ● Fabio Ciceri11 Lucia Lopez-Corral12 Claudia Crippa13 Maria Laura Fox14 Anna Grassi15 Maria-Jose Jimenez16 ● ● ● ● ● ● Safiye Koçulu Demir 17 Mi Kwon 18 Carlos Vallejo Llamas19 José Luis López Lorenzo20 Stephan Mielke1,21 ● ● ● ● ● Kim Orchard22 Rocio Parody Porras23 Daniele Vallisa24 Alienor Xhaard 25 Nina Simone Knelange26 ● ● ● ● ● Angel Cedillo27 Nicolaus Kröger 28 José Luis Piñana 29 Jan Styczynski 30 ● ● ● Received: 14 February 2021 / Revised: 10 May 2021 / Accepted: 17 May 2021 / Published online: 2 June 2021 © The Author(s) 2021. This article is published with open access Abstract This study reports on 382 COVID-19 patients having undergone allogeneic (n = 236) or autologous (n = 146) hematopoietic 1234567890();,: 1234567890();,: cell transplantation (HCT) reported to the European Society for Blood and Marrow Transplantation (EBMT) or to the Spanish Group of Hematopoietic Stem Cell Transplantation (GETH). The median age was 54.1 years (1.0–80.3) for allogeneic, and 60.6 years (7.7–81.6) for autologous HCT patients. The median time from HCT to COVID-19 was 15.8 months (0.2–292.7) in allogeneic and 24.6 months (−0.9 to 350.3) in autologous recipients. 83.5% developed lower respiratory tract disease and 22.5% were admitted to an ICU. Overall survival at 6 weeks from diagnosis was 77.9% and 72.1% in allogeneic and autologous recipients, respectively. Children had a survival of 93.4%. In multivariate analysis, older age (p = 0.02), need for ICU (p < 0.0001) and moderate/high immunodeficiency index (p = 0.04) increased the risk while better performance status (p = 0.001) decreased the risk for mortality. Other factors such as underlying diagnosis, time from HCT, GVHD, or ongoing immunosuppression did not significantly impact overall survival. We conclude that HCT patients are at high risk of developing LRTD, require admission to ICU, and have increased mortality in COVID-19. Introduction achievements in the management of COVID-19, but the mortality remains high especially in patients with risk fac- A novel coronavirus named SARS-CoV-2 emerged at the tors. Recently, extensive vaccination programs were initi- end of 2019, and Coronavirus Disease 2019 (COVID-19) ated to control transmission and to reduce morbidity and started spreading worldwide [1–3]. The WHO classified mortality. COVID-19 a pandemic on March 11, 2020, and as of Hematopoietic cell transplant recipients (HCT) are prone February 8, 2021, more than 106 million cases have been to develop severe infections with many viruses including verified worldwide, and more than 2,300,000 have died. community-acquired respiratory viruses. To better under- The EBMT has published recommendations regarding stand the impact of COVID-19, data collection began via polices and patient management [4]. There have been major the Infectious Diseases Working Party of the EBMT and the Spanish Hematopoietic Stem Cell Transplantation and Cell Therapy Group (GETH). This manuscript presents the first results of this collaborative effort. These authors contributed equally: Per Ljungman, Rafael de la Camara This paper aimed to analyze the outcome of the first Supplementary information The online version contains wave of COVID-19 for patients registered in the study supplementary material available at https://doi.org/10.1038/s41375- and identified risk factors for lower respiratory tract dis- 021-01302-5. ease (LRTD), the requirement for intensive care, and * Per Ljungman mortality. Per.Ljungman@ki.se Extended author information available on the last page of the article 2886 P. Ljungman et al. Methods purpose of this study we used it also to analyze the complete population as well as allogeneic and autologous separately. This is an EBMT and GETH prospective survey merging Absolute lymphocyte count/C-reactive protein (ALC/CRP) newly collected data with previous data existing in the ratio was defined according to Lagunas-Rangel, 2020 [6]. EBMT registry. All patients give informed consent for their data to be included in the registry. Questions included the Statistics symptoms at the time of diagnosis, potential risk factors for development of pneumonia, the need for hospitalization, The main characteristics of patients were reported by intensive care, and outcome. Criteria for inclusion in the descriptive statistics. Median, minimum and maximum study were that the patient should be PCR positive for values were used for continuous variables, while absolute SARS-CoV-2 regardless of symptoms and have undergone and percentage frequencies were used for categorical vari- an allogeneic or autologous HCT at any time before the ables. The overall survival was estimated by using the diagnosis of COVID-19. A parallel data collection with Kaplan–Meier methods, considering the death due to any forms written in Spanish was used to collect data from cause as an event and the time from COVID-19 infection to Spain by GETH. The two sets of case record forms (CRFs) the latest follow-up as survival time; the difference between were almost identical with a few additional data fields used groups was tested by the log-rank test. Univariate and in the Spanish forms. The Swedish central Ethical Board multivariate risk factor analysis for overall survival were (EPM 2020-01731) approved the study and other approvals performed with the Cox regression model. Univariate and if required, were obtained according to