key: cord-0882087-xpalf5me
authors: Schaffrath, Judith; Brummer, Christina; Wolff, Daniel; Holtick, Udo; Kröger, Nicolaus; Bornhäuser, Martin; Kraus, Sabrina; Hilgendorf, Inken; Blau, Igor-Wolfgang; Penack, Olaf; Wittke, Christoph; Steiner, Normann; Nachbaur, David; Thurner, Lorenz; Hindah, Heidrun; Zeiser, Robert; Maier, Claus-Philipp; Bethge, Wolfgang; Müller, Lutz P.
title: High mortality of COVID-19 early after allogeneic stem cell transplantation – a retrospective multicenter analysis on behalf of the German Cooperative Transplant Study Group
date: 2022-03-13
journal: Transplant Cell Ther
DOI: 10.1016/j.jtct.2022.03.010
sha: 6973970863bb56a928e7ed6f31aaf3ec5f6f8ec6
doc_id: 882087
cord_uid: xpalf5me

BACKGROUND: Patients after allogeneic stem cell transplantation (alloSCT) are at high risk for contracting infectious diseases with high morbidity and mortality. COVID-19 is a viral respiratory disease that can lead to severe pneumonia and ARDS with potentially fatal outcome. OBJECTIVES: We aimed to analyze risk factors, disease course and outcome of COVID-19 in patients after alloSCT. STUDY DESIGN: Patients after alloSCT who became infected with SARS-CoV-2 at German and Austrian transplant centers between February 2020 and July 2021 were included in our retrospective study on behalf of the German Cooperative Transplant Study Group. Classification of COVID-19 severity into mild, moderate-severe and critical disease and the division of the course of the pandemic into 4 phases were performed according to the German Robert Koch Institute (RKI). Main endpoint was overall mortality at the end of follow up. We further analyzed need for treatment on an intensive care unit (ICU) and severity of disease. Risk factors were evaluated using univariate and multivariate analysis, survival analysis was performed using Kaplan-Meier method. RESULTS: 130 patients from 14 transplant centers with a median age at diagnosis of COVID-19 of 59 (20-81) years and a median time between alloSCT and COVID-19 of 787 (19-8138) days were included. The most common underlying diseases were acute myeloid leukemia (45.4 %) and lymphoma (10.8 %). The majority of patients (84.9 %) were infected in the later phases of the pandemic. 20.8 % developed moderate-severe and 12.3 % critical disease, 19.2 % were treated on an ICU. After a median follow up of 127 days overall mortality was 16.2 %, among patients on ICU 52.0 %. Risk factors for mortality in multivariate analysis were active disease (OR 4.46), infection with SARS-CoV-2 ≤ 365 days after alloSCT (OR 5.60), age > 60 years (OR 5.39) and ongoing immunosuppression with cyclosporine (OR 8.55); risk factors for developing moderate-severe or critical disease were concurrent immunosuppression (OR 4.06) and age > 40 years (OR 4.08). CONCLUSION: Patients after alloSCT exhibit a substantially increased mortality risk after COVID-19 infection compared to the normal population, without considerable improvement over the course of the pandemic. Risk factors include age, early infection post alloSCT and active immunosuppression. Further studies are needed to improve prevention and treatment in this high-risk patient group.

Allogeneic stem cell transplantation (alloSCT) is an important therapeutic option for patients with various hemato-oncological diseases and often offers the only curative approach.

However, patients after alloSCT are at high risk for contracting infectious diseases, including viral infections. In this highly immunocompromised patient group, infections are associated with pronounced morbidity and mortality and are the main cause of non-relapse mortality after alloSCT [1] . These infections includebut are not limited torespiratory tract infections with potential lethal disease courses [2] [3] [4] . Within the general population, known risk factors for a severe course of the disease and mortality include, among others, older age, male gender, history of heart disease, hypertension, diabetes, autoimmune disease, asthma, chronic obstructive pulmonary disease (COPD), chronic kidney disease and obesity [5] [6] [7] [8] [9] [10] .

Furthermore, both an active cancer disease and a history of cancer are risk factors for a severe infection and SARS-CoV-2 related mortality [5, [10] [11] [12] .

