key: cord-0840592-sxkhazhh authors: Quante, Markus; Brake, Linda; Tolios, Alexander; Della Penna, Andrea; Steidle, Christoph; Gruendl, Magdalena; Grishina, Anna; Haeberle, Helene; Guthoff, Martina; Tullius, Stefan G.; Königsrainer, Alfred; Nadalin, Silvio; Löffler, Markus W. title: SARS-CoV-2 in solid organ transplant recipients - a structured review of 2020 date: 2021-08-16 journal: Transplant Proc DOI: 10.1016/j.transproceed.2021.08.019 sha: 8cb39653c362c65dbf0b43bb23ab971013b48f07 doc_id: 840592 cord_uid: sxkhazhh BACKGROUND: : The SARS-CoV-2 pandemic is challenging health systems all over the world. Particularly high-risk groups show considerable mortality rates after infection. In 2020, an inexorable number of case reports, case series and ultimately various systematic reviews have been published reporting on morbidity and mortality risk of SARS-CoV-2 in solid organ transplant (SOT) recipients. However, this vast array of publications resulted in an increasing complexity of the field, overwhelming even the expert reader. METHODS: : We performed a structured literature review comprising electronic databases, transplant journals and included literature from previous systematic reviews covering the entire year 2020. From 164 included articles we identified 3451 cases of SARS-CoV-2 infected SOT recipients. RESULTS: : Infections resulted in a hospitalization rate of 84% and 24% intensive care unit admissions (ICU) in the included patients. Whereas 53.6% of patients were reported to have recovered, cross-sectional overall mortality reported after COVID-19 was at 21.1%. Synoptic data concerning immunosuppressive medication attested to the reduction or withdrawal of antimetabolites (81.9%) and calcineurin inhibitors (48.9%) as a frequent adjustment. In contrast, steroids were reported to be increased in 46.8% of SOT patients. CONCLUSIONS: : COVID-19 in SOT recipients is associated with high morbidity and mortality worldwide. Conforming with current guidelines, modifications of immunosuppressive therapies mostly comprised a reduction or withdrawal of antimetabolites and calcineurin inhibitors, while frequently maintaining or even increasing steroids. Here, we provide an accessible overview to the topic and synoptic estimates of expectable outcomes regarding in-hospital mortality of SOT patients diseased with COVID-19. Since the World Health Organization (WHO) has declared the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak starting in 2019 a pandemic, many countries have been severely affected by continuously rising infection rates. This unprecedented situation has challenged health systems on a global scale straining patient treatment inter alia due to an altered risk assessment for a variety of patient cohorts. Based on rapidly emerging data, factors such as age, diabetes, chronic lung disease and hypertension have been identified to increase disease-related mortality [1] . This is why close attention has been paid to vulnerable patient populations. For instance, in patients undergoing surgery, an international cohort study has established an excessive mortality risk, when patients became infected with SARS-CoV-2 directly before or during the first month after surgery [2] . Although this risk profile is most probably modulated by a variety of factors, the scale of these effects is unparalleled and calls for cautionary and preventative measures in regions affected by SARS-CoV-2 propagation. Against this background, patients who received a solid organ transplantation (SOT) have been identified as another high-risk group. An analysis of > 17 million electronic health care records from the UK, including > 10.000 COVID-19 related deaths, suggests a 6-fold increased sex and age adjusted risk of death (95% confidence interval 4. 73-7.61 ) in SOT recipients [3] . This relates both to recently transplanted patients and long-term SOT patients. In addition to immunosuppression, transplant patients frequently have additional risk factors that may favor detrimental outcomes. Meanwhile an array of case reports and case series has been published, as well as several case-control studies, predominantly confirming an increased fatality risk for SOT patients when infected with SARS-CoV-2 or developing coronavirus disease 2019 (COVID-19). Multiple systematic reviews on the topic have become available throughout 2020 with steadily increasing case numbers. However, the massive increment of publications on SARS-CoV-2 has resulted in an unprecedented complexity of the field, which results overwhelming even for the expert reader [4] . Of note, this situation has also fostered a surge of non-peer reviewed research published as preprints [5] . While this development acknowledges the need for rapid distribution of latest research findings and might represent a valuable tool to combat the pandemic, it is also linked to inherent limitations. Furthermore, pandemic pressure and the urge to catch-up with the flood of information and findings already supplied by news and social media