national regulations. multivariate risk factor analyses for COVID-19 resolution For this analysis, patients diagnosed with SARS-CoV-2 were performed with the cause-specific Cox regression infection at or before July 31, 2020, were included and model, considering the resolution as the event of interest patients needed to have at least 6 weeks of follow-up. In and death due to any cause as a competing event. Univariate addition to the COVID-19 specific forms, the EBMT reg- and multivariate risk factor analyses for the requirement of istry’s so-called Minimal Essential Data A (MED-A) was admission to an intensive care unit (ICU) and LRTD used to extract previously submitted data regarding baseline development were performed with the logistic regression patient information, data regarding the underlying diag- model. Variables with a p value <0.2 at univariate analysis nosis, and the transplant procedure, which were used in the were entered into the multivariate models and selected analysis. according to a stepwise selection. A p value <0.05 was considered statistically significant. All p values are two- Definitions sided. All the analyses were performed using the statistical software SAS v. 9.4 (SAS Institute Inc., Cary, NC, USA). Resolution The resolution was defined as being alive with either clin- Results ical or virologic resolution of COVID-19. Number of included patients Lower respiratory tract disease Three hundred eighty-two patients from 22 countries ful- Since signs of LRTD are diverse and may develop over filled the criteria for inclusion. Two hundred thirty-six time, several questions in the CRFs (i.e., oxygen support patients had undergone allogeneic HCT and 146 auto- requirements, pulmonary radiology findings, the results of logous. The median age in the entire cohort was 56.8 years bronchoalveolar lavage, and the presence of clinical signs of (min–max; 1.0–81.6). The corresponding median ages were LRT such as shortness of breath, sibilants, rales, and 54.1 years (min–max; 1.0–80.3) for allogeneic and 60.6 cough), were used to define LRTD. This assessment was years (7.7–81.6) for autologous HCT patients, respectively. performed by two of the investigators (JLP and PL) and Thirty-two patients were children (<18 years of age; median used for the analysis. age 9.5 (1.0–16.9)). The median time from the most recent HCT to diagnosis of COVID-19 was 17.9 months Immunodeficiency scoring index (ISI) (min–max; −0.9 to 350.3). The corresponding median times were 15.8 months (min–max 0.2–292.7) in allogeneic This was calculated as previously described [5]. This score and 24.6 months (min–max; −0.9 to 350.3) in autologous was prepared for allogeneic HCT patients. Still for the HCT recipients, respectively. COVID-19 and stem cell transplantation; results from an EBMT and GETH multicenter prospective survey 2887 Table 1 Characteristics of patients having undergone allogeneic HCT. N = 236 Stem cell source BM (bone marrow) 37 (15.7) PB (peripheral blood) 186 (78.8) CB (cord blood) 4 (1.7) Missing 9 (3.8) HLA match Matched family 78 (33.0) Unrelated 111 (47.0) Fig. 1 Overall survival after diagnosis of COVID-19 infection in allogeneic and autologous HCT recipients. Mismatched family 35 (14.8) Missing 12 (5.1) Conditioning Interventions Myeloablative 108 (45.8) Reduced 111 (47.0) Different interventions were attempted in this patient cohort Missing 17 (7.2) reflecting the knowledge at the time of COVID-19. These In-vivo T-cell depletion are summarized in Supplementary Table 3. Data is not No 109 (46.2) available regarding the use of anticoagulation as prophy- Yes 121 (51.3) laxis against or treatment of thromboembolic events. Missing 6 (2.5) aGvHD at time of COVID-19 Outcome of COVID-19 no aGvHD/grade 1 132 (55.9) At the time of analysis, 107/377 (28.4%) patients had died grade 2–4 12 (5.1) (66/231 allogeneic; 41/146 autologous). 69/236 (29.2%) of Chronic GvHD at time of COVID-19 males and 38/146 (26.0%) of females had died at time of No (never) 137 (58.0) analysis (p = 0.48). The corresponding percentages in Yes, ongoing 77 (32.6) allogeneic HCT recipients were 28.5% vs. 27.2% in males Resolved 12 (5.1) and females, respectively. The median age of patients, who Missing 10 (2.8) died, was 62.2 years (4.5–80.3). Twelve patients died from Corticosteroids other causes than COVID-19 giving an attributable mor- No 133 (56.3) tality from COVID-19 of 25.2%. No follow-up had been Yes 88 (37.3) received for five patients. The median time from confirmed Missing 15 (6.3) infection to death was 18 days. Thirty-two children were included in the study: 29 after allogeneic and three after autologous HCT. Three of 32 Additional patient characteristics are shown in supple- children died: all after allogeneic HCT. The median time mentary Table 1. Details about donor type, conditioning, from HCT to COVID-19 diagnosis in the children, who stem cell source, and GVHD for the patients having died, was 2 months (2–15) while it was 4 months (−1 to 56) undergone allogeneic HSCT are shown in Table 1. 