Received: 29 March 2021 Revised: 4 June 2021 Accepted: 7 June 2021 DOI: 10.1111/ctr.14390 ORIGINAL ARTICLE COVID-19 in heart transplant recipients during February–August 2020: A systematic review Carlos Diaz-Arocutipa1,2,3 Darla Carvallo-Castañeda3,4 Odalis Luis-Ybañez3,5 Marcos Pariona6 Mercedes Rivas-Lasarte7,8 Jesús Álvarez-García8,9,10 1 Vicerrectorado de Investigación, Universidad San Ignacio de Loyola, Lima, Peru Abstract 2 Programa de Atención Domiciliaria The coronavirus disease 2019 (COVID-19) pandemic represents a major concern (PADOMI) – EsSalud, Lima, Peru in immunosuppressed patients such as heart transplant recipients. Therefore, we 3 Asociación para el Desarrollo de la Investigación Estudiantil en Ciencias de la performed a systematic review to summarize the clinical features, treatment, and Salud (ADIECS), Lima, Peru outcomes of heart transplant recipients with COVID-19. We searched electronic 4 Puesto de Salud Pacaycasa, Ministerio de databases from inception to January 11, 2021. Thirty-nine articles (22 case reports and Salud, Ayacucho, Peru 5 17 cohorts) involving 415 patients were included. The mean age was 59.9 ± 15.7 years Facultad de Medicina de San Fernando, Universidad Nacional Mayor de San Marcos, and 77% of patients were men. In cohort studies including outpatients and inpatients, Lima, Peru the hospitalization rate was 77%. The most common symptoms were fever (70%) and 6 Departamento de Cardiología, Hospital cough (67%). Inflammatory biomarkers (C-reactive protein and procalcitonin) were Nacional Edgardo Rebagliati Martins, Lima, Peru above the normal range. Forty-eight percent of patients presented with severe or criti- 7 Unidad de Insuficiencia Cardiaca Avanzada y cal COVID-19. Hydroxychloroquine (54%), azithromycin (14%), and lopinavir/ritonavir Trasplante Cardiaco, Hospital Universitario (14%) were the most commonly used drugs. Forty-nine percent of patients discontin- Puerta de Hierro, Madrid, Spain 8 Centro de Investigación Biomédica en Red de ued the baseline regimen of antimetabolites. In contrast, 59% and 73% continued the Enfermedades Cardiovasculares (CIBERCV), same regimen of calcineurin inhibitors and corticosteroids, respectively. Short-term Madrid, Spain mortality among cohorts limited to inpatients was 25%. Our review suggests that heart 9 Unidad de Insuficiencia Cardíaca Avanzada. Servicio de Cardiología del Hospital transplant recipients with COVID-19 exhibited similar demographic and clinical fea- Universitario Ramón y Cajal, Madrid, Spain tures to the general population. However, the prognosis was poor in these patients. 10 Universidad Autónoma de Barcelona, Barcelona, Spain KEYWORDS COVID-19, heart transplantation, systematic review Correspondence Carlos Diaz-Arocutipa, Vicerrectorado de Investigación, Universidad San Ignacio de Loyola, Av. La Fontana 550, La Molina, Lima 00012, Peru. Email: carlosdiaz013@gmail.com 1 INTRODUCTION approved vaccines are increasingly available, many countries are cur- rently facing new waves of cases with even higher transmission rates Coronavirus disease 2019 (COVID-19) is caused by Severe Acute Res- than the initial peak of the pandemic.3 piratory Syndrome Coronavirus 2 (SARS-CoV-2) and was first detected Heart transplant recipients are a particularly vulnerable population in December 2019 in Wuhan, China.1 Since then, it has spread world- for worse outcomes given the state of immunosuppression and their wide, causing significant morbidity and mortality to date.2 Although high prevalence of comorbidities. Moreover, SARS-CoV-2 has proven © 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Clinical Transplantation. 