as well as in preprints has resulted in more rapid review processes by many scientific journals and the publication of preliminary reports. Taken together, revisiting available empirical data systematically seems highly relevant. Here, comprehensive synoptic analyses are a gateway to access the available literature and e.g. allowing a broad-ranging overview and risk assessment for SARS-CoV-2-infected SOT recipients, which may help with addressing the many unanswered key questions urgently arising in this context [6] . Thus, we performed a structured literature review, providing an overview that compiles all relevant scientific literature from January 1 until December 31, 2020 to produce a current synoptic assessment of mortality and clinical outcomes subsequent to infection and COVID-19 in SOT recipients as well as a comprehensive summary of the relevant scientific literature that even a multitude of preceding systematic reviews fall short to provide so far [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] . We performed a structured review searching for publications reporting on patients after SOT with confirmed SARS-CoV-2 infections and/or suffering from COVID- 19 In addition, due to the high current interest in the topic, we also systematically searched PubMed for previously published systematic reviews relevant to the topic and identified 99 references from 13 systematic reviews (see Table 1 ), amounting to 728 references in total after duplicate removal to be screened. In a first screening step 519 of these publications were excluded and the 209 remaining articles were individually assessed and screened in detail for the relevant minimum required information defined by us. Characteristics searched for were SOT recipients aged ≥ 10 years with confirmed SARS-CoV-2 infection and/ or COVID-19. Additional essential information required before article inclusion were the number of SARS-CoV-2-positive/ COVID-19 affected SOT recipients, transplanted organs and clinical outcomes. Review articles, unassignable registry data, surveys and non-English language articles were excluded. After excluding 40 full-text-publications with reasons, ultimately 169 suitable articles were identified and reporting on the same set of patients. Data was compiled and tabulated using Microsoft Excel, data analysis and visualization was performed by using the free and open-source programming language GNU R [21] with the additional packages easyPubMed [22] as well as ggplot2 [23] . Figures were drawn using Inkscape (available at: https://inkscape.org) and Biorender (https://biorender.com/). Data was processed to depict the relative number of cases up to each time point, both overall as well as separated by group (type of study as well as geographic area). Data are presented in total numbers and percentages. References to all included articles and extracted data used for evaluations with transparent and reproducible methodology are available from the authors upon request. This systematic literature review ultimately identified 164 publications overall within our defined scope, which report on 3451 patients in total. The literature search strategy for the selection of scientific articles is illustrated in Fig. 1 . Most included studies were case reports (n=89) , followed by cohort studies (n=38) , case series (n=26) , multi center cohort studies or case series (n=8) [177] [178] [179] [180] [181] [182] [183] [184] and three case control studies [185] [186] [187] . An overview on the largest patient cohorts is provided in Table 2 . The majority of included patients had received a kidney allograft (n=2439; 70.7%), followed by liver (n=499; 14.5%), heart (n=274; 7.9%) and lung (n=170; 4.9%) transplants. Only a minor fraction has had multiple organs (n=59; 1.7%) transplanted ( Fig. 2 A) . An analysis of the global distribution revealed that the largest proportion of included patients were treated either in Europe (n=1481; 42,9%) or North America (n=1279; 37.1%), whereas a smaller part of patients was reported from countries located in Asia (538; 15.6%). Additionally, 153 patients (4.4%) were reported from other countries/ regions or could not be allocated. Overall, only two patients were reported from South American countries ( Fig. 2 B) . Among 3451 patients reported with confirmed SARS-CoV-2 infection and/or diseased with COVID-19, data on the clinical course and outcome was available for 3353 patients. According to this, 84% required hospitalization, while the remainder of 536 patients was treated in an outpatient setting. It may be mentioned here that for one study respective data was unavailable [156] and hospitalization was assumed as the default option. Among all included 2817 hospitalized patients, 53.6% recovered from SARS-CoV-2 infection or could be discharged. While 21.1% (n=709) of patients were deceased at the time of data reporting and 10.2% of the patients remained affected by the disease, yet 15.1% remained with an unknown outcome (Fig. 2 C) . For 57.9% of the patients