74.4% in the children surviving COVID-19. Furthermore, there of the patients were hospitalized during the COVID-19 was no difference in age between the children, who died (8 episode. years; 4–12) or survived (10 years; 1–17). Symptoms at diagnosis Overall survival Symptoms at diagnosis are summarized in Supplementary The Kaplan–Meier overall survival curves for allogeneic Table 2. Thirty-four patients (8.9%) were reported to be and autologous HCT patients are shown in Fig. 1. The asymptomatic during SARS-CoV-2 infection. On the other probabilities for survival at 6 weeks from diagnosis of hand, 132/376 patients (35.1%) required supplemental COVID-19 were 77.9% and 72.1% in allogeneic and oxygen to keep saturation above 92% (data missing for six autologous HCT recipients, respectively. There was no patients). The median time to diagnosis from the start of significant difference in survival between autologous and symptoms was 3 days (from thirty days before to 40 days allogeneic HCT patients (p = 0.8). Children had a higher after the onset of symptoms). survival rate (p = 0.03; Fig. 2). 2888 P. Ljungman et al. performance status (p < 0.0001), need for admission to ICU (p < 0.0001), and ISI group intermediate or high (p = .0.0005). The age effect also remained when only adults were included in the analysis. In multivariate analy- sis, excluding ICU admission age (HR 1.28; 95% CI 1.05–1.55; p = 0.01) and performance status (HR 0.79; 95% CI 0.68–0.92; p = 0.002) had a significant impact on overall survival. Only age (HR 1.29; 95% CI 1.05–1.58; p = 0.01) remained significant when ICU (HR 4.42; 95% CI 2.25–8.65; p < 0.0001) was included in the model. Fig. 2 Survival after diagnosis of COVID-19 in adults and children. The factors significant in univariate analysis for overall survival in autologous HCT patients were age (p = 0.01), Table 2 Impact of time between HCT and diagnosis of COVID-19 on performance status (p = 0.02), and admission to ICU (p = mortality. 0.002). The age effect also remained when only adults were Total Allo Auto included in the analysis. The only factor impacting overall survival in multivariate analysis (Table 3) was higher age Time after HCT Patients Deaths Patients Deaths Patients Deaths (HR 2.26; 95% CI 1.22–4.20; p = 0.01). 0–100 67 24 44 17 23 7 100-6 mm 31 9 22 7 9 2 Resolution 6mm-1y 56 19 37 12 19 7 12–18 mm 36 12 24 10 12 2 Of the patients reported to be alive, the median follow-up 18mm-2y 26 6 18 2 8 4 was 47 days (5–250 days). One hundred eighty-six (64.3%) ≥2yy 161 37 89 18 72 19 patients (117 allogeneic; 69 autologous), excluding patients who died from COVID-19, had virologic resolution of the COVID-19 infection. The median time to virologic resolu- tion was 24 days with the longest being 210 days. In In univariate analysis (Supplementary Table 4), risk addition, 58 patients (37 allogeneic and 21 autologous) had factors influencing overall survival in the total population clinical resolution but had not been tested again with PCR. were age (p < 0.0001), performance status (p < 0.0001), 25 patients were alive but known to be still COVID-19 time from HCT to COVID-19 (p = 0.04), ISI intermediate positive (13 allogeneic; 12 autologous). We had no infor- + high vs. low (p = 0.0008), ANC (p = 0.018), and the mation on five patients. ALC/CRP ratio (p = 0.009). The age effect also remained Factors impacting on resolution were in univariate ana- when only adults were included in the analysis. In addition, lysis high-performance status (1.14 (1.02–1.27), p = 0.02), the need for admission to ICU had a very strong impact on moderate/high ISI group (0.73 (0.54–0.99), p = 0.04), lung overall survival (p < 0.0001). Looking more in detail on pathology (0.70 (0.48–1.01), p = 0.05), the underlying time from HCT to COVID-19, the mortality in patients diagnosis (NHL/Hodgkin/CLL vs. AML/ALL 0.65 developing COVID-19 the first 100 days after HCT was (0.45–0.94), p = 0.02), and ALC ≥ 200 (1.64 (1.02–2.66), 35.8% vs. 26.8% (p = NS) in those developing COVID-19 p = 0.04; supplementary table 4). Besides, ICU admission beyond 100 days from HCT. The distribution of times from impacted on resolution (0.47 (0.32–0.70), p = 0.0002). In HCT to diagnosis of COVID-19 and mortality is shown in multivariate analysis (Table 3), only the underlying disease Table 2. The outcome in patients on or off immunosup- had a significant impact if ICU was not in the model, while pression split by time from HCT to COVID-19 is shown in ICU admission and performance status were significant in a Supplemenary Fig. 1. model including ICU care. In multivariate analysis (Table 3), age (HR 1.21; 95% CI In allogeneic HCT patients the factors influencing reso- 1.03–1.43; p = 0.02) and higher ISI group (HR 1.84; 95% lution in univariate analysis were high-performance status CI 1.02–3.33; p = 0.04) increased the risk and better per- (1.24 (1.08–1.43), p = 0.003), ISI group moderate/high formance status decreased the risk for fatal outcome (HR (0.58 (0.39–0.84), p = 0.004), presence of GVHD (0.70 0.83; 95% CI 0.74–0.93; p = 0.0001). These factors (0.50–0.99), p = 0.04), ALC ≥ 200 (2.03 (1.08–3.83), p = remained significant also when adjusting for type of trans- 0.03), need for ICU care (0.42 (0.25–0.70), p = 0.001), and plantation and if admission to ICU was not included as a ongoing immunosuppressive treatment (0.57 (0.39–0.83), variable in the analysis. p = 0.003; Supplementary Table 4). In multivariate analysis Factors significant in univariate analysis for overall sur- the underlying diagnosis excluding the ICU variable, time vival in allogeneic HCT recipients were age (p = 0.0007), from HCT to COVID-19, the diagnosis, and ISI group Table 3 Multivariate analysis for risk factors for different analyzed