2021;1–10. wileyonlinelibrary.com/journal/ctr 1 2 DIAZ-AROCUTIPA ET AL . its virulence extends beyond the respiratory system, and as such, car- using a standardized data extraction form that was previously piloted. diovascular involvement of COVID-19, in particular, has been reported Any disagreement was resolved by a third author (Carlos Diaz- by way of myocardial injury,4–6 heart failure,7 and even cardiogenic Arocutipa). If additional data was needed, the corresponding author shock.8 was contacted through e-mail. We extracted the following data: first To date, several centers across the world have reported the clinical author name, publication year, country, study design, sample size, age, impact of COVID-19 in these patients. Therefore, we performed a sys- sex, comorbidities, clinical features, diagnostic methods, treatment, tematic review to summarize the clinical features, treatment, and out- and outcomes. comes of heart transplant recipients with COVID-19. 2.5 Statistical analysis 2 METHODS Frequencies and proportions were used to summarize categorical vari- This review was reported according to the PRISMA (Preferred Report- ables. Means ± standard deviations or median (interquartile range) ing Items for Systematic Reviews and Meta-Analyses) statement.9 were used for continuous variables. Data were presented according to study type (case reports and cohorts) and type of population (inpa- 2.1 Search strategy tients and outpatients/inpatients). All analyses were performed using the statistical software R 3.6.3 (www.r-project.org). 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 3 RESULTS “heart transplantation”. The search was conducted from inception to October 1, 2020, with an update until January 11, 2021. The complete 3.1 Study selection search strategy is available in Table S1. In addition, we conducted a hand-searching of reference lists of all included studies and relevant Our electronic search retrieved 730 articles. After the removal of reviews to identify further studies. duplicates, 352 articles were screened by title and abstract, and of those, 299 articles were excluded. After full-text evaluation of 53 remaining articles, 14 were excluded. The reasons for exclusion were 2.2 Eligibility criteria as follows: type of article (commentary [four], other population [four], and review [one]), or incomplete data (five). Finally, 39 articles (22 case The inclusion criteria were the following: (i) studies that included adult reports and 17 cohorts) were selected (Figure 1).10–48 All studies patients (≥18 years of age) and (ii) studies that reported data on clini- included as cohorts included all known cases of COVID-19 at their cal features, treatment, or outcomes of heart transplant recipients with heart transplant centers during each study period. Characteristics of COVID-19 diagnosed by reverse transcription-polymerase chain reac- the included studies are summarized in Table 1. tion (RT-PCR). There were no restrictions on language or publication date. We excluded animal studies, abstracts, editorials, commentaries, systematic reviews, and narrative reviews. 3.2 Demographics and clinical features A total of 415 heart transplant patients with COVID-19 were included. 