In patients after alloSCT, a history of hemato-oncological disease is combined with a profound immunosuppression both due to the incomplete immunological reconstitution leading to a combined humoral and cellular immunodeficiency and immunosuppressive treatment required to prevent graft versus host disease (GvHD).

While the mortality rate of COVID-19 in the German general population in October is 2.2 %, data on the outcome of immunocompromised patients and / or patients with underlying hemato-oncological diseases are still inconsistent and limited [12] [13] [14] [15] [16] [17] [18] [19] . In solid organ transplant recipients, some studies find no difference in survival [20] , while others report a significantly increased mortality of more than 20 % in some cohorts [21] [22] [23] .

Therefore, the aim of our study on behalf of the German Cooperative Transplant Study Group was to analyze the outcome of patients with SARS-CoV-2 infections after alloSCT and identify risk factors for a severe disease course and mortality.

A total of 130 patients who became infected with SARS-CoV-2 between February 2020 and July 2021 and who had previously received a first or second alloSCT were included. In this multicenter study, patients from 14 German and Austrian transplant centers were included.

Patients had received an alloSCT from either an unrelated or related donor. In patients with two alloSCTs, data referring to the second alloSCT were included. COVID-19 had to be confirmed via polymerase chain reaction (PCR) from nasopharyngeal swab, bronchoalveolar lavage or liquid throat rinse or via antibody detection in the peripheral blood. The type of antibody test was not obtained.

In patients with an unknown exact date of COVID-19 diagnosis, the 15 th of the corresponding month was used for calculation if the month of diagnosis was known. If the month of diagnosis could not be determined, patients were completely excluded from the analysis of time-related variables. Only for calculation of the median age at diagnosis of our cohort the 01.01.2021 was used as the date of diagnosis in these patients.

Severity of COVID-19 was classified according to the recommendation of the German Robert Koch Institute (Table 1 ) [24] . To facilitate classification and due to missing data on radiological pulmonary patterns and oxygen saturation, we combined the categories moderate and severe disease into one category (moderate-severe disease). Briefly, patients were classified as having critical disease, if they had ARDS or signs of hyperinflammation such as sepsis or multiple organ failure. Moderate-severe disease referred to patients with pneumonia. All other patients were considered as having mild disease.

We did not inquire whether patients had been retested at the end of treatment or the resolution of symptoms. There was no differentiation between different causes of death, therefore COVID-19-related death and death from other causes were not analyzed separately.

For the comparison between the phases of the pandemic, we refer to the division of the pandemic course in Germany into 4 phases by Schilling et al.: phase 0 (calendar week 5/2020 to 09/2020), phase 1 (calendar week 10/2020 to 20/2020), phase 2 (calendar week 21/2020 to 39/2020) and phase 3 (calendar week 40/2020 to 08/2021) [25] . Infections with SARS-CoV-2 after calendar week 08/2021 were included into the 3 rd phase and due to the small number of patients in phase 0 and 2, both phase 0 and 1 as well as phase 2 and 3 were combined for comparison.

In this multicenter study all data were collected retrospectively by the transplant centers for all patients diagnosed with COVID-19 after alloSCT during the given time period. In April 2020, centers were asked to document all patients who had already been infected and all applicable patients consecutively from that time forward. Sources for data were local inpatient and outpatient documentation.

Analyses of the data were performed centrally at our center. Varying n for different parameters resulted from missing data that could not be obtained in the participating centers.

In case of missing data, the item was classified as unknown.

All patients had consented to treatment according to local standards. During all stages of collection and analysis, data were handled pseudonymized. Patients consented to the collection and analysis of their data. All analyses were in line with the declaration of Helsinki.

The study was approved by the local ethics committee of the Martin Luther University Halle (Saale) (registry number 2021-079).

All statistical analyses were conducted using software SPSS (version 25, IBM). To describe the characteristics of COVID-19 and its treatment, descriptive statistics on the basis of the available data were utilized, stating absolute and percentage frequencies for categorical and median and range for continuous variables.