outcomes. Variable Characteristics Overall survival COVID-19 resolution LRTD ICU admission HR (95% CI) p HR (95% CI) p OR (95% CI) p OR (95% CI) p Age at COVID-19 Continuous (10-yr effect) 1.21 (1.03–1.43) 0.02 ns 1.41 (1.17–1.69) 0.0002 – ns Time from most recent transplant to COVID-19 ≥1 year vs <1 year – ns ns – ns ns Performance status Continuous (10-point effect) 0.83 (0.74–0.93) 0.001 1.16 (1.02–1.32) 0.02 – ns – ns ICU admission Yes 3.17 (2.00–5.01) <0.0001 0.36 (0.22–0.60) <0.0001 ns ns ISI group Moderate /high 1.84 (1.02–3.33) 0.04 2.59 (1.33–5.05) 0.005 ALC/CRPa median Underlying disease AML/ALL CML/MDS/MPN NHL/Hodgkin/ CLL ns ns ns ns Other Country Spain 1.00 Italy–UK ns ns ns 0.94 (0.42–2.12) 0.007 Other 2.51 (1.31–4.80) Allo only Age at COVID-19 Continuous (10-yr effect) 1.29 (1.05–1.58) 0.01 – ns 1.39 (1.14–1.71) 0.002 – ns Time from most recent transplant to COVID-19 ≥1 year vs <1 year – ns – ns – ns – ns Performance status Continuous (10 point effect) ns 1.20 (1.07–1.36) 0.003 – ns ns ICU admission Yes 4.42 (2.25–8.65) <0.0001 0.37 (0.24–0.59) <0.0001 ns Current IS therapy Yes ns ns 2.78 (1.02–7.60) 0.046 3.69 (1.06–12.87) 0.04 Country Spain 1.00 Italy-UK ns 1.20 (0.81–1.80) 0.009 ns ns Other 1.70 (1.20–2.40) Auto only Age at COVID-19 Continuous (10-yr effect) 2.26 (1.22–4.20) 0.01 – ns 1.72 (1.07–2.74) 0.02 – ns ICU admission Yes 0.48 (0.32–0.71) 0.0002 Time from most recent transplant to COVID-19 ns ns 3.93 (1.38–11.22) 0.01 ns COVID-19 and stem cell transplantation; results from an EBMT and GETH multicenter prospective survey ISI immunodeficiency scoring index, ICU intensive care unit. a ALC/CRP absolute lymphocyte count/CRP ratio. 2889 2890 P. Ljungman et al. influenced the time to resolution while with ICU variable acquired respiratory viruses [7–12]. Here, we present a included, ICU admission, performance status and country- series of 382 patients from 22 countries collected pro- influenced resolution (Table 3). spectively through the EBMT registry and in close colla- boration with the Spanish GETH, which is the largest Lower respiratory tract disease (LRTD) patient cohort with COVID-19 after HCT presented to date. Overall, COVID-19 was a severe complication in HCT 308/369 (83.5%) patients developed LRTD (data missing recipients with an attributable mortality of 25%. This can be for 13 patients). Results of the univariate analyses are compared to the case fatality rates during the 1st wave in shown in Supplementary Table 1. In multivariate analysis some European countries and the USA, 4–10% (Table 3), increasing age (HR 1.41; 95% CI 1.17–1.69; p = (https://www.worldometers.info/coronavirus/). The median 0.0002) and lymphocyte/CRP ratio (HR 0.32; 95% CI age in our population of patients having undergone allo- 0.13–0.80; p = 0.015) were significant in the total popula- geneic HCT was 54.1 years and 60.6 years in patients tion. In allogeneic HCT patients, age (HR 1.39; 95% CI having undergone autologous HCT, with the majority being 1.14–1.71; p = 0.002) and ongoing immunosuppression below 70 years of age. We found a 6-week probability of (HR 2.78; 95% CI 1.02–7.60; p = 0.046) increased the risk survival of 77.9% and 72.1% in allogeneic and autologous for LRTD while in autologous patients age (HR 1.72; 95% HCT recipients, respectively. The mortality rates in Sweden 1.07–2.74; p = 0.02) and longer time after HCT (HR 3.93; were 4.6%, 1.1%, and 0.1% in patients 60–69, 50–59, and 95% 1.38–11.22; p = 0.01) had a significant impact on the <50 years of age, respectively (www.folkha risk for LRTD. lsomyndigheten.se/ August 13, 2020). This date corre- sponds approximately with the cut-off date for inclusion in Requirement of admission to an intensive care unit this patient series. Thus, the mortality in our cohort is much higher than in the general population. In the general 80/356 (22.5%) patients received ICU care (data missing for population, mortality seems to be lower in the second wave 26 patients). The median time from diagnosis of COVID-19 and it remains to be seen if that is the case in HCT recipients to admission to ICU among 69 patients for whom we have as well. information (data missing on 11 patients) was five days (−5 The CIBMTR published results on 314 patients with to 35). The median time from diagnosis to ICU care was COVID-19 [13]. Their 30-day survival after diagnosis of seven days in allogeneic and four days in autologous HCT COVID-19 was 68% among allogeneic HCT recipients and patients. 38/69 patients died within six weeks from the day 67% among autologous HCT recipients. They found age of ICU admission. over 50, male sex, and time from HCT to COVID-19 Patients diagnosed with COVID-19 later than one year diagnosis of less than a year to be significant risk factors for after HCT had in univariate analysis (Supplementary mortality among allogeneic recipients. In contrast, only table 4) a lower risk of admission to an ICU (p = 0.02). diagnosis of lymphoma had an impact on survival among Other factors are shown in Supplementary Table 1. In autologous recipients. They did not report the impact per- multivariate analysis, moderate/high ISI group (OR 2.59; formance status at COVID-19 as a potential risk factor, 95% CI 1.33–5.05; p = 0.005) and country (p = 0.007) which was highly significant in our series. On the other were significant factors for ICU admission. If ISI was not hand, we could not find any impact of sex on mortality. included in the model, the ALC/CRP ratio was significant They reported only 10.9% mortality among female allo- together with country (Table 3). geneic HCT recipients compared to 27.2% in our series. In multivariate analysis including only allogeneic HCT The corresponding percentages in males were 33.7% vs. recipients, only ongoing immunosuppression increased the 28.5% in the CIBMTR and our series, respectively. These risk for ICU admission (HR 3.69; 95% CI 1.06–12.87; p = differences are unexplained. 