key: cord-1035574-h36jmola
authors: Ao, Guangyu; Wang, Yushu; Qi, Xin; Nasr, Basma; Bao, Mulong; Gao, Ming; Sun, Ying; Xie, Dili
title: The association between severe or death COVID-19 and solid organ transplantation: A systematic review and meta-analysis
date: 2021-05-21
journal: Transplant Rev (Orlando)
DOI: 10.1016/j.trre.2021.100628
sha: 93c5aa492aba7a5a31a9c60c454e1692547de773
doc_id: 1035574
cord_uid: h36jmola

BACKGROUND: The effect of solid organ transplantation (SOT) on the severity and mortality of coronavirus disease 2019 (COVID-19) remained controversial. There is still no consensus on whether solid organ transplantation (SOT) recipients with COVID-19 are at greater risk of developing severe or fatal COVID-19. Therefore, we conducted a systematic review and meta-analysis to investigate the association between SOT, severe COVID-19 illness, and mortality. METHODS: A systemically comprehensive search in Pubmed, Embase, the Cochrane Library, Web of Science, and China National Knowledge Infrastructure was performed for relevant studies and articles. Consequently, we pooled the odds ratio (OR) from individual studies and performed heterogeneity, quality assessment and subgroup/sensitivity analysis. RESULTS: A total number of 15 articles with 265,839 participants were included in this study. Among the total number of participants, 1485 were SOT recipients. The meta-analysis results showed that transplant patients with COVID-19 were remarkably associated with a higher risk of intensive care unit admission than non-transplant patients (OR = 1.57, 95%CI: 1.07 to 2.31, P = 0.02). On the other hand, there were no statistically significant differences between SOT recipients and non-SOT recipients in mechanical ventilation need (OR = 1.55, 95%CI: 0.98 to 2.44, P = 0.06). In addition, we found that SOT recipients with COVID-19 had 1.40-fold increased odds of mortality than non-SOT recipients (OR = 1.40, 95%CI: 1.10 to 1.79, P = 0.007). Moreover, pooled analysis of adjusted results revealed that SOT recipients had a greater risk of mortality compared with non-SOT patients (HR = 1.54, 95%CI: 1.03 to 2.32, P = 0.037). LIMITATIONS: The main limitations in our study are attributed to the relatively small sample size, short follow-up period, and the fact that most of the studies included were retrospective in design. CONCLUSIONS: The results of this study indicate that SOT recipients with COVID-19 had a more significant risk of COVID-19 severity and mortality than the general population.

Coronavirus disease-2019 (COVID-19), caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), has now claimed over 1.6 million lives worldwide and has led to an unprecedented global health crisis. The clinical manifestations of COVID-19 may range from asymptomatic or mild symptoms to severe pneumonia, including acute respiratory distress syndrome (ARDS) and multiple organ dysfunction syndrome (MODS) 1 . Several risk factors for severe or fatal COVID-19 were identified, including old age, male gender, obesity, hypertension, cardiovascular disease, chronic kidney disease, and chronic lung disease [2] [3] [4] . Besides, recent studies indicated that the magnitude of specific immunity is associated with the severity of COVID-19 5 .

Most SOT recipients have one or several associated risk factors of severe or death COVID-10, such as hypertension, cardiovascular disease, and chronic kidney disease 6 . Moreover, SOT recipients require several immunosuppressive drugs, such as calcineurin inhibitors, antimetabolites, and steroids, which may moderate their immune system and significantly increase their susceptibility to viral infections and bacterial and fungal superinfection 7 . Hence, some studies reported that SOT recipients had a higher COVID-19 related mortality rate than non-transplant patients 8, 9 . In contrast, some other studies found that both mortality and severity rates of COVID-19 among SOT recipients were similar to the general population 10,11 . Severe COVID-19 manifestations were mainly associated with a disproportionate hyperinflammatory reaction due to cytokine release syndrome. Thus, the serum concentrations of J o u r n a l P r e -p r o o f Journal Pre-proof proinflammatory cytokines were found to be of higher levels in severe cases compared to mild ones 12,13 . Subsequently, under such circumstances, commencing the immunosuppressive agents may modulate and reduce the inflammatory response by blunting excessive cytokine release, thus promoting the prevention of severe complications in SOT patients 14, 15 It remains highly controversial whether SOT recipients were more prone to develop severe or fatal COVID-19 or whether immunosuppression could protect them from "cytokine storm" and prevent potential severe complications. To the best of our knowledge, no existing meta-analysis compared the severity and mortality of COVID-19 in SOT recipients and the general population. Therefore, we aimed to perform a systematic review and meta-analysis to investigate the association between severe or fatal COVID-19 and SOT. (2) letters, case reports, review articles, abstracts, comments. Data extraction included study characteristics (e.g., name of the first author, country, sample size, type of SOT, and duration of follow-up) and baseline patient characteristics (e.g., age, gender, and comorbidities, adjusted variables). Outcome data extraction included the severity of the disease (intensive care unit admission and mechanical ventilation need), mortality, and the results of multivariable regression analyses (including the level of statistical adjustment). Disagreements were resolved by consensus or by a third investigator.