2.3 Study selection Baseline characteristics of the study population are summarized in Table 2. The mean age was 59.9 ± 15.7 years and 77% of patients were We downloaded all articles from electronic search to EndNote X8 men. Most cases (35%) were from the United States of America. In software and duplicate records were removed. Titles and abstracts addition to immunosuppression, hypertension (69%), diabetes (36%), were independently screened by three review authors (Carlos Diaz- and chronic kidney disease (36%) were the most common comorbidi- Arocutipa, Darla Carvallo-Castañeda, and Odalis Luis-Ybañez) to iden- ties. The mean body mass index 26.7 ± 5.6 kg/m2 (n = 168 patients). tify relevant studies. Likewise, the same review authors independently The mean time from transplantation to COVID-19 diagnosis was 8.8 ± assessed the full-text of each eligible study and registered reasons for 9 years (n = 409 patients). In 95% of cases, the only transplanted organ the exclusion. Any disagreement on title/abstract and full-text selec- was the heart, while in the rest, it was the heart plus the kidney or tion was resolved by consensus. lungs. The baseline immunosuppressive regimen was mainly composed by antimetabolites (mycophenolate mofetil, mycophenolic acid, or aza- 2.4 Data extraction thioprine) in 69%, calcineurin inhibitors (tacrolimus or cyclosporine) in 89%, and corticosteroids (prednisone) in 59% of patients. A minority The information from each study was independently extracted by two of cases (20%) were managed in the outpatient setting. The median review authors (Darla Carvallo-Castañeda and Odalis Luis-Ybañez) of the average duration of hospitalization was 12.4 (5.7–22.7) days DIAZ-AROCUTIPA ET AL . 3 FIGURE 1 Flow diagram of study selection across eight studies. The most common symptoms included fever 3.4 Management and outcomes (70%), cough (67%), and dyspnea (61%). Six cases were reported as asymptomatic.13,14 One patient died at home by cardiac arrest and no Table 2 shows that the most used drugs for the treatment of data on the post-mortem examination was provided.10 According to COVID-19 were hydroxychloroquine (54%), azithromycin (14%), and the World Health Organization criteria for the classification of COVID- lopinavir/ritonavir (14%). One patient22 who received hydroxychloro- 19 severity,49 34% and 14% of patients were classified as severe and quine presented QT interval prolongation on the electrocardiogram critical, respectively. No cases of protracted or relapsing clinical dis- but did not develop ventricular arrhythmias. Tocilizumab was given in ease were reported. Detailed information about each included study 8% of cases and other IL-6 inhibitors were not used. can be found in Table S2. In addition, the results according to study type The main changes of the maintenance immunosuppressive regimen (case reports and cohorts) and type of population (inpatients and out- during the COVID-19 infection were as follows: discontinuation (49%) patients/inpatients) are presented in Table 2. or no modification (41%) of antimetabolites, no modification (59%) or reduction (28%) of calcineurin inhibitors, no modification (73%) of cor- ticosteroids, and no modification (80%) of mTOR inhibitors (Figure 2). 3.3 Laboratory and imaging findings Three patients30,34,41 developed allograft rejection after COVID-19 infection. Of those, only one was re-transplanted.41 Information about The mean white blood cell count was 6100 ± 3500 cells/µl the change of baseline immunosuppressive regimen during COVID- (n = 228 patients), the mean lymphocytes was 958 ± 803 cells/µl 19 infection was only available in one case of rejection. Lima et al.34 (n = 250 patients), the mean C-reactive protein was 82 ± 124 mg/L reported that mycophenolate mofetil was discontinued and tacrolimus (n = 180 patients), and the mean procalcitonin was 1.7 ± 2.9 ng/ml was reduced. No patients received rituximab for the treatment of (n = 162 patients) (Table 2). In only 28% of patients, the chest imaging rejection. Soquet et al.41 reported a patient who developed lymphoma (X-ray or computed tomography) was normal. and was treated with four cycles of rituximab two months prior to 4 DIAZ-AROCUTIPA