0.04). No factor had significant impact on the risk for In another smaller series, Shah et al. reported a 30-day admission to ICU among autologous patients in multivariate survival of 78% in 72 HCT patients and 5 CAR T-cell- analysis. treated patients [14]. Their median time from HCT to COVID-19 diagnosis was slightly more than 2 years com- pared to 18 months in our study. Although in our cohort, in Discussion multivariate analysis, time from HCT to COVID-19 was not an independent risk factor for poor outcome, the mortality The emergence of SARS-CoV-2 and COVID-19 has had a was 36% in patients diagnosed the first 100 days after HCT. very strong impact on transplant centers fearing for the Coll et al. reported in a series, which included solid organ outcome of this disease in a population known to be vul- transplant patients [15], a mortality of 20% and 24% among nerable to viral infections in general and to community- 56 allogeneic HCT and 29 autologous HCT patients, COVID-19 and stem cell transplantation; results from an EBMT and GETH multicenter prospective survey 2891 respectively. In this study, the time median from HCT to COVID-19 in the general population [26–28]. Poor per- COVID-19 was similar as in our study (15 months in formance status is usually due to comorbidities such as allogeneic and 18 months in autologous HCT recipients). extensive GVHD, but in this cohort, we were unable to find Other studies of HCT patients have reported similar out- a correlation of specific comorbidities with the HCT out- comes [14–22]. comes. Kates et al. also found age and comorbid conditions Cancer patients are more vulnerable to develop severe as drivers of mortality in solid organ transplant recipients COVID-19. In a study of 107 cancer patients in China with [24]. Children seemed to do better. We present results of a median age of 66 years, the mortality was 21.5% [3], COVID-19 in 32 children after HCT of whom 29 survived. which is comparable to our patient cohort. However, our This also fits with what has been reported in the general cohort’s median age was a decade younger. Scarfò et al population [29], and also with a report of eight HCT chil- reported high mortality in patients with CLL with a median dren with COVID-19 of whom seven survived [17]. age of 72 years and found that the risk for severe COVID- More surprising was that the type of transplantation did 19 disease was associated with higher age (>65 years). Still, not impact on overall survival. Allogeneic HCT patients are neither older age nor comorbidities influenced mortality much more likely to develop severe complications from [23]. In a series of solid organ transplanted patients, Kates other respiratory viruses such as RSV and parainfluenza et al. reported a similar mortality of 20.5% at 28 days after viruses [30–32]. However, studies reported no difference diagnosis of infection [24]. between risk for mortality in autologous and allogeneic Other indicators of the severity of COVID-19 in our HCT patients with influenza such as during the H1N1 patients were a rate of LRTD of 83.5% and a rate of “Swine flu” pandemic [25, 33]. admission to ICU of 22.5%. These figures can be compared It was also surprising that the time from HCT did not to the experience with the H1N1 “Swine flu” pandemic in impact overall survival and neither did ongoing immuno- which the corresponding numbers were 32.5% and 11.5% suppression, presence of GVHD, preexisting pulmonary for LRTD development and need of intensive care, morbidity, or the granulocyte or lymphocyte count. Several respectively [25]. The figures can also be compared to the of these factors have been shown to be of importance for rates of ICU admission in Sweden during the 1st wave, outcome in other respiratory virus infections which is a country where there was no lack of ICU beds [5, 7, 12, 34, 35]. Contracting SARS-CoV-2 infection later during the pandemic. Given that the median age of the HCT than a year after allogeneic HCT was associated with a cohort was 56 years the best corresponding rates of ICU higher rate of resolution. Furthermore, when using the ISI, admission in Sweden were 8.9% in patients 60–69 years, which includes several of these factors to create an assess- 4.3% in those 50–59 years, and 1.1% in patients below 50 ment of the total immunodeficient status [5], patients with a years of age (www.folkhalsomyndigheten.se/ August 13, moderate or high index had increased mortality if ICU 2020). Nine percent of our cases were asymptomatic, but it admission was not included as a variable. Furthermore, high is likely that our numbers reflect a selection bias since not ISI increased the patient’s risk to require ICU care and all patients having undergone HCT and infected with negatively impacted on time to resolution among allogeneic SARS-CoV-2 have sought medical care, especially