The severity of the disease was mainly determined by developing specific symptoms (e.g. intubation and mechanical ventilation need or intensive care unit admission).

Two investigators (YW and GA) evaluated the risk of bias/quality of studies using the Newcastle-Ottawa Scale (NOS). A total score of ≥ 7 was used to indicate a high-quality study, while a study with a total score of <7 was considered a low-quality study. This study is registered with PROSPERO, number CRD42020207387.

The literature search, study selection and data extraction were performed independently by two investigators (YW and QX). Disagreements were resolved by discussion. Review Manager 5.3 (Cochrane Collaboration) and Stata 15.0 (StataCorp) were applied to calculate odds ratios (OR) and their 95% confidence intervals. We J o u r n a l P r e -p r o o f Journal Pre-proof used the adjusted hazard ratios (HR) with 95% confidence intervals (CI) for the overall effect estimate, if possible, to reduce the effects of potential confounders. We assessed between-study heterogeneity among combined study results with Cochran's Q test and the I 2 statistic, with an I 2 less than 25%, 25% to 50%, and greater than 50% indicated low, moderate, and high heterogeneity, respectively. When I 2 < 50%, we used a fixed effect model; otherwise, a random-effect model was used. We also preformed sub-analysis based on countries and sensitivity analysis by excluding one study at a time to explore the cause of heterogeneity and evaluate the stability of the results of this meta-analysis. Publication bias was assessed by Begg's adjusted rank correlation test and Egger's regression asymmetry test (P < 0.10 was considered indicative of statistically significant heterogeneity). P < 0.05 was considered statistically significant.

The database search resulted in 584 studies, with two studies identified through manual searching of reference lists from extracted studies. After removing duplicates, we conducted a review of the titles and abstracts of the 491 articles. As a result, 491 studies were excluded based on the title and abstract. After further evaluation of the remaining 58 full-text eligible papers, we excluded 43 papers due to insufficient data for calculation. Eventually, a total number of 15 papers, including 265839 participants, were involved in this meta-analysis [8] [9] [10] [11] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] (Figure 1 Table 1 . The overall quality of available literature was moderate with NOS scores ranging from 7 to 9. Characteristics of SOT and non-SOT recipients with COVID-19 are summarized in Table 2 . Included patients were predominately male. SOT recipients were more likely to present with higher proportions of co-morbidities, including hypertension and diabetes mellitus. The quality of the included articles is evaluated and shown in Table 3 . Eight studies 9,10,18,20,21,13,26,27 provided data on patients who required admission to intensive care unit (ICU). The meta-analysis showed that transplant patients with COVID-19 were associated with a higher risk of ICU admission than non-transplant patients (OR=1.57, 95%CI: 1.07 to 2.31, P=0.02; I 2 =76%) ( Figure 2A ). According to the subgroup analysis based on countries, analysis of studies from America did not reveal significant differences in ICU admission between transplant patients and non-transplant patients; however, the heterogeneity decreased to none (OR=1.19, 95%CI: 0.89 to 1.58, P=0.24; I 2 =0%). In addition, eleven studies 8, 10, 11, 19, [20] [21] [22] [23] [24] 26, 27 provided results of patients who needed mechanical ventilation. We found no significant differences in mechanical ventilation need between SOT recipients and non-SOT recipients (OR=1.55, 95%CI: 0.98 to 2.44, P=0.06; I 2 =84%) ( Figure 2B ).