changes in immunosuppressive medication were reported and for at least 22.6% of SOT recipients disease progression involved an impaired allograft function (Fig. 2 D) . We further analyzed the types of publications and the loco-regional origin of the included studies throughout the year 2020, thereby revealing clear longitudinal trends for both, origin and publication type. Starting with the SARS-CoV-2 outbreak, first reports on disease outcomes in SOT patients became available from Asia. In spring 2020, when Europe was severely hit by a first SARS-CoV-2 wave, this resulted in increasing publication numbers reporting on SOT patients. By mid of April 2020, also sizeable numbers of publications on SARS-CoV-2 and SOT patients from North America were published. Of note, relevant publications from other continents were only published late in 2020 and remained scarce when compared to the publication output from Asia, Europe and North America (Fig. 3 A) . Similar longitudinal trends can also be shown when analyzing the type of data published. While early in the pandemic data on SARS-CoV-2 in SOT patients were derived mainly from case reports, this was later followed by case series, with steadily increasing patient numbers reported in each publication and then succeeded by publications of cohort studies starting in late April 2020. Ultimately, also case-control studies became available but only in the second half of the year. However, their number remained small, thus accounting only for a minor proportion of patients reported (Fig. 3 A, B) . Among a subgroup of 1192 transplant recipients from five large cohorts [119, 132, 164, 177, 179] , we analyzed the available data on modification and management of the immunosuppressive therapies. Accordingly, the most frequent measure mentioned was the reduction or withdrawal of antimetabolites in 81.9% of SOT recipients with SARS-CoV-2 infection initially receiving this treatment. Reduction or withdrawal of calcineurin inhibitors was also reported frequently (48.9%). In contrast, steroids have been increased in 46.8% of respective patients, while reporting a reduction or withdrawal remained an exception (1.3%) ( Table 3) . To obtain a more conclusive picture, we additionally screened the most recent recommendations Based on data from other patient cohorts, it was reasonable to assume early on in the pandemic that SOT recipients do also exhibit a high-risk profile after infection with SARS-CoV-2, due to indispensable immunosuppressive medication and a high rate of additional medical risk factors. Data from first small cohort studies that had become available in kidney transplant recipients confirmed this notion, with reported mortality rates of up to 30% [168] . Notably, a case-control study with a more robust study design conducted in 151 liver transplant recipients and 627 non-transplanted hospitalized control patients surprisingly concluded that SOT status by itself was not independently associated with higher mortality. Instead, multivariate analysis established that mortality was primarily associated with age and disease severity [184] . Here, our comprehensive evaluations confirm that during the course of 2020 better studies with a more robust scientific design have increasingly become available. However, the SARS-CoV-2 pandemic has also fundamentally impacted research publishing, as reflected by increasing submission numbers, preprint rush, expedited review and in some cases retractions, even in high-profile peer-reviewed journals [5] . Therefore, our work may provide a robust overview and facilitate orientation within the tsunami of information linked to COVID-19. and/or suffering from COVID-19, predominantly from the US and Europe and therefore sheds additional light on key issues in SOT recipients exposed to SARS-CoV-2 facilitating an easy overview. In contrast, the largest patient cohort previously reported on in a systematic review with 2772 SOT patients [19] and 1955 and 223 for kidney [13] and liver [8] transplant recipients respectively were considerably smaller. About 70.7% of patients included by us were kidney transplant recipients, which is relevant since chronic kidney disease has been implicated in COVID-19 related mortality [188] . The overall mortality in our dataset was 21.1%, which is well in line with previous work [7, 8, 14, 15, 17] . Compared to the status quo before the pandemic these data are alarming, even when assuming the very low end of estimates concerning the COVID-19-related case fatality rate reported at only 8.1% and 4.6% in men and women, respectively [189] . However, a large observational study in > 10.000 hospitalized patients in Germany found in-hospital mortality rates at 22% among the general population [190] , which is in line with our review findings among SOT recipients. It is also noteworthy that our compiled data suggest that SARS-CoV-2 infection and/or COVID-19 resulted in a hospitalization rate of 84% with 24% of patients requiring ICU admission. We may speculate that the