those HCT recipients. In addition, ongoing immunosuppressive with no or mild symptoms or those being a long time after therapy impacted the risk for LRTD and the need for ICU HCT and without complications from the transplantation. admission in allogeneic HCT recipients. An essential factor Additional studies of serological evidence of COVID-19 for the morbidity in COVID-19 is immune system activa- might elucidate this question. tion including effects on the T-cell responses [36–38]. It We calculated indices to see if any of those helped pre- could be that patients on immunosuppression might be dict outcome. ISI impacted on survival and ICU admission partly protected against this aspect of COVID-19 patho- in the total population. It also impacted on resolution and genesis. In contrast, immunosuppression could prolong ICU admission in patients having undergone allogeneic viral excretion by suppressing viral clearance either by the HCT but had no added value in autologous patients. This production of specific antibodies or by suppressing the T index was developed for allogeneic HCT with RSV infec- cell or NK cell functions. These possibilities will have to be tions. This report supports that it is also useful for COVID- investigated in a larger cohort. 19. The ALC/CRP ratio also had a significant impact on the It should be recognized that this study included patients risk for LRTD and need for ICU admission but not for developing COVID-19 during the 1st wave. Although we survival. Both these are easy to calculate and might be have information on used therapeutic interventions, the data helpful in the clinical assessment of SARS-CoV-2 patients. do not allow detailed analysis of the potential effects of Some of our findings were expected such as that overall antiviral drugs or anti-inflammatory agents due to the het- survival was influenced by patient age and performance erogeneity of the population, the non-controlled nature of status. Age has been an important factor in most reports on the study, and the variation in different interventions 2892 P. Ljungman et al. making it too difficult, even with the size of this study, to infection in 107 patients with cancer from Wuhan, China. Cancer. get reliable estimates of potential therapeutic effects. 2020;126:4023–31. 4. Ljungman P, Mikulska M, de la Camara R, Basak GW, Cha- We can conclude from this study that COVID-19 resul- bannon C, Corbacioglu S, et al. The challenge of COVID-19 and ted in high rates of morbidity and mortality supporting that hematopoietic cell transplantation; EBMT recommendations for preventing infections in these patients is of uttermost management of hematopoietic cell transplant recipients, their importance. Furthermore, even in a high-risk cohort such as donors, and patients undergoing CAR T-cell therapy. Bone Mar- row Transplant. 2020;55:2071–6. HCT recipients, there are groups at higher and lower risk for 5. Shah DP, Ghantoji SS, Ariza-Heredia EJ, Shah JN, El Taoum KK, poor outcome. The most critical factors are older age and Shah PK, et al. Immunodeficiency scoring index to predict poor poor performance status presumably due to comorbidities outcomes in hematopoietic cell transplant recipients with RSV although we could not pinpoint important individual infections. Blood. 2014;123:3263–8. 6. Lagunas-Rangel FA. Neutrophil-to-lymphocyte ratio and comorbidities. Hopefully, this knowledge can help patients lymphocyte-to-C-reactive protein ratio in patients with severe and transplant centers to design interventions and protective coronavirus disease 2019 (COVID-19): a meta-analysis. J Med measures including vaccines to decrease this risk in this Virol. 2020;92:1733–4. highly vulnerable patient group. 7. Kim YJ, Guthrie KA, Waghmare A, Walsh EE, Falsey AR, Kuypers J, et al. Respiratory syncytial virus in hematopoietic cell transplant recipients: factors determining progression to lower Acknowledgements We are grateful for the collaboration with the respiratory tract disease. J Infect Dis. 2014;209:1195–204. British Society for Blood and Marrow Transplantation and Cellular 8. Hirsch HH, Martino R, Ward KN, Boeckh M, Einsele H, Therapy (BSBMTCT). We are also grateful to all physicians, nurses, Ljungman P. Fourth European Conference on Infections in Leu- and other staff treating these patients under very challenging circum- kaemia (ECIL-4): guidelines for diagnosis and treatment of human stances and still being able to help with providing data for this respiratory syncytial virus, parainfluenza virus, metapneumovirus, manuscript. JA acknowledges the support of the UK NIHR Imperial rhinovirus, and coronavirus. Clin Infect Dis. 2013;56:258–66. College Biomedical Research Centre. 9. Ison MG, Hirsch HH. Community-acquired respiratory viruses in transplant patients: diversity, impact, unmet clinical needs. Clin- Author contributions PL, RdeC, JS, NK, MM designed the study and ical Microbiol Rev. 2019;32:e00042–00019. worked as a writing committee. GT is the study statistician. NSK and 10. Boeckh M. The challenge of respiratory virus infections in AC managed the registry data. JLP participated in case classification. hematopoietic cell transplant recipients. Br J Haematol. All others provided data and critically reviewed first a preliminary and 2008;143:455–67. then the final version of the manuscript. 