key: cord-0942596-r51beb23 authors: Diaz‐Arocutipa, Carlos; Carvallo‐Castañeda, Darla; Luis‐Ybañez, Odalis; Pariona, Marcos; Rivas‐Lasarte, Mercedes; Álvarez‐García, Jesús title: COVID‐19 in heart transplant recipients during February–August 2020: A systematic review date: 2021-06-29 journal: Clin Transplant DOI: 10.1111/ctr.14390 sha: e060d3e8f7bc53ff274f296e018f6727a003ee72 doc_id: 942596 cord_uid: r51beb23 The coronavirus disease 2019 (COVID‐19) pandemic represents a major concern in immunosuppressed patients such as heart transplant recipients. Therefore, we performed a systematic review to summarize the clinical features, treatment, and outcomes of heart transplant recipients with COVID‐19. We searched electronic databases from inception to January 11, 2021. Thirty‐nine articles (22 case reports and 17 cohorts) involving 415 patients were included. The mean age was 59.9 ± 15.7 years and 77% of patients were men. In cohort studies including outpatients and inpatients, the hospitalization rate was 77%. The most common symptoms were fever (70%) and cough (67%). Inflammatory biomarkers (C‐reactive protein and procalcitonin) were above the normal range. Forty‐eight percent of patients presented with severe or critical COVID‐19. Hydroxychloroquine (54%), azithromycin (14%), and lopinavir/ritonavir (14%) were the most commonly used drugs. Forty‐nine percent of patients discontinued the baseline regimen of antimetabolites. In contrast, 59% and 73% continued the same regimen of calcineurin inhibitors and corticosteroids, respectively. Short‐term mortality among cohorts limited to inpatients was 25%. Our review suggests that heart transplant recipients with COVID‐19 exhibited similar demographic and clinical features to the general population. However, the prognosis was poor in these patients. its virulence extends beyond the respiratory system, and as such, cardiovascular involvement of COVID-19, in particular, has been reported by way of myocardial injury, 4-6 heart failure, 7 and even cardiogenic shock. 8 To date, several centers across the world have reported the clinical impact of COVID-19 in these patients. Therefore, we performed a systematic review to summarize the clinical features, treatment, and outcomes of heart transplant recipients with COVID-19. This review was reported according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. 9 An electronic systematic review of the literature was conducted in PubMed, Embase, Scopus, and Web of Science. The keywords used were chosen according to the MESH terminology: "COVID-19″ and "heart transplantation". The search was conducted from inception to October 1, 2020, with an update until January 11, 2021. The complete search strategy is available in Table S1 . In addition, we conducted a hand-searching of reference lists of all included studies and relevant reviews to identify further studies. The inclusion criteria were the following: (i) studies that included adult patients (≥18 years of age) and (ii) studies that reported data on clinical features, treatment, or outcomes of heart transplant recipients with COVID-19 diagnosed by reverse transcription-polymerase chain reaction (RT-PCR). There were no restrictions on language or publication date. We excluded animal studies, abstracts, editorials, commentaries, systematic reviews, and narrative reviews. We downloaded all articles from electronic search to EndNote X8 software and duplicate records were removed. Titles and abstracts were independently screened by three review authors (Carlos Diaz-Arocutipa, Darla Carvallo-Castañeda, and Odalis Luis-Ybañez) to identify relevant studies. Likewise, the same review authors independently assessed the full-text of each eligible study and registered reasons for the exclusion. Any disagreement on title/abstract and full-text selection was resolved by consensus. The information from each study was independently extracted by two review authors (Darla Carvallo-Castañeda and Odalis Luis-Ybañez) using a standardized data extraction form that was previously piloted. Frequencies and proportions were used to summarize categorical variables. Means ± standard deviations or median (interquartile range) were used for continuous variables. Data were presented according to study type (case reports and cohorts) and type of population (inpatients and outpatients/inpatients). All analyses were performed using the statistical software R 3.6.3 (www.r-project.org). A total of 415 heart transplant patients with COVID-19 were included. Baseline characteristics of the study population are summarized in The mean white blood cell count was 6100 ± 3500 cells/µl (n = 228 patients), the mean lymphocytes was 958 ± 803 cells/µl (n = 250 patients), the mean C-reactive protein was 82 ± 124 mg/L (n = 180 patients), and the mean procalcitonin was 1.7 ± 2.9 ng/ml (n = 162 patients) ( Table 2 ). In only 28% of patients, the chest imaging (X-ray or computed tomography) was normal. Table 2 shows that the most used drugs for the treatment of COVID-19 were hydroxychloroquine (54%), azithromycin (14%), and lopinavir/ritonavir (14%). One patient 22 who received hydroxychloroquine presented QT interval prolongation on the electrocardiogram but did not develop ventricular arrhythmias. Tocilizumab was given in 8% of cases and other IL-6 inhibitors were not used. The main changes of the maintenance immunosuppressive regimen during the COVID-19 infection were as follows: discontinuation (49%) or no modification (41%) of antimetabolites, no modification (59%) or reduction (28%) of calcineurin inhibitors, no modification (73%) of corticosteroids, and no modification (80%) of mTOR inhibitors ( Figure 2 ). SARS-CoV-2 infection. This patient presented with critical COVID-19 and required heart re-transplantation due to allograft dysfunction. We found four cases of prolonged positive RT-PCR testing. 