key: cord-0893811-jkb2a0pj authors: An, Wen; Wang, Qiuyang; Kim, Tae-Eun; Kang, Ju-Seop title: Clinical characteristics and outcome of coronavirus disease 2019 infection in patients with solid organ transplants: A systematic review and meta-analysis date: 2022-02-19 journal: J Infect Public Health DOI: 10.1016/j.jiph.2022.02.002 sha: 1cf81650141e30e43d8fa400839249e5cf075a5d doc_id: 893811 cord_uid: jkb2a0pj BACKGROUND: Although many studies have reported cases of COVID-19 infection in transplant recipients, most of them only involve a small number of patients and narrow geographic areas. This study aims to investigate the clinical characteristics, morbidity, severity, and mortality of COVID-19 infection among solid organ transplant (SOT) recipients by meta-analysis. METHOD: We performed a literature search using the databases PubMed, Web of Science, and Google Scholar as of November 26, 2020. We included randomized controlled trials and cohort studies, excluding case reports and small case series (n < 10). The pooled incidence proportion and 95% confidence intervals (CI) were used to estimate the combined results of forty-seven studies were included for the meta-analysis. Heterogeneity was assessed using I(2). Freeman-Tukey double arcsine transformation was used to stabilize the specific rate variance. Publication bias was using Egger’s test. RESULTS: The morbidity rate of COVID-19 in SOT recipients was 2.10% [95% CI 1.35–3.01], and the proportion of severe infection was 22.46% [95% CI 15.74–29.90]. The mortality rate was 17.38% [95% CI 13.72–21.34]. In the analysis by transplanted organ, the proportion of patients with severe infection was highest in recipients of two or more transplants 48.85% [95% CI 11.88–86.38]. The mortality rate was highest in lung transplant recipients 25.12% [95% CI 16.94–34.00]. The most common symptoms of COVID-19 in SOT recipients were fever (73.39%), cough (58.90%), and respiratory symptoms (45.77%). CONCLUSION: SOT was a risk factor for worse COVID-19 outcomes, although the morbidity of COVID-19 in SOT recipients was not markedly higher than the general population. These results may change when our understanding of the disease progress. In December 2019, the first case of coronavirus disease 2019 was reported in Wuhan, China. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent, is a pathogenic virus capable of rapid person-to-person spread. As of December 1, 2020, the COVID-19 pandemic has affected over 60 million people, with over 1.4 million deaths worldwide [1] . Although many studies have identified risk factors associated with COVID-19 morbidity and mortality, such as old age, obesity, diabetes, cardiovascular disease, and chronic kidney disease [2] , there are conflicting views on whether immunosuppression is a risk factor for morbidity and mortality associated with COVID-19 infection. While the U.S. Center for Disease Control and Prevention has stated that an immunocompromised state increases the risk for COVID- 19 [3] and compromised immunity renders the host more vulnerable to viral infection, some argue that immunosuppression may limit the hyperinflammatory response to COVID-19 caused by cytokine storm syndrome [4] . Furthermore, immunocompromised patients were not at an increased risk of contracting a viral infection or experiencing worse clinical outcomes in the epidemics of Middle East Respiratory Syndrome and SARS-CoV-1 [5] . Solid-organ transplant (SOT) recipients are at an increased risk of some opportunistic infections because immunisuppressants are administered to prevent rejection against transplanted organs. Although many people live with SOTs, information on the susceptibility to and clinical outcome of COVID-19 infection among these patients is lacking, and then it is difficult to make a decision for prevention and management of COVID-19 infected patients. Although many studies have reported on the association between COVID-19 and SOT, these cases are relatively small and from limited geographic areas. Thus, we performed a meta-analysis to delineate the clinical characteristics and outcomes such as mortality, morbidity and severity of COVID-19 infection in SOT recipients. Articles published in English were selected from the online databases of PubMed, Web of Science, and Google Scholar as of November 26, 2020. The following terms, both separately and in combination, were used for the search: ("SARS-CoV-2" or "COVID-19" or "Novel coronavirus 2019" or "coronavirus disease 2019") and ("SOT" or "solid organ transplantation" or "kidney transplant" or "heart transplant" or "liver transplant" or "lung transplant"). This meta-analysis and systematic review were screened by the Agency for Healthcare Research and Quality (AHRQ) and reported according to the meta-analysis guidelines (PRISMA). (Supplement Table S1 ) We included randomized controlled trials and cohort studies, case reports were excluded. We also excluded studies involving patients with suspected infection, such as chest imaging abnormalities and symptoms, and studies without RT-PCR detection. In the meta-analysis, we only included articles with 10 or more patients to minimize the impact of small studies. The following variables were collected from the included