11. Zhu W, Wang Y, Xiao K, Zhang H, Tian Y, Clifford SP, et al. Establishing and managing a temporary coronavirus disease Compliance with ethical standards 2019 specialty hospital in Wuhan, China. Anesthesiology. 2020;132:1339–45. 12. Seo S, Xie H, Campbell AP, Kuypers JM, Leisenring WM, Conflict of interest The authors declare no competing interests. Englund JA, et al. Parainfluenza virus lower respiratory tract disease after hematopoietic cell transplant: viral detection in the Publisher’s note Springer Nature remains neutral with regard to lung predicts outcome. Clin Infect Dis. 2014;58:1357–68. jurisdictional claims in published maps and institutional affiliations. 13. Sharma A, Bhatt NS, St Martin A, Abid MB, Bloomquist J, Chemaly RF, et al. Clinical characteristics and outcomes of Open Access This article is licensed under a Creative Commons COVID-19 in haematopoietic stem-cell transplantation recipients: Attribution 4.0 International License, which permits use, sharing, an observational cohort study. Lancet Haematol. 2021;8: adaptation, distribution and reproduction in any medium or format, as e185–e193. long as you give appropriate credit to the original author(s) and the 14. Shah GL, DeWolf S, Lee YJ, Tamari R, Dahi PB, Lavery JA, source, provide a link to the Creative Commons license, and indicate if et al. Favorable outcomes of COVID-19 in recipients of hema- changes were made. The images or other third party material in this topoietic cell transplantation. J Clin Investig. 2020;130:6656–67. article are included in the article’s Creative Commons license, unless 15. Coll E, Fernandez-Ruiz M, Sanchez-Alvarez JE, Martinez- indicated otherwise in a credit line to the material. If material is not Fernandez JR, Crespo M, Gayoso J, et al. COVID-19 in trans- included in the article’s Creative Commons license and your intended plant recipients: the Spanish experience. Am J Transplant. use is not permitted by statutory regulation or exceeds the permitted 2021;21:1825–37. use, you will need to obtain permission directly from the copyright 16. Saraceni F, Scortechini I, Mancini G, Mariani M, Federici I, holder. To view a copy of this license, visit http://creativecommons. Gaetani M, et al. Severe COVID-19 in a patient with chronic org/licenses/by/4.0/. graft-versus-host disease after hematopoietic stem cell transplant successfully treated with ruxolitinib. Transplant Infect Dis. 2021;23:e13401. References 17. Vicent MG, Martinez AP, Trabazo Del Castillo M, Molina B, Sisini L, Moron-Cazalilla G, et al. COVID-19 in pediatric 1. Zhang Y, Xu J, Li H, Cao B. A novel coronavirus (COVID-19) hematopoietic stem cell transplantation: the experience of Spanish outbreak: a call for action. Chest. 2020;157:e99–e101. Group of Transplant (GETMON/GETH). Pediatr Blood Cancer. 2. Zhang J, Wang X, Jia X, Li J, Hu K, Chen G, et al. Risk factors 2020;67:e28514. for disease severity, unimprovement, and mortality in COVID-19 18. Gampel B, Troullioud Lucas AG, Broglie L, Gartrell-Corrado RD, patients in Wuhan, China. Clin Microbiol Infect. 2020;26:767–72. Lee MT, Levine J, et al. COVID-19 disease in New York City 3. Zhang H, Wang L, Chen Y, Wu Q, Chen G, Shen X, et al. pediatric hematology and oncology patients. Pediatr Blood Can- Outcomes of novel coronavirus disease 2019 (COVID-19) cer. 2020;67:e28420. COVID-19 and stem cell transplantation; results from an EBMT and GETH multicenter prospective survey 2893 19. Kanellopoulos A, Ahmed MZ, Kishore B, Lovell R, Horgan C, adolescents in Europe: a multinational, multicentre cohort study. Paneesha S, et al. COVID-19 in bone marrow transplant reci- Lancet Child Adolesc Health. 2020 ;4:653–61. pients: reflecting on a single centre experience. Br J Haematol. 30. Seo S, Campbell AP, Xie H, Chien JW, Leisenring WM, Englund 2020;190:e67–e70. JA, et al. Outcome of respiratory syncytial virus lower respiratory 20. Malard F, Genthon A, Brissot E, van de Wyngaert Z, Marjanovic tract disease in hematopoietic cell transplant recipients receiving Z, Ikhlef S, et al. COVID-19 outcomes in patients with hemato- aerosolized ribavirin: significance of stem cell source and oxygen logic disease. Bone Marrow Transplant. 2020;55:2180–4. requirement. Biol Blood Marrow Transplant. 2013;19:589–96. 21. He W, Chen L, Chen L, Yuan G, Fang Y, Chen W, et al. COVID- 31. Seo S, Xie H, Karron RA, Thumar B, Englund JA, Leisenring 19 in persons with haematological cancers. Leukemia. WM, et al. Parainfluenza virus type 3 Ab in allogeneic hemato- 2020;34:1637–45. poietic cell transplant recipients: factors influencing post- 22. Martin-Moro F, Marquet J, Piris M, Michael BM, Saez AJ, Cor- transplant Ab titers and associated outcomes. Bone Marrow ona M, et al. Survival study of hospitalised patients with con- Transplant. 2014;49:1205–11. current COVID-19 and haematological malignancies. Br J 32. Ljungman P, Ward KN, Crooks BN, Parker A, Martino R, Shaw Haematol. 2020;190:e16–e20. PJ, et al. Respiratory virus infections after stem cell transplanta- 23. Scarfo L, Chatzikonstantinou T, Rigolin GM, Quaresmini G, tion: a prospective study from the Infectious Diseases Working Motta M, Vitale C, et al. COVID-19 severity and mortality in Party of the European Group for Blood and Marrow Transplan- patients with chronic lymphocytic leukemia: a joint study by tation. Bone Marrow Transplant. 2001;28:479–84. ERIC, the European Research Initiative on CLL, and CLL Cam- 33. Choi SM, Boudreault AA, Xie H, Englund JA, Corey L, Boeckh pus. Leukemia. 