key: cord-0970637-9h3vwlra
authors: Gatti, Milo; Rinaldi, Matteo; Bussini, Linda; Bonazzetti, Cecilia; Pascale, Renato; Pasquini, Zeno; Faní, Francesca; Pinho Guedes, Mariana Nunes; Azzini, Anna Maria; Carrara, Elena; Palacios-Baena, Zaira R.; Caponcello, Giulia; Reyna-Villasmil, Eduardo; Tacconelli, Evelina; Rodríguez-Baño, Jesús; Viale, Pierluigi; Giannella, Maddalena
title: Clinical outcome in solid organ transplant recipients affected by COVID-19 compared to general population: a systematic review and meta-analysis
date: 2022-03-12
journal: Clin Microbiol Infect
DOI: 10.1016/j.cmi.2022.02.039
sha: beab5768055e50c6ea8ca7c66d7bb5b505058c47
doc_id: 970637
cord_uid: 9h3vwlra

BACKGROUND: A significant increased risk of complications and mortality in immunocompromised patients affected by COVID-19 has been described. However, the impact of COVID-19 in solid organ transplant (SOT) recipients is an issue still on debate, due to conflicting evidence emerged from different observational studies. OBJECTIVE: We performed a systematic review with meta-analysis to assess the clinical outcome in SOT recipients with COVID-19 compared to general population. DATA SOURCE: PubMed-MEDLINE and Scopus were independently searched until 13 October 2021. STUDY ELIGIBILITY CRITERIA: Prospective or retrospective observational studies comparing clinical outcome in SOT recipients versus general populations affected by COVID-19. Primary endpoint was 30-day mortality. PARTICIPANTS: Patients with confirmed COVID-19. INTERVENTION: Solid organ transplant recipients. ASSESSMENT OF RISK OF BIAS: Quality of included studies was independently assessed according to ROBINS-I tool for observational studies. METHODS OF DATA SYNTHESIS: Meta-analysis was performed by pooling odds ratio (OR) retrieved from studies providing adjustment for confounders using a random-effect model with inverse variance method. Multiple subgroup and sensitivity analyses were conducted to investigate source of heterogeneity. RESULTS: 3,501 articles were screened, and thirty-one observational studies (N=590,375; 5,759 SOT recipients vs. 584,616 general population) were included in the meta-analyses. No difference in 30-day mortality rate was found in primary analysis including studies providing adjustment for confounders (N=17; 3,752 SOT recipients vs. 159,745 general population; OR 1.13, 95%CI 0.94-1.35; I(2)=33.9%). No evidence of publication bias was reported. Higher risk of ICU admission (OR 1.56, 95%CI 1.03-2.63) and occurrence of acute kidney injury (OR 2.50 95%CI 1.81-3.45) was found in SOT recipients. CONCLUSIONS: No increased risk in mortality was found in SOT recipients affected by COVID-19 compared to general population when adjusted for demographic and clinical features and COVID-19 severity.

As a significant increased risk of complications and mortality in immunocompromised patients affected by 64

Coronavirus disease 2019 (COVID-19) has been widely described [1, 2] , the impact of COVID-19 in solid 65 organ transplant (SOT) recipients is an issue still on debate. Particularly, although SOT recipients commonly 66 exhibit a relevant burden of comorbidities affecting COVID outcome, the role of immunosuppressant 67 therapy in reducing hyper-inflammatory status may counterbalance this issue [3] . Furthermore, the majority 68 of data derives from small cohorts of patients or large registries without appropriate control groups. The first 69 retrospective studies reported higher mortality rates among SOT recipients if compared to general population 70 [4, 5] . However, results from an international registry study conducted during the first wave suggest that 71 transplantation was not independently associated with increased risk of death, but SOT recipients had a 72 rapidly evolving course in term of intensive care unit (ICU) admission and invasive ventilation rates [6] . 73

These findings have been further confirmed in a propensity-score analysis [7] . Nevertheless, subsequent 74 studies involving SOT recipients from different waves yielded conflicting results [8, 9] . With these 75 assumptions, we conducted a systematic review with meta-analysis in order to assess the clinical outcome in 76 SOT recipients affected by COVID-19 compared to general population. 77 78 Methods 79 2021). Additionally, requirement for non-invasive pressure-positive ventilation, mechanical ventilation, or 114 ICU admission were also considered as criteria for severe Three pairs of authors (MiGa and MR, CB and ZP, LB and RP) independently screened titles and abstracts 116 of each predefined group of records for potential relevance and assessed eligibility of relevant full texts. Any 117 disagreement was resolved by means of discussion or consultation with a third reviewer (MaGi). 118