ET AL . TA B L E 1 Comparison of case series of heart transplant recipients with COVID-19 Study Year Country Date of inclusion Sample size Mortality Cohorts Ahluwalia et al. 2020 USA March 10–May 15 5 20% Al-Darzi et al. 2020 USA March 13–May 1 6 0% Bottio 1 et al. 2020 Italy February 21–June 30 47 30% Bottio 2 et al. 2020 Italy July 1–August 30 6 0% Caraffa et al. 2020 Italy Not reported 6 33% Cavagna et al. 2020 Italy February 5 40% Coll et al. 2020 Spain February 20–July 13 69 22% Felldin et al. 2020 Sweden February 21–June 22 6 33% Garcia-Cosio et al. 2020 Spain February 28–April 28 13 23% Hoek et al. 2020 The Netherlands Not reported 4 25% Iacovoni et al. 2020 Italy February–March 26 27% Kates et al. 2020 USA March 7–May 14 57 14% Ketcham et al. 2020 USA March 21–April 22 13 15% Latif et al. 2020 USA March 1–April 24 28 25% Lima et al. 2020 USA March 14–April 19 5 0% Rivinius et al. 2020 Germany March–June 21 33% Singhvi et al. 2020 USA March 1–May 15 22 23% Trapani et al. 2020 Italy February 21–June 22 53 36% a Case reports 2020 Several countries January–June 23 4% Abbreviations: USA, United States of America. a Italy, Germany, USA, China, France, Switzerland, Russia, and Turkey. SARS-CoV-2 infection. This patient presented with critical COVID- 4.2 Clinical profile of heart transplant patients 19 and required heart re-transplantation due to allograft dysfunction. with COVID-19 We found four cases of prolonged positive RT-PCR testing.34,41,42,46 Twenty-one percent of patients developed acute respiratory distress We found that COVID-19 in heart transplant recipients shares some syndrome, 16% required invasive mechanical ventilation, and 23% demographic and clinical characteristics with the general population in were admitted to the intensive care unit. Overall, 23% of patients terms of male predominance, type of comorbidities, and clinical pre- died during hospitalization. The mortality rate based on cohorts that sentation. Whether heart transplant recipients are more vulnerable included only inpatients was 25%. In addition, the mortality rate of to acquiring COVID-19 due to their chronic immunosuppression state cohorts that included outpatients and inpatients was 24% (Table 2). remains unclear. However, the prevalence of SARS-CoV-2 infection may be underestimated because asymptomatic transplant recipients 4 DISCUSSION are not routinely tested. As occurs in non-transplanted patients with COVID-19, our results 4.1 Main findings show that heart transplant recipients exhibited an elevation of C- reactive protein and procalcitonin. These inflammatory biomarkers To our knowledge, this is the first systematic review that summarizes have proven to be useful as prognostic factors for poor outcomes in clinical data from the largest international series of heart transplant COVID-19.50 Furthermore, most cases presented absolute lymphope- recipients with COVID-19. The mean age was nearly 60 years and most nia. This is a common finding during COVID-19 and has been inde- cases were men. The majority of cases were managed in the inpatient pendently associated with increased mortality.50 While this finding setting and almost half of the patients had mild or moderate COVID-19. may be explained by the SARS-CoV-2 infection itself, the myelotoxicity The regimen of calcineurin inhibitors, corticosteroids, and mammalian related to the immunosuppressive therapy in transplant recipients may target of rapamycin (mTOR) inhibitors were not modified in more than also be involved. Although the role of these biomarkers in heart trans- half of the patients. In contrast, antimetabolites were discontinued in plant recipients with COVID-19 remains to be determined, it could be half of the cases. One-fifth of the patients required admission to the considered during the risk stratification of hospitalized patients with intensive care unit. Overall, the short-term mortality was 23%. COVID-19. DIAZ-AROCUTIPA ET AL . 