studies: sample size, type of organ transplantation, symptoms, follow-up period, number of COVID-19 diagnoses, number of intensive care unit (ICU) residents, and all-cause mortality. After obtaining these results, we excluded studies focusing only on critical patient admissions, ICU admissions, mechanical ventilation, and all-cause mortality to avoid selection bias and heterogeneity. The severity of the study was based on whether to be admitted to the ICU. The mortality rate was determined by death regardless of other causes. Morbidity refers to the prevalence of COVID-19 infection in patients with SOT. The methodology of morbidity is the number of COVID-19 in SOT recipients/ the total number of covid-19 patients reported in the study. Two researchers (An and Wang) independently screened the articles' titles and abstracts to evaluate study eligibility. Data were extracted using a predesigned Microsoft Excel® worksheet. The following data were extracted from the studies: first author, year, sample size, study design, age of patients, transplanted organs, and outcome indicators. Disagreements were resolved by a third researcher (Kim and Kang). All statistical analyses were performed using the R version 3.6.1. The pooled incidence proportion (i.e., cumulative incidence) and 95% confidence intervals (CI) were used to estimate the morbidity, severity, and mortality of COVID-19 in SOT recipients, as well as clinical symptoms. The Cochrane Q statistic and Higgins I 2 statistic were used to evaluate heterogeneity among the studies. Freeman-Tukey double arcsine transformation was used to stabilize the specific rate variance to minimize the impact of studies with extremely low or highly significant rates on overall estimates. When I 2 < 50%, a fixedeffect model was used to estimate the risk. In contrast, the randomeffects model was used when I 2 was > 50%. Publication bias was estimated using a funnel plot and Egger's linear regression test. Sensitivity analyses were conducted to assess the impact of each study on the pooled effect. This study did not receive nor require ethics approval, as it does not involve human & animal participants. The IRB approval and Patient and Public Involvement were not required. A total of 1189 articles were retrieved based on the keywords. After screening the abstracts and titles of 1189 studies, 237 studies were selected for full-text evaluation. Among them, 190 studies were excluded owing to lack of sufficient data. Finally, a total of 47 studies were included in the meta-analysis: 37 articles were analyzed for clinical characteristics; 16 articles (kidney: 9; liver: 6; lung: 5; heart: 9) for morbidity analysis, 36 articles (kidney: 18; liver: 12; lung: 8; heart: 9; multi-organ: 4) for severity analysis; 41 articles (kidney: 31; liver: 15; lung: 11; heart: 12; multi-organ: 7) for mortality analysis (Fig. 1) . The characteristics of the included studies are presented in Table 1 . The morbidity rate was investigated in 64,916 patients with SOT from 10 articles. The overall morbidity rate of COVID-19 in SOT recipients was 2.10% (95% confidence intervals [CI], 1.35-3.01) ( Fig. 2A) . When it was analyzed per organ, the COVID-19 morbidity rates of kidney 5.09% (95% CI 3.26-7.27), liver 0.61% (95% CI 0.05-1.55), lung 0.38% (95% CI 0.00-2.47), and heart transplant recipients 2.14% (95% CI 0.73-4.06), respectively (Fig. 3A) . The severity of infection was evaluated in 1574 patients with COVID-19 and SOT from 17 articles. The overall proportion of patients who experienced a severe clinical process resulting in admitting ICU admission was 22.46% (95% CI 15.74-29.90) (Fig. 2B) 38 ), which was a markedly higher proportion than that in single organ transplant recipients (Fig. 3B) . The overall mortality rate of COVID-19 in SOT recipients among 2161 patients with COVID-19 and SOT in 18 articles was 17.38% (95% CI 13.72-21.34) (Fig. 2C) . When analyzed per organ, the COVID-19 mortality rates of kidney 18 (Fig. 3C) . The clinical characteristics of COVID-19 infection in SOT recipients were evaluated in 2064 patients from 37 articles. The most common symptoms of SOT recipients with COVID- 19 Table 2 . To our knowledge, this is the first meta-analysis to report the morbidity, severity, and mortality of COVID-19 among SOT recipients. Our study showed that the mortality rate of COVID-19 in SOT recipients was 17.38%, which is approximately eight times higher than that in the population. This result is roughly the same as the mortality rate of COVID-19 in SOT recipients reported in the previous narrative review of 21% (n = 39) [6] , 25.64% (n = 403) [7] , and 18.6% (n = 2772) [8] . The Globally, as of December 1, 2020, the mortality rate has been reported to be 2.3%. Although there were differences by country, the mortality rate generally has not been reported to exceed 4.0%. In cases of diabetes mellitus, a known risk factor for COVID-19, the mortality rate because of COVID-19 has been reported to be 10-20%, which is comparable to the results of this study. In our study, the morbidity rate of COVID-19 in SOT recipients was 2.10%. Compared to the global morbidity rate reported by the World Health Organization [9] , it seems similar to that in the general