To identify potential risk factors, unifactorial analysis of associations of parameters with mortality and disease severity was performed using cross-tabulation with chi²-test. A p value of < 0.05 was considered significant. Multivariate analysis was performed by binary logistic regression model with stepwise backward likelihood inclusion for parameters showing an association in univariate analysis and relevant cofactors as stated. Results are stated as odds ratio (OR) with 95% confidence interval (CI). If values of zero precluded calculation of the odds ratio, an estimated odds ratio was calculated by adding 0.5 to each cell of the 2x2 table. Survival analysis was performed using the Kaplan-Meier method with log rank testing.

General patient characteristics are summarized in Table 2 . 130 patients from 14 transplant centers in Germany and Austria were included in our study. Median age at diagnosis of COVID-19 was 59 years (20-81) and median age at alloSCT was 55 years . Median time between alloSCT and COVID-19 was 787 days . Four patients had received two alloSCTs. 

Characteristics of COVID-19 in our cohort are summarized in Table 3 . Infection with SARS-CoV-2 was detected via nasopharyngeal swab PCR test in 84.6 % of the patients, via PCR from liquid throat rinse in 3.1 % and via antibody detection in the peripheral blood in 1.5 % of the patients (missing data for 10.8 % of the patients). The two patients diagnosed via antibody detection only were diagnosed before availability of vaccination, were previously symptomatic and had close contact to patients with COVID-19. We did not inquire vaccination status, but based on the study period, it is very unlikely that vaccinated patients were included in the study.

The median follow up after confirmation of SARS-CoV-2 infection was 127 days (1-504). Figure 1A .

Mortality at the end of follow up among the severity groups was 2.4 %, 25.9 % and 68.8 % for patients with mild, moderate-severe and critical disease, respectively. Overall survival according to severity group is shown in Figure 1B , indicating a significant difference in survival times both between mild and moderate-severe disease (489.6 vs. 220.1 days, p<.001) as well as moderate-severe and critical disease (220 vs. 172.9 days, p<.001).

Of the 25 patients requiring treatment on an ICU, 13 (52.0 %) died. Difference in survival times compared to patients without ICU treatment (470.5 days with ICU vs. 254.9 days without ICU) was significant (p<.001, Figure 1C ). Given the wide range of different treatment modalities and drugs used and the ensuing small number of patients in each group we did not analyze the impact of different methods of treatment on the outcome.

Evaluation of potential risk factors for mortality was performed using univariate and multivariate analysis and is summarized in Table Patients aged > 40 years also had an increased risk for mortality (OR 12.32, estimated, p=.017, data not shown), while the age group 41-60 years alone did not show an increased mortality risk compared to patients ≤ 40 years.

Interestingly, when compared to the whole cohort, patient with acute GvHD had an increased mortality risk (OR 3.95, p=.021, data not shown). However, when compared to patients without GvHD, i.e. excluding patients with chronic GvHD, acute GvHD did not remain a significant risk factor.

In the multivariate analysis, we included all parameters for which univariate analysis yielded significant differences and which where independent of the disease itself. Therefore, severity group, pneumonia, ARDS and treatment modalities were not included. Active hematooncological disease (OR 4.46), infection with SARS-CoV-2 ≤ 365 days after alloSCT (OR 5.60), age > 60 years (OR 5.39) and immunosuppression with cyclosporine (OR 8.55) remained significant. If included in the analysis, neither acute GvHD nor age > 40 years remained a significant risk factor for mortality.

Kaplan-Meier analysis comparing survival according to age groups, time after alloSCT, medication with cyclosporine and remission status of the underlying disease are shown in Figure 2 .

A significant difference in survival times between the age groups ≤ 40 years and > 60 years (p=.030), but not between the age groups ≤ 40 and 41-60 years or 41-60 and > 60 years was seen ( Figure 2A ). Patients diagnosed with COVID-19 less than one year after alloSCT had a significantly reduced survival time compared to those patients diagnosed > 1 years after alloSCT (p<.001, Figure 2B ). Medication with cyclosporine at the time of COVID-19 diagnosis also led to a significantly reduced survival time after alloSCT (p<.001, Figure 2C ). The difference in survival times between patients with complete remission of their underlying disease and those with active disease was not significant (p=.136, Figure 2D ).

Additionally, acute GvHD was also a risk factor significantly reducing survival times compared to those patients with no or chronic GvHD (p=.013, data not shown).