5 TA B L E 2 Characteristics of heart transplant recipients with COVID-19 Cohorts Cohorts (outpatients and Total Case reports Cohorts (inpatients) inpatients) Characteristics n/N b % n/N b % n/Nb % n/Nb % n/Nb % Age (years)a 59.9 ± 15.7, 53.3 ± 14.4, n = 23 60.3 ± 15.8, 58.9 ± 18.5, n = 48 60.6 ± 15.4, n = 415 n = 392 n = 344 Male 278/362 77% 18/23 78% 260/339 77% 40/48 83% 220/291 76% Country USA 147/415 35% 11/23 48% 136/392 35% 18/48 37% 118/344 34% Germany 24/415 6% 3/23 13% 21/392 5% 21/48 44% 0/344 0% China 2/415 .5% 2/23 9% 0/392 0% 0/48 0% 0/344 0% Italy 145/415 35% 2/23 9% 143/392 36% 5/48 10% 138/344 40% France 2/415 .5% 2/23 9% 0/392 0% 0/48 0% 0/344 0% Switzerland 1/415 .2% 1/23 4% 0/392 0% 0/48 0% 0/344 0% Russia 1/415 .2% 1/23 4% 0/392 0% 0/48 0% 0/344 0% Turkey 1/415 .2% 1/23 4% 0/392 0% 0/48 0% 0/344 0% Spain 82/415 20% 0/23 0% 82/392 21% 0/48 0% 82/344 24% Sweden 6/415 1.5% 0/23 0% 6/392 2% 0/48 0% 6/344 2% The Netherlands 4/415 1% 0/23 0% 4/392 1% 4/48 8% 0/344 0% Comorbidities Immunosuppression 272/272 100% 16/16 100% 256/256 100% 39/39 100% 217/217 100% Hypertension 189/272 69% 10/16 62% 179/256 70% 31/39 79% 148/217 68% Diabetes 99/272 36% 7/16 44% 92/256 36% 17/39 43% 75/217 34% Chronic kidney disease 99/272 36% 8/16 50% 91/256 35% 19/39 49% 72/217 33% Chronic lung disease 22/272 8% 1/16 6% 21/256 8% 4/39 10% 17/189 6% BMI (kg/m ) 2 a 26.7 ± 5.6, n = 168 38.2 ± 11.2, n = 3 26.5 ± 5.5, n = 165 26.9 ± 6.9, n = 39 26.4 ± 5, n = 126 Time since heart transplantation 8.8 ± 9, n = 409 6.3 ± 6.8, n = 22 9 ± 9.2, n = 387 8.3 ± 9.4, n = 43 9.1 ± 9.3, n = 344 (years)a Transplanted organ Heart 395/415 95% 18/23 78% 377/392 96% 44/48 91% 333/344 97% Heart + kidney 18/415 4% 5/23 22% 13/392 3% 3/48 6% 10/344 3% Heart + lung 2/415 .5% 0/23 0% 2/392 .5% 1/48 2% 1/344 .3% Baseline immunosuppressive regimen Antimetabolites 238/346 69% 17/21 81% 221/325 68% 32/43 74% 189/282 67% Calcineurin inhibitors 314/351 89% 21/21 100% 293/330 89% 41/48 85% 252/282 89% Corticosteroids 203/346 59% 13/21 62% 190/325 58% 27/43 56% 163/282 58% mTOR inhibitors 73/346 21% 4/21 19% 69/325 21% 10/43 23% 59/282 21% Clinical setting Inpatient 304/382 79% 19/21 90% 285/361 79% 27/27 100% 258/334 77% Outpatient 78/382 20% 2/21 9% 76/361 21% 0/27 0% 76/334 23% Symptoms Fever 193/276 70% 15/21 71% 178/255 70% 29/39 74% 149/216 69% Cough 163/242 67% 12/21 57% 151/221 68% 31/39 79% 120/182 66% Dyspnea 138/226 61% 13/21 62% 125/205 61% 31/39 79% 94/166 57% Gastrointestinal 105/276 38% 8/21 38% 97/255 38% 16/39 41% 81/216 37% Myalgias 53/166 32% 6/21 28% 47/145 32% 0/5 0% 47/140 33% (Continues) 6 DIAZ-AROCUTIPA ET AL . TA B L E 2 (Continued) Cohorts Cohorts (outpatients and Total Case reports Cohorts (inpatients) inpatients) Characteristics n/N b % n/N b % n/Nb % n/Nb % n/Nb % Laboratory White blood cells (cells/µL)a 6100 ± 3500, 5200 ± 200, n = 11 6200 ± 3600, 9200 ± 4800, 5500 ± 3300, n = 228 n = 217 n = 39 n = 178 Lymphocytes (cells/µL)a 958.1 ± 803.5, 939 ± 427, n = 11 959 ± 820.9, 1018 ± 618, n = 39 989 ± 886, n = 200 n = 250 n = 239 C-reactive protein (mg/L)a 81.7 ± 124, n = 180 119 ± 213, n = 17 77.8 ± 115, n = 163 110 ± 90, n = 26 86 ± 120, n = 137 Procalcitonin (ng/ml) a 1.7 ± 2.9, n = 162 2.3 ± 6, n = 8 1.7 ± 2.8, n = 154 4.4 ± 6.7, n = 39 .7 ± 1.55, n = 115 Abnormal chest X-ray or CT 176/243 72% 15/17 88% 161/226 71% 37/43 86% 124/183 68% Treatment Hydroxychloroquine 175/323 54% 13/21 62% 162/302 54% 22/48 46% 140/254 