population. However, morbidities differ across countries and some countries show much higher morbidity: the morbidity rate of the US is 4.6% as of December 1, 2020. Considering this, we believe that SOT recipients are not more susceptible to COVID-19 than the general population. Although there was no marked difference in morbidity by transplanted organs, the proportion of severe COVID-19 infection in multi-organ transplant recipients was significantly higher than that in SOT recipients. Interestingly, the mortality rate was not substantially higher than that in SOT recipients. Consistent with the clinical course of severe COVID-19 infection leading to respiratory failure and acute respiratory distress syndrome, the mortality rate was highest in lung transplant recipients. It has been shown that SOT patients have severe peripheral lymphopenia and have a low frequency of IFN-γ, IL-2, IFN-γ/ IL-2-producing T cells against membrane antigens. SOT patients have a degree of delayed immunity and are unable to achieve a strong immune response immediately, as evidenced by a lower rate of IgG seroconversion and frequency of cytokine-producing T cells [10] . This may be related to the long-term use of immunosuppressants in SOT patients, which will aggravate the COVID-19 infection after SOT patients are infected with COVID-19. The presence of this condition is a challenge for SOT patients infected with COVID-19 during the acute infection period. Inflammatory markers as well as IL-6, a risk factor for COVID-19-related mortality in hospitalized patients, are significantly increased in SOT patients [11] . Therefore, SOT patients infected with COVID-19 have a high level of mortality. Lung transplantation exhibited high mortality among the five transplant types, which may be related to the fact that the SARA-COV-2 viral target ACE2 receptors are mostly distributed in alveolar epithelial cells, alveolar space, and primary bronchus [12] . Even though, the morbidity and severity of COVID infection in lung SOT patients is lower than other organ SOT patients but is highest in mortality of COVID infections in lung SOT patients. Therefore, we believe that we need to be very careful care in managing COVID-19 infection in lung SOT patients. Heart transplant recipients had the lowest proportion of severity. The clinical manifestations of COVID-19 in SOT recipients were not different from those in the general population; however, the patients experiencing respiratory distress were over 40%, which was relatively higher than the 24-26% reported in other meta-analyses involving patients with COVID-19 in the general population [13, 14] . We found significant heterogeneity among some studies, and the following reasons may account for this. First, this study did not address the clinical history and characteristics of individual transplant recipients. Susceptibility to opportunistic infection among SOT recipient changes over time and the susceptibility and outcome of COVID-19 are likely to differ across transplant recipient dependent upon the period of transplantation and the type of immunosuppressive regimen. Second, this study did not consider other risk factors for COVID-19, such as age, obesity, and comorbidities. /37 90 16 27 47 13 17 9 NA 2 Hoek et al. [16] Netherlands 59 18/5 23 5 2 15 1 3 2 NA 3 Ravanan et al. [17] England NA 387/210 597 154 NA 470 64 13 23 22 4 Yi et al. [ Malekhosseini et al. [61] Third, there are still a small number of patients who have not been discharged at the time of publication, affecting mortality accuracy. Finally, it may be related to the lack of uniformity in treatment and hospitalization management. Although almost all articles adopted measures to reduce the dosage of immunosuppressants, calcineurin inhibitors, etc., in combination with antiviral and symptomatic treatment (mechanical ventilation, etc.), there was heterogeneity in the kinds of medication administered to individual patient between and within groups. On the other hand, all the inpatients in the study were required to meet the hospitalization standards set by their respective hospitals before they could be admitted for treatment. There were many differences in the hospitalization standards of each study, which led to significant heterogeneity between the studies. Despite these limitations, we believe that the large sample size of various publications can attenuate our limitations to some extent. In conclusion, we conducted a systematic review and metaanalysis of the symptoms and outcomes of the SOT receptor covid-19. Based on this review and meta-analysis, we concluded that although the incidence rate of COVID-19 in SOT recipients is not significantly higher than that of the general population. Once patients with SOT are infected with COVID-19, COVID-19 is a risk factor for worse prognosis, and the mortality and severity are also higher. These results may change when our understanding of the disease progress. The authors received no financial support for the research, authorship, and/or publication of this article. 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Not applicable. Not applicable. Supplementary data associated with this article can be found in the online version at doi:10.1016/j.jiph.2022.02.002.