hospitalization rate derived from respective articles published in 2020 is most likely an overestimation due to reporting bias, which is inherent to this kind of evaluations. Understandably, these findings concur with previous reports e.g. in 36 adult kidney transplant recipients from the US, where the hospitalization rate was 78%, however among them 39% required mechanical ventilation with a mortality rate of 28% [114] . Then again, a single center report from Italy, which had been severely impacted early on in the pandemic, has reported 100% hospitalization, frequent occurrence of acute respiratory distress syndrome (55%) and 25% mortality among 20 SARS-CoV-2-infected renal allograft recipients [152] , suggesting the local situation may likely have impacted reporting. The management of immunosuppressive therapies in COVID-19 diseased SOT recipients is crucial but has not been conclusively addressed until now. Here, balancing the risks of allograft rejection and viral infection is paramount for the affected patients, yet the available data are scarce and scattered so far. Therefore, current guidelines from transplantation societies are mainly based on expert opinion, consistently recommending the withdrawal or reduction of antimetabolites followed by a reduction in calcineurin inhibitor dosage, depending on disease severity. Those recommendations are in line with the summary results of our literature overview, considering available retrospective clinical evidence. Along the same lines, tacrolimus could be linked with a positive independent effect on survival in liver transplant recipients [191] , while baseline immunosuppression containing mycophenolatemofetil was an independent predictor of severe COVID-19 [192] . Of note, some guidelines even recommend dexamethasone administration for up to 10 days in patients who require supplemental oxygen or are mechanically ventilated, thus conforming with the RECOVERY trial results [193] and treatment guidelines for the general population. The only review of guidelines addressing the usage of immunosuppressants during the coronavirus pandemic for diverse indications also concluded that steroid usage should not be stopped and emphasized the role of an individualized risk-benefit assessment, weighing the risk of COVID-19 infection and drug-induced immunosuppression for each patient [194] . Another critical aspect in COVID-19 diseased SOT recipients is the preservation of transplant function. Graft impairment or failure has been reported for about 22.6% of the cases we have compiled. Of note, such complications were frequently reported for kidney and liver transplant recipients. Corresponding data for acute kidney injury have been reported to range between 25% and 57% in COVID-19 diseased kidney transplant recipients [41, 65, 152, 154, 185] , linking it with a particularly poor prognosis [195] . We believe that the presented overview should be fairly comprehensive due to the amount of data compiled, while at the same time providing a representative number regarding clinical outcomes and inhospital mortality rates that may be expectable in COVID-19 diseased SOT patients. Of note, our data are unfortunately not suitable for a general assessment due to inherent study limitations. Here, especially asymptomatic SARS-CoV-2 infected SOT patients may not be reflected by our evaluations and any deductive conclusions should therefore be avoided. As potential limitations of our aggregate findings it must be considered that a relevant selection bias is probable, due to the design of our work. In detail, we assume e.g. mortality rates may be overestimated and most probably apply to the in-hospital setting. Another limitation is that follow-up duration was inhomogeneous and ranged widely, with many included cases having ongoing disease at time of reporting or unknown outcomes, which may render results premature. Nevertheless, most patients had a sufficiently long follow-up period in our view, considering mortality in infected SOT recipients is mainly observed within the first 15 days after hospitalization [185] . We intentionally refrained from any meta-analyses of data or reporting estimates of uncertainty, which was deliberately not within the scope of our work. We believe that preceding publications have proven this attempt to be most likely futile, while at the same time lacking significant added value [19] . Hence the aggregated data come with limitations that are defined by the nature of the available data and should therefore be considered as rough ballpark estimates rather than detailed outcomes. 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A distinction is made between the origin of the studies (graph above) the types of publication (graph below). The dashed line represents overall numbers of patients, the color area represents the relative number of patients reported until that time. (B) The graph depicts the number of patients per publication reported over time None. The authors declare no conflicts of interest.