55% Azythromycin 47/323 14% 4/21 19% 43/302 14% 9/48 19% 34/254 13% Lopinavir/ritonavir 44/323 14% 3/21 14% 41/302 13% 0/48 0% 41/254 16% Remdesivir 4/323 1% 1/21 5% 3/302 1% 1/48 2% 2/201 1% Tocilizumab 26/323 8% 4/21 19% 22/302 7% 4/48 8% 18/201 9% Modification of immunosuppressive regimen Antimetabolites No modification 40/98 41% 5/15 33% 35/83 42% 8/30 27% 27/53 51% Reduction 29/127 23% 1/15 7% 28/112 25% 0/30 0% 28/82 34% Discontinuation 48/98 49% 8/15 53% 40/83 48% 22/30 73% 18/53 34% Increase 1/98 1% 1/15 7% 0/83 0% 0/30 0% 0/53 0% Calcineurin inhibitors No modification 47/79 59% 11/19 58% 36/60 60% 7/17 41% 29/43 67% Reduction 42/152 28% 5/19 26% 37/133 28% 10/17 59% 27/116 23% Discontinuation 5/79 6% 1/19 5% 4/60 7% 0/17 0% 4/43 9% Increase 1/79 1% 1/19 5% 0/60 0% 0/17 0% 0/43 0% Initiation 1/79 1% 1/19 5% 0/60 0% 0/17 0% 0/43 0% Corticosteroids No modification 50/68 73% 5/11 45% 45/57 79% 16/25 64% 29/32 91% Discontinuation 1/68 1% 1/11 9% 0/57 0% 0/25 0% 0/32 0% Increase 4/68 6% 2/11 18% 2/57 3% 1/25 4% 1/32 3% Reduction 1/68 1% 1/11 9% 0/57 0% 0/25 0% 0/32 0% Change from oral to intravenous 12/68 18% 2/11 18% 10/57 17% 8/25 32% 2/32 6% mTOR inhibitors No modification 20/25 80% 1/3 33% 19/22 86% 8/9 89% 11/13 85% Discontinuation 5/25 20% 2/3 67% 3/22 14% 1/9 11% 2/13 15% Reduction 3/37 8% 0/3 0% 3/34 9% 0/9 0% 3/25 12% COVID-19 severity Mild 28/91 31% 8/23 35% 20/68 29% 4/10 40% 16/58 27% Moderate 30/91 33% 4/23 17% 26/68 38% 4/10 40% 22/58 38% Severe 49/144 34% 6/23 26% 43/121 35% 0/10 0% 43/111 39% Critical 20/144 14% 5/23 22% 15/121 12% 2/10 20% 13/111 12% (Continues) DIAZ-AROCUTIPA ET AL . 7 TA B L E 2 (Continued) Cohorts Cohorts (outpatients and Total Case reports Cohorts (inpatients) inpatients) Characteristics n/N b % n/N b % n/Nb % n/Nb % n/Nb % Acute respiratoty distress 42/196 21% 5/23 22% 37/173 21% 2/10 20% 35/163 21% syndrome Non-invasive oxygen 100/212 47% 11/23 48% 89/189 47% 11/31 35% 78/158 49% supplementation Mechanical ventilation 50/315 16% 4/23 17% 46/292 16% 15/44 34% 31/248 12% Intensive care unit admission 86/374 23% 7/23 30% 79/351 22% 23/44 52% 56/307 18% Outcome Discharged 256/405 63% 18/23 78% 238/382 62% 26/48 54% 212/334 63% Remained hospitalized 20/405 5% 2/23 9% 18/382 5% 8/48 47% 10/334 3% Ambulatory 35/405 9% 2/23 9% 33/382 9% 2/48 4% 31/334 9% Dead 94/405 23% 1/23 4% 93/382 24% 12/48 25% 81/334 24% Abbreviations: USA, United States of America; COVID-19, coronavirus disease 2019; CT, computed tomography; mTOR, mammalian target of rapamycin. a Mean ± standard deviation. b Data are n/total (denominator varies among variables according to available information). 4.3 Management therapy (with the maintenance of corticosteroids) should be consid- ered in infected patients who have not had recent episodes of rejec- In our study, nearly half of the patients received hydroxychloroquine, tion, especially, in severe cases. This disparity in the recommendations azithromycin, or lopinavir/ritonavir as pharmacological therapy for reflects the need for more studies to clarify what is the best approach COVID-19. These drugs were initially recommended for COVID-19 to immunosuppressive therapy for these patients. management due to the evidence of in vitro inhibition of SARS-CoV- Interestingly, three patients developed allograft rejection after 2 replication and to the positive results from some observational SARS-CoV-2 infection. Lima et al.34 reported one case of mild acute studies.51,52 However, recent large randomized controlled trials have cellular rejection (at two weeks after COVID-19 diagnosis) based shown that none of these drugs have a clinically beneficial effect on on the preponderance of lymphocytic infiltrate