Three pairs of authors (MiGa and MR, CB and ZP, LB and RP) independently extracted data of each 120 included study retrieved in the assigned group in a pre-specified form. The following data were extracted: a) 121 study author and year of publication, as well as the country in which the study was conducted; b) study 122 characteristics including study design, time period, sample size, exclusion criteria, and funding; c) features of 123 the patients including age, sex, type of SOT, time from transplant to COVID-19 occurrence, graft function at 124 COVID-19 diagnosis, immunosuppressive treatment at baseline, adjustments in immunosuppressive 125 treatment, and severity of COVID-19 at enrolment; specific COVID-19 treatment (including administration 126 of monoclonal antibodies, corticosteroids, tocilizumab, remdesivir, or other drugs) or preventive strategies 127 (including vaccination and implementation of telemedicine); and d) types of outcome measurements. 128 and general population (adjusted OR), through the implementation of matched cohorts, regression, or 139 propensity score analyses. Treatment effects were calculated as OR, with 95% confidence interval (CI) for 140 dichotomous data, by using a random-effect model with inverse variance method. Significance was assessed 141 by using a Z-test, where p<0.05 is considered as significant. Statistical heterogeneity among studies was 142 assessed by χ² test (p<0.10 indicated significant heterogeneity) and I 2 (degree of heterogeneity). An I 2 of 143 >50% was considered indicative of substantial heterogeneity. Subgroup analysis was pre-especified 144 according to comparator group (SOT waitlisted patients), the type of SOT, the type of immunosuppressive 145 agents at baseline, or change in immunosuppressant management after occurrence of COVID-19 infection. 146

At least three studies providing available adjusted data for primary outcome were required to progress to 147 subgroup analyses. Sensitivity analyses were also conducted by pooling also included studies without 148 adjustment for confounding factors, by excluding each study ("leave-one-out" approach), and according to 149 the risk of bias in order to investigate the confidence of the outcomes. Publication bias was assessed by 150 visual inspection of the funnel plot and Egger's test [12] . Electronic and manual search identified 3,501 potential studies, and among these 1,300 were removed as 156 being duplicates. After initial screening of titles and abstracts, 2,164 studies were excluded. Overall, 37 full-157 text articles were assessed for eligibility, and finally thirty-one studies met the inclusion criteria. Six studies 158

were excluded according to the following criteria: use of the same transplant registry in multiple included 159 studies (4 studies); systematic review (2 studies; Figure 1 ). 160 (15 in USA and one in Canada), fourteen in Europe, and one in Asia. Mean or median patient age ranged 165 from 38 to 65.5 years, with male preponderance (up to 83.0%). Most studies (28 out of 31) were conducted 166 during the first wave of COVID-19, while in three cases, the analysis was prolonged up to January 2021. 167

According to the study periods, no vaccinated patients were included among SOT recipients or general 168 populations due to lack of COVID-19 vaccine availability. 169

Liver and kidney transplant recipients accounted for more than 85% of included transplant patients. Severe 170 COVID-19 at diagnosis ranged from 1.1% to 78.0% in transplant recipients' group. Median timing of SOT in 171 relationship with COVID-19 infection was provided in eighteen studies, ranging from 3.4 to 9 years. Seven 172 and three studies included only kidney or liver transplant recipients, respectively. In seventeen studies, a 173 match between SOT recipients and control group was performed according to demographic and/or clinical 174 features ( Table 1) . In six studies, control group consisted in SOT waitlisted patients (kidney or 175 kidney/pancreas in four studies, lung and all SOT in one study each). 176

A summary of the results of meta-analysis for primary and secondary outcomes is shown in Table 2 . 178

Thirty-day mortality was assessed after hospital admission, after COVID-19 diagnosis, and after ICU 180 admission in 16, 14 and 1 studies, respectively. 181