2020;34:2354–63. M. Differences in clinical outcomes after 2009 influenza A/H1N1 24. Kates OS, Haydel BM, Florman SS, Rana MM, Chaudhry ZS, and seasonal influenza among hematopoietic cell transplant reci- Ramesh MS, et al. COVID-19 in solid organ transplant: a multi- pients. Blood. 2011; 117:5050–6. center cohort study. Clin Infect Dis. 2020;7:ciaa1097. 34. Seo S, Xie H, Leisenring WM, Kuypers JM, Sahoo FT, Goyal S, 25. Ljungman P, de la Camara R, Perez-Bercoff L, Abecasis M, Nieto et al. Risk factors for parainfluenza virus lower respiratory tract Campuzano JB, Cannata-Ortiz MJ, et al. Outcome of pandemic disease after hematopoietic cell transplantation. Biol Blood Mar- H1N1 infections in hematopoietic stem cell transplant recipients. row Transplant. 2019;25:163–71. Haematologica. 2011;96:1231–5. 35. Renaud C, Xie H, Seo S, Kuypers J, Cent A, Corey L, et al. 26. Epidemiology Working Group for Ncip Epidemic Response Mortality rates of human metapneumovirus and respiratory syn- CCfDC, Prevention. [The epidemiological characteristics of an cytial virus lower respiratory tract infections in hematopoietic cell outbreak of 2019 novel coronavirus diseases (COVID-19) in transplantation recipients. Biol Blood Marrow Transplant. China]. Zhonghua Liu Xing Bing Xue Za Zhi. 2020;41:145–51. 2013;19:1220–6. 27. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course 36. De Biasi S, Meschiari M, Gibellini L, Bellinazzi C, Borella R, and risk factors for mortality of adult inpatients with COVID-19 in Fidanza L, et al. Marked T cell activation, senescence, exhaustion Wuhan, China: a retrospective cohort study. Lancet. and skewing towards TH17 in patients with COVID-19 pneu- 2020;395:1054–62. monia. Nature Commun. 2020;11:3434. 28. Ciceri F, Castagna A, Rovere-Querini P, De Cobelli F, Ruggeri A, 37. Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, et al. Clinical Galli L, et al. Early predictors of clinical outcomes of COVID-19 and immunological features of severe and moderate coronavirus outbreak in Milan, Italy. Clin Immunol. 2020;217:108509. disease 2019. J Clin Investig. 2020;130:2620–9. 29. Gotzinger F, Santiago-Garcia B, Noguera-Julian A, Lanaspa M, 38. Yuki K, Fujiogi M, Koutsogiannaki S. COVID-19 pathophysiol- Lancella L, Calo Carducci FI, et al. COVID-19 in children and ogy: a review. Clin Immunol. 2020;215:108427. Affiliations Per Ljungman 1,2 Rafael de la Camara 3 Malgorzata Mikulska 4 Gloria Tridello5 Beatriz Aguado3 ● ● ● ● ● Mohsen Al Zahrani 6 Jane Apperley7 Ana Berceanu8 Rodrigo Martino Bofarull9 Maria Calbacho10 ● ● ● ● ● Fabio Ciceri11 Lucia Lopez-Corral12 Claudia Crippa13 Maria Laura Fox14 Anna Grassi15 Maria-Jose Jimenez16 ● ● ● ● ● ● Safiye Koçulu Demir 17 Mi Kwon 18 Carlos Vallejo Llamas19 José Luis López Lorenzo20 Stephan Mielke1,21 ● ● ● ● ● Kim Orchard22 Rocio Parody Porras23 Daniele Vallisa24 Alienor Xhaard 25 Nina Simone Knelange26 ● ● ● ● ● Angel Cedillo27 Nicolaus Kröger 28 José Luis Piñana 29 Jan Styczynski 30 ● ● ● 1 Department of Cellular Therapy and Allogeneic Stem Cell 6 King Abdul – Aziz Medical City, Riyadh, Saudi Arabia Transplantation, Karolinska Comprehensive Cancer Center, 7 Karolinska University Hospital Huddinge, Stockholm, Sweden Centre for Haematology, Imperial College, London, UK 8 2 Division of Hematology, Department of Medicine Huddinge, Hopital Jean Minjoz, Besancon, France Karolinska Institutet, Stockholm, Sweden 9 Hospital Santa Creu i Sant Pau, Barcelona, Spain 3 Department of Hematology, Hospital de la Princesa, 10 Hospital Universitario 12 de Octubre, Madrid, Spain Madrid, Spain 11 4 Ospedale San Raffaele s.r.l., Milan, Italy Division of Infectious Diseases, University of Genoa and Ospedale Policlinico San Martino, Genova, Italy 5 Pediatric Hematology Oncology, Verona, Italy 2894 P. Ljungman et al. 12 21 Hematology Department, Complejo Asistencial Universitario de Department of Laboratory Medicine, Karolinska Institutet, Salamanca-IBSAL; Centro de Investigación del Cáncer-IBMCC, Stockholm, Sweden Salamanca, Spain 22 Southampton General Hospital, Southampton, UK 13 Spedali Civili, Brescia, Italy 23 ICO – Hospital Duran i Reynals, Barcelona, Spain 14 Servei d’Hematologia, Vall d’Hebron Hospital Universitari, 24 Experimental Hematology, Vall d’Hebron Institute of Oncology Hospital Guglielmo da Saliceto, Piacenza, Italy (VHIO), Vall d’Hebron Barcelona Hospital Campus, 25 Hôpital St. Louis, Paris, France Barcelona, Spain 26 15 EBMT Data Office, Department of Medical Statistics & ASST Papa Giovanni XXIII, Bergamo, Italy Bioinformatics, Leiden, Netherlands 16 ICO-Hospital Germans Trias i Pujol. Josep Carreras Research 27 GETH Spanish Registry, Madrid, Spain Institute, Badalona, Spain 28 17 Department of Stem cell Transplantation, University Hospital HSCT unit, Demiroglu Bilim University, Istanbul, Turkey Eppendorf, Hamburg, Germany 18 Hospital General Universitario Gregorio Marañon, Instituto de 29 Department of Hematology, Hospital Clinico Universitario de Investigación sanitaria Gregorio Marañon, Madrid, Spain Valencia. Fundación de investigación INCLIVA, Hospital Clinico 19 Hospital Universitario Donostia, San Sebastian, Spain Universitario de Valencia, Valencia, Spain 30 20 Fundación Jiménez Díaz, Madrid, Spain Pediatric Hematology and Oncology, University Hospital, Collegium Medicum, Nicolaus Copernicus University Torun, Bydgoszcz, Poland