without evidence of COVID-19 patients; thus, they are not currently used.53,54 In addition, myocardial injury. Soquet et al.41 reported another case of severe the use of hydroxychloroquine and azithromycin has been associated allograft dysfunction leading to heart retransplantation, although it with an increased risk of QT interval prolongation predisposing to ven- was ultimately considered as chronic rejection. The last case of acute tricular arrhythmias.55 Overall, only a few patients received remdesivir cellular rejection was reported by Kates et al.30 ; however, further as part of COVID-19 treatment. Of note, none of the trials on drugs for details were not provided. The actual incidence of allograft rejection in COVID-19 included immunocompromised individuals. solid-organ recipients with COVID-19 is currently unknown because Our review shows that the modification of the baseline immunosup- endomyocardial biopsy is not routinely performed in these patients. pressive regimen varied across studies. Overall, 72% of antimetabo- Nevertheless, an unusually high rate of acute allograft rejection after lites, 34% of calcineurin inhibitors, 2% of corticosteroids, and 88% COVID-19 in kidney transplant recipients was reported in a small case of mTOR inhibitors were reduced or discontinued during COVID- series.59 Whether the allograft rejection is due to SARS-CoV-2 infec- 19 infection. Without supporting clinical data to guide decision- tion through direct and/or indirect mechanisms,60 or is related to the making, the appropriate approach to immunosuppression management change in immunosuppressive therapy is still largely unclear. is unknown. Currently, several international transplant societies have provided some mixed recommendations to guide the management of immunosuppression during COVID-19. The International Society of 4.4 Prognosis of heart transplant patients with Heart and Lung Transplantation56 recommends holding antimetabo- COVID-19 lites and mTOR inhibitors in COVID-19 patients with moderate or severe disease. In contrast, the British Transplantation Society57 pro- The short-term mortality of heart transplant recipients with COVID-19 poses discontinuing antimetabolites in all cases and, in patients requir- was 23% considering ambulatory and hospitalized patients. Our results ing hospitalization, recommends reducing or stopping calcineurin were similar to those reported in solid-organ transplant recipients as inhibitors and increasing corticosteroids. The American Society of shown in a recent meta-analysis, which found an all-cause mortality of Transplantation58 only suggests that reduction of immunosuppressive 18.6%.61 Among the possible causes that may explain this increased 8 DIAZ-AROCUTIPA ET AL . 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 comor- assess the impact of changes in immunosuppressive therapy on clinical bidities, and the use of chronic immunosuppressive therapy. outcomes. 4.5 Limitations 5 CONCLUSION Our systematic review has some limitations. First, we included 22 Our review shows that heart transplant recipients with COVID-19 case reports in our study. Although publication and selection bias may presented demographic and clinical features similar to the general arise because only data from patients with unusual characteristics population. The immunosuppressive regimen of calcineurin inhibitors, and poor outcomes may have been published, we have also included corticosteroids, and mTOR inhibitors was not modified in more than cohort studies. Second, while the majority of cases were from the in- half of the patients. In contrast, antimetabolites were discontinued hospital setting, others were from a surveillance