Evaluation of potential risk factors for severity of COVID-19 as well as ICU admission was also performed using univariate and multivariate analysis and is summarized in Table 4 . In order to avoid multicollinearity, immunosuppression with steroids, GvHD overall and age > 40 years were excluded from multivariate analysis. Immunosuppression (OR 4.06) and age > 60 years (OR 2.38) remained significant. In a model including the age group > 40 years instead of > 60 years, age > 40 years also remained a significant risk factor (OR 4.08) for developing moderate-severe or critical disease. 

Herein we report the results of an observational multicenter retrospective study of COVID-19 in patients after alloSCT. Overall mortality among this high-risk cohort was 16.2 % at the end of follow up and median time from diagnosis to death was 32 days. Significant risk factors for mortality in multivariate analysis were infection with SARS-CoV-2 ≤ 365 days after alloSCT, age > 60 years, active disease and immunosuppression with cyclosporine at the time of COVID-19 diagnosis. To our knowledge, this is the first analysis of patients after alloSCT who contracted COVID-19 in the so-called second and third wave of the pandemic.

The majority of patients in our cohort had myeloid malignancies as their underlying disease, followed by Hodgkin and Non-Hodgkin Lymphoma, which is comparable to the overall patient population undergoing alloSCT in Europe [26] . The median age of 55 years at the time of alloSCT in our cohort was only slightly above the median age of patients receiving alloSCT in Germany in 2020 [27] . Median age at the time of infection with SARS-CoV-2 was 59 years.

Comparison of our cohort to other studies or the general age distribution of patients with COVID-19 is hindered by the rapid changes in the epidemiological distribution of COVID-19 during the course of the pandemic. During the first wave of COVID-19 in Germany (until October 2020), the median age of patients diagnosed with COVID-19 in the general population was 50 years and therefore slightly younger than our cohort [28] .

Mortality of 16.2 % in our cohort was clearly higher than in the general German population [29] . This underlines the very high risk of infection-related mortality in alloSCT patients and corresponds to the high mortality of these patients after infections with other respiratory viruses [30, 31] . This high mortality rate is also comparable to that of solid organ transplant recipients contracting COVID-19, who are persistently taking immunosuppressant medication [32] [33] [34] . considerably higher mortality rate compared to our study with 28.6% and 22% respectively [17, 18] . Similar to our study both studies referred to all-cause mortality and therefore a comparable endpoint.

One reason for the lower mortality rate may be the temporal distribution in our study with less than 12 % of the infections in phase 0 and 1 of the pandemic. Within our cohort, mortality was significantly higher in these first 2 phases in univariate analysis. This difference may be influenced by an unequal distribution of patients within our cohort caused by a large number of patients from an outbreak within a single center in the first phase. A similar observation was made in a large study of patients with hematological malignancies on behalf of the European Hematology Association (EHA), with a significantly decreased mortality rate between the first (March-May 2020) and the second COVID-19 wave (October-December 2020, 40.7 % vs. 24.8 %) [16] . In contrast, several studies on hospitalized COVID-19 patients show diverging results with both equal, lower and increased in-hospital mortality in the later phases of the pandemic [38] [39] [40] . Comparing treatment modalities is hindered by the variety of treatments used, but only 6.1 % of patients in our cohort received specific monoclonal antibodies that were not available in the first phases. Therefore, new therapeutic options do not seem to have contributed to the better outcome, although this remains speculative.

Interestingly, despite the high mortality rates of alloSCT patients with COVID-19 compared to the general population, mortality in our cohort was lower than in various studies of nontransplant patients with hematological malignancies [12] [13] [14] [15] . This finding is consistent with studies comparing mortality after SARS-CoV-2 infection in transplant and non-transplant patients with hematological malignancies [16, 37] . In both studies the worse outcome of non-SCT patients was attributed to the different composition of the cohortspatients without SCT were older, had been both diagnosed with and treated for their malignancy more recently before SARS-CoV-2 infection and had higher rates of uncontrolled hematological disease and / or comorbidities. This contrasts the usual prerequisites for undergoing alloSCT, and may therefore explain the higher mortality in non-SCT patients.