34, 41, 42, 46 Twenty-one percent of patients developed acute respiratory distress syndrome, 16% required invasive mechanical ventilation, and 23% were admitted to the intensive care unit. Overall, 23% of patients died during hospitalization. The mortality rate based on cohorts that included only inpatients was 25%. In addition, the mortality rate of cohorts that included outpatients and inpatients was 24% (Table 2 ). To our knowledge, this is the first systematic review that summarizes clinical data from the largest international series of heart transplant recipients with COVID-19. The mean age was nearly 60 years and most cases were men. The majority of cases were managed in the inpatient setting and almost half of the patients had mild or moderate COVID-19. The regimen of calcineurin inhibitors, corticosteroids, and mammalian target of rapamycin (mTOR) inhibitors were not modified in more than half of the patients. In contrast, antimetabolites were discontinued in half of the cases. One-fifth of the patients required admission to the intensive care unit. Overall, the short-term mortality was 23%. We found that COVID-19 in heart transplant recipients shares some demographic and clinical characteristics with the general population in terms of male predominance, type of comorbidities, and clinical presentation. Whether heart transplant recipients are more vulnerable to acquiring COVID-19 due to their chronic immunosuppression state remains unclear. However, the prevalence of SARS-CoV-2 infection may be underestimated because asymptomatic transplant recipients are not routinely tested. show that heart transplant recipients exhibited an elevation of Creactive protein and procalcitonin. These inflammatory biomarkers have proven to be useful as prognostic factors for poor outcomes in COVID-19. 50 Furthermore, most cases presented absolute lymphopenia. This is a common finding during COVID-19 and has been independently associated with increased mortality. 50 In our study, nearly half of the patients received hydroxychloroquine, azithromycin, or lopinavir/ritonavir as pharmacological therapy for COVID-19. These drugs were initially recommended for COVID-19 management due to the evidence of in vitro inhibition of SARS-CoV-2 replication and to the positive results from some observational studies. 51, 52 However, recent large randomized controlled trials have shown that none of these drugs have a clinically beneficial effect on COVID-19 patients; thus, they are not currently used. 53, 54 In addition, the use of hydroxychloroquine and azithromycin has been associated with an increased risk of QT interval prolongation predisposing to ventricular arrhythmias. 55 30 ; however, further details were not provided. The actual incidence of allograft rejection in solid-organ recipients with COVID-19 is currently unknown because endomyocardial biopsy is not routinely performed in these patients. Nevertheless, an unusually high rate of acute allograft rejection after COVID-19 in kidney transplant recipients was reported in a small case series. 59 Whether the allograft rejection is due to SARS-CoV-2 infection through direct and/or indirect mechanisms, 60 or is related to the change in immunosuppressive therapy is still largely unclear. The short-term mortality of heart transplant recipients with COVID-19 was 23% considering ambulatory and hospitalized patients. Our results were similar to those reported in solid-organ transplant recipients as shown in a recent meta-analysis, which found an all-cause mortality of 18.6%. 61 Among the possible causes that may explain this increased F I G U R E 2 Modification of baseline immunosuppression treatment in heart transplant recipients with COVID-19. mTOR, mammalian target of rapamycin; COVID-19, coronavirus disease 2019 mortality are older age, male predominance, high prevalence of comorbidities, and the use of chronic immunosuppressive therapy. Our systematic review has some limitations. First, we included 22 case reports in our study. Although publication and selection bias may arise because only data from patients with unusual characteristics and poor outcomes may have been published, we have also included cohort studies. Second, while the majority of cases were from the in- Our review shows that heart transplant recipients with COVID-19 presented demographic and clinical features similar to the general population. The immunosuppressive regimen of calcineurin inhibitors, corticosteroids, and mTOR inhibitors was not modified in more than half of the patients. In contrast, antimetabolites were discontinued in half of the cases. Overall, we found a high short-term mortality in these patients. Nevertheless, given that our results were from case reports and cohorts, further prospective multicenter studies with larger samples are required to guide the clinical care of this population. None. None of the authors reported any conflicts of interest. Carlos Diaz-Arocutipa, Darla Carvallo-Castañeda, and Odalis Luis-Ybañez involved in concept/design. Carlos Diaz-Arocutipa, Darla Ybañez involved in data acquisition. Carlos Diaz-Arocutipa, Darla Carvallo-Castañeda, Odalis Luis-Ybañez, Marcos Pariona, Mercedes Rivas-Lasarte, and Jesús Álvarez-García involved in data analysis/interpretation. Carlos Diaz-Arocutipa, Darla Carvallo-Castañeda García critically revised the article. 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Carlos Diaz-Arocutipa https://orcid.org/0000-0002-5101-2832