program of COVID- in half of the cases. Overall, we found a high short-term mortality in 19 in cohorts of solid-organ transplant recipients. Therefore, our pool these patients. Nevertheless, given that our results were from case of patients may not represent the entire population of heart trans- reports and cohorts, further prospective multicenter studies with plant recipients with SARS-CoV-2 infection, since asymptomatic and larger samples are required to guide the clinical care of this population. mild cases could be underestimated leading to overestimation of mor- bidity and mortality. Third, most of the studies were from the “first ACKNOWLEDGMENTS wave” and the drugs used for the treatment of COVID-19 (hydroxy- None. chloroquine, azithromycin, and lopinavir/ritonavir) are no longer rec- ommended. Fourth, information about patients was incomplete in a CONFLICT OF INTEREST high proportion of studies, especially concerning COVID19 sever- None of the authors reported any conflicts of interest. ity and modification on immunosuppressive regimen. Fifth, we were unable to compare our findings to the general population because, only AUTHOR CONTRIBUTIONS transplant recipients were evaluated in the included studies. Finally, Carlos Diaz-Arocutipa, Darla Carvallo-Castañeda, and Odalis Luis- since only aggregated data were available, it was not possible to Ybañez involved in concept/design. Carlos Diaz-Arocutipa, Darla DIAZ-AROCUTIPA ET AL . 9 Carvallo-Castañeda, and Odalis Luis-Ybañez involved in data acqui- 15. Caraffa R, Bagozzi L, Fiocco A, et al. Coronavirus disease 2019 sition. Carlos Diaz-Arocutipa, Darla Carvallo-Castañeda, Odalis Luis- (COVID-19) in the heart transplant population: a single-centre expe- rience. Eur J Cardiothorac Surg. 2020;58(5):899-906. Ybañez, Marcos Pariona, Mercedes Rivas-Lasarte, and Jesús Álvarez- 16. Cavagna L, Seminari E, Zanframundo G, et al. Calcineurin inhibitor- García involved in data analysis/interpretation. Carlos Diaz-Arocutipa, based immunosuppression and COVID-19: results from a multi- Darla Carvallo-Castañeda, and Odalis Luis-Ybañez drafted the article. disciplinary cohort of patients in Northern Italy. Microorganisms. Carlos Diaz-Arocutipa, Darla Carvallo-Castañeda, Odalis Luis-Ybañez, 2020;8(7):977. 17. Çınar G. Heart transplant recipient survivor from COVID-19: the first Marcos Pariona, Mercedes Rivas-Lasarte, and Jesús Álvarez-García case of Turkey. Turk Gogus Kalp Damar Cerrahisi Derg. 2020;28(4):674- critically revised the article. Carlos Diaz-Arocutipa, Darla Carvallo- 679. Castañeda, Odalis Luis-Ybañez, Marcos Pariona, Mercedes Rivas- 18. Coll E, Fernández-Ruiz M, Sánchez-Álvarez JE, et al. COVID-19 Lasarte, and Jesús Álvarez-García approved the article. in transplant recipients: the Spanish experience. Am J Transplant. 2020;21(5):1825-1837. 19. Decker A, Welzel M, Laubner K, et al. Prolonged SARS-CoV-2 shedding DATA AVAILABILITY STATEMENT and mild course of COVID-19 in a patient after recent heart transplan- The data that support the findings of this study are available from the tation. Am J Transplant. 2020;20(11):3239-3245. corresponding author upon reasonable request. 20. Felldin M, Søfteland JM, Magnusson J, et al. Initial report from a Swedish High-Volume Transplant Center after the first wave of The ORCID COVID-19 pandemic. Transplantation. 2020;105(1):108-114. 21. Fung M, Chiu CY, Devoe C, et al. Clinical outcomes and serologic Carlos Diaz-Arocutipa https://orcid.org/0000-0002-5101-2832 response in solid organ transplant recipients with COVID-19: a case series from the United States. Am J Transplant. 2020;20(11):3225- REFERENCES 3233. 1. 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