Subgroup analysis of studies from America did not indicate significant differences in mechanical ventilation need between transplant patients and non-transplant patients, however the heterogeneity decreased significantly (OR=1.26, 95%CI: 1.00 to 1.59, P=0.05; I 2 =33%). Moreover, we found that SOT recipients with COVID-19 had 1.40-fold increased odds of mortality than non-SOT recipients (OR=1.40, 95%CI:

1.10 to 1.79, P=0.007; I 2 =54%) ( Figure 3A ). Pooled analysis of adjusted results [8] [9] [10] [11] 17 ,20,21,23,24,26 also revealed that SOT recipients had a higher risk of mortality compared with non-SOT patients (HR=1.54, 95%CI: 1.03 to 2.32, P=0.037) with substantial heterogeneity (I 2 =87.3%) ( Figure 3B ). Excluding the one study 21 (Trapani et al.) with the largest sample size did not alter the overall estimate; however, the heterogeneity decreased significantly (HR=1.27, 95%CI: 1.09 to 1.47, P=0.002; I 2 =24.8%). In addition, pooled analysis of three studies 8, 17 ,26 that matched SOT recipients with the general population based on age, sex and comorbidities also indicated that SOT recipients were associated with increased risk of mortality compared with non-SOT patients (HR=1.42, 95%CI: 1.01 to 2.00, P=0.046, I 2 =0%).

Sensitivity analyses by excluding each study at a time did not significantly alter the overall results. Egger's or Begg's tests did not reveal significant publication bias in the analysis of mortality (Egger P = 0.502 and Begg P = 0.858).

Solid organ transplant recipients face a substantial threat of COVID-19 infection due to the chronic use of immunosuppression agents and increased comorbidities risks. Moreover, SOT recipients have a higher prevalence of comorbidities, such as hypertension, diabetes, chronic kidney disease, and others, which will increase the severity and mortality of COVID-19 42 . In a large cohort study, the mortality among hospitalized SOT recipients with COVID-19 was 20.5%. The author pointed out that age and underlying comorbidities rather than immunosuppression intensity-related measures were significant mortality drivers among SOT recipients 43 . Besides, Coll et al. found that the mortality rate among transplant recipients with COVID-19 was 27%.

Such a high mortality rate may be predominantly influenced by the demographic profile, comorbidity burden, and type of transplant organ than by the direct impact of transplantation or associated immunosuppression 44 . In our study, a large proportion of Although we performed a comprehensive review of the recent literature, some limitations to this study should be noted. The studies' sample size was relatively small, and most of the studies were retrospective in design, which also limited the number of included studies assignable to specific subgroups. The included observational studies were subject to potential confounders that may weaken the effect estimate. The proportion of SOT recipients was relatively small (0.5%), and the lack of sufficient data on different types of SOT hindered analyzing the possibility of different clinical outcomes. Additionally, one study 9 involved patients who had been already admitted to the intensive care unit, which may have potentially impacted the results of both disease severity and mortality. All included studies had a relatively short follow-up; therefore, we could not further analyze the short-term versus long-term follow-up J o u r n a l P r e -p r o o f clinical outcomes. Apart from that, this meta-analysis is not an individual patient data meta-analysis. Although the final total number of SOT recipients was 1485, there may be an overlap in the SOT recipients in which one patient may have been involved in more than one individual study. Finally, despite the high heterogeneity in the meta-analysis, we further conducted sub-analysis based on countries and sensitivity analysis to explain the cause of heterogeneity.

To the best of our knowledge, this study is the first systematic literature review to explore the association between severe or fatal COVID-19 and SOT recipient. In conclusion, the results of this study indicated that SOT recipients with COVID-19 had a higher risk of developing severe COVID-19 and mortality compared with the general population. Further research is needed to shed more light on the risk-benefit balance of using specific immunosuppression and immunomodulatory agents in this particular setting.

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

Data sharing is not applicable to this article as no new data were created or analyzed in this study Table legend   Table 1 Characteristics of included studies Table 2 Clinical characteristics of solid organ transplant patients and non-transplant patients with COVID-19 Table 3 Study quality assessment using the Newcastle-Ottawa Scale 

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