A total of 17 studies (3,752 SOT recipients vs. 159,745 patients in general population) provided adjusted 182 data for 30-day mortality rate [5-7,9,14-16,20,21,23,25-28,30,31,33]. In 11 studies, adjustment for 183 confounders was performed by using a propensity score analysis, while exact matched cohorts and regression 184 analysis were implemented in 5 and 1 study, respectively. Overall, no significant difference emerged 185 between SOT recipients and general population (OR 1.13; 95%CI 0.94-1.35; Figure 2 Figure 1 ). Moderate degree of heterogeneity 208 was observed (I 2 =46.3%, p=0.13), while no evidence of publication bias was reported. As regards secondary 209 outcomes, no significant difference was found between kidney transplant recipients and general population 210 Figure 2 ). Substantial degree of heterogeneity was observed (I 2 =53.8%, p=0.11), while no evidence of publication bias was reported. As 216 regards secondary outcomes, liver transplant recipients were associated with increased risk of hospitalization 217 compared to general population (N=2; OR 1.75; 95%CI 1.19-2.57; Supplementary Table 2) . 218

Subgroup analyses for other types of SOTs (namely lung and heart transplant recipients), according to 219 different number and type of immunosuppressive agents at baseline, or according to change in 220 immunosuppressant management after occurrence of COVID-19 infection were not allowed due to lack of 221 outcome data. 222

After inclusion of studies providing unadjusted outcome data, SOT recipients showed a significant higher 224 risk of 30-day mortality rate compared to general population (N=30; OR 1. performed, and in three cases the adjustment was performed only for age and gender. All studies were 244 classified at low risk of bias for measurement of primary outcome (i.e., mortality rate), and for bias due to 245 missing data. Thirteen studies were classified as being at moderate risk of bias, while none exhibited a low 246 risk of bias (Supplementary Table 4) . 247 248

Our meta-analysis found that SOT recipients affected by COVID-19 were not associated with an increased possible that both sides of the coin are counterbalanced, being thus comorbidities to play a crucial role in outcome of SOT recipients with COVID-19. Unfortunately, our analysis was not able to assess the impact of 269 different immunosuppressive approaches implemented in SOT recipients affected by COVID-19 due to lack 270 of outcome data. 271

A higher risk of ICU admission in SOT recipients affected by COVID-19 compared to general population 272 emerged from our analysis. However, according to lacking of significant differences in mortality rate, it 273 could be suggested that higher ICU admission rate may not entirely reflect COVID-19 severity but rather a 274 closer management strategy implemented by treating physicians and a massive use of healthcare resources in 275 this fragile population [29, 44] . Indeed, in SOT patients, the hospitalization rates ranged between 60% to 276 86.5%, while that of COVID-19 severity from 23% to 35%. The prompt use of healthcare resources in SOT 277 patients may also have contributed to a more favorable outcome. 278

Notably, our analysis found a 2.5-fold greater risk of AKI occurrence in SOT recipients affected by COVID-279 19 compared to general population, as previously reported [3, 45] . This could probably reflect kidney 280 function vulnerability in SOT recipients, mainly due to the chronic use of calcineurin inhibitors, known to 281 cause nephrotoxicity, and which levels may increase during acute phase of infections [46] . Furthermore, it is 282 worth remarking that more than half of included cases consisted of kidney transplants. To the best of our knowledge, only a previous meta-analysis comparing clinical outcome between SOT 296 recipients and general population affected by COVID-19 currently exists [48] . Our findings are only partially 297 consistent with those reported by Ao et al. [48] , considering that a slightly higher risk of mortality was found 298

in SOT recipients in their pooled analysis of adjusted results. However, it is important to highlight that our 299 meta-analysis included more than double the number of studies and participants (of which the number of 300 SOT recipients was almost 4-fold greater) compared to the previous meta-analysis [48] , thus providing an 301 updated assessment of this issue. 302

Limitations of our meta-analysis have to be addressed. First, none of the included observational studies 303 exhibited a low risk of bias, thus unmeasured confounders could affect our findings. However, we performed 304 sensitivity analysis including only studies showing no serious/critical risk of biases in order to minimize the 305 relevance of potential unmeasured confounders. High statistical heterogeneity was found for most of 306 outcomes, possibly reflecting a certain degree of clinically meaningful heterogeneity between comparator 307 groups of the included studies. Additionally, no other subgroup analysis according to different clinical 308 features (e.g., management of immunosuppressant therapy in SOT recipients) was performed due to lack of 309 available data. Most studies were retrospective with a limited follow-up. Thus, we were able to measure only 310 some of the indicators of COVID-19 impact but, for example, the burden of long-COVID in SOT recipients 311 vs. general population has yet to be investigated. Finally, findings of our systematic review may not be 312 applicable to emerging variants causing milder disease such as the omicron variant [49] . 313

In conclusion, no increased risk in mortality was found in SOT recipients affected by COVID-19 compared 

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