In our cohort, significant risk factors for mortality in multivariate analysis were age > 60 years, infection with SARS-CoV-2 ≤ 365 days after alloSCT, active disease and / or immunosuppression with cyclosporine at the time of COVID-19 diagnosis.

The higher mortality rate in elderly patients is consistent with the outcome in the general population, where several studies have shown that older age is an independent risk factor for COVID-19 mortality [41, 42] . In univariate analysis of our study cohort, even patients > 40 years were at higher risk for mortality and had a significantly increased risk for developing moderate-severe or critical disease. This underscores the vulnerability of this patient group and may lead to greater caution for intermediate-aged patients in the clinical practice.

An increased mortality risk of patients who contracted SARS-CoV-2 early after alloSCT was also observed in other studies [18, 19] , but not in the EBMT cohort [17] . This finding is of particular importance, because in these patients a sufficient response to vaccination and therefore an adequate protection cannot be expected [43] . Patients early after alloSCT regularly receive immunosuppressive medication for GvHD prophylaxis. Interestingly, only medication with cyclosporine represented a risk factor while ongoing immunosuppression with any other medication did not. Cyclosporine and its inhibition of the calcineurin pathway has been discussed as a treatment option in COVID-19 [44, 45] and some data suggest that immunosuppressive treatment may reduce the COVID-19-related overreaction of the immune system [46] . However, most studies find immunosuppression to be an independent predictor of mortality [42, 47] . In patients after alloSCT, most studies have found an impact of immunodeficiency on mortality and / or severity. Ljungman et al. found a high immunodeficiency index (including absolute neutrophile and lymphocyte count, among other criteria) to predict higher mortality [17] . A low lymphocyte count <0.3 Gpt/l was a risk factor in the CIBMTR cohort and concurrent immunosuppression predicted disease severity in the cohort of Mushtaq et al. [18, 35] . Two studies identified neutropenia as a risk factor for disease severity or mortality [36, 37] .

Active disease at the time of COVID-19 diagnosis was also an independent risk factor for mortality in our study. This finding has also been described by Piñana et al. in their non-SCTspecific cohort and underlying malignancy has been identified as a risk factor for severe COVID-19 and mortality [37, 42, 48] .

Taken together, compared to previous studies on COVID-19 after alloSCT including mostly patients from the first phase of the pandemic, risk factors for mortality appear to have remained similar.

There were several limitations to our study. Data was collected retrospectively, therefore some information, especially on time of diagnosis, clinical characteristics of the infection and treatment modalities, was not complete for all patients and could not be inquired in hindsight.

Additionally, our study might be further limited by a potential recall bias prior to starting consecutive patient accrual in April 2020.

Due to its multicenter design and the lack of guidelines in the early phase of the pandemic, treatment modalities differed greatly, both between the centers and the time periods during the pandemic. Therefore, our study does not allow conclusions regarding the effect of different therapies on the outcome of COVID-19 in patients after alloSCT.

Unfortunately, we did not have any laboratory data and only limited data on both comorbidities and transplantation modalities. Therefore, some risk factors may not have been recognized.

Additionally, as done by health authorities for the general population and other studies on COVID-19 after alloSCT, we chose all-cause mortality as our endpoint [49] . This was based on the rationale that mortality in this patient cohort is often multifactorial. In particular, COVID-19 may trigger GvHD or prevent intensive treatment for relapse. Therefore, a precise distinction between COVID-19-related and COVID-19-independent mortality was considered prone to bias and not performed in our study.

As a final point, there is an overlap between the study period until July 2021 and the availability of COVID-19 vaccines, which became available in January 2021 and widely accessible in spring 2021. Since the study was initiated in April 2020, vaccination status was not obtained. Inclusion of patients who became infected after vaccination is therefore very unlikely, but cannot be excluded.

Despite these limitations, our study confirms the significantly increased mortality risk of patients after alloSCT. Mortality was several times higher than that of the normal population and especially patients early after transplantation, of older age and those receiving immunosuppression were particularly at risk. Further studies are needed to identify the best treatment and vaccination options for this vulnerable patient group.

The authors have no competing interests to disclose. . Overall survival according to treatment on an intensive care unit. Significance of difference in survival times is stated using log rank test. Overall survival according to remission status of the underlying disease. Significance of difference in survival times is stated using log rank test.

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