J Cardiovasc Thorac Res. 14(4):258-262. doi: 10.34172/jcvtr.2022.31583Short Communication
COVID-19 in heart transplant recipients
Sepideh Taghavi 1
, Hoda Raffiei Jelodar 2, *, Ali Rafati 1, Nasim Naderi 2, Marzieh Mirtajaddini 2, Ahmad Amin 2, Leili Valizadeh 2, Razieh Omidvar 2, Monireh Kamali 2, Soroush Naseh 3
1Heart Valve Disease Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
2Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
3University of Auckland, Auckland, New Zealand
*Corresponding Author: Hoda Raffiei Jelodar, Email: h.b.raffiei@gmail.com
Abstract
Introduction:
After solid organ transplantation, patients require lifelong immunosuppressive medication, increasing susceptibility to COVID-19. We evaluated the clinical outcomes of heart transplant recipients in patients with COVID-19.
Methods:
We enrolled twenty-two COVID-19 cases of adult heart transplantation from February 2020 to September 2021.
Results:
The most common symptoms in patients were fever and myalgia. The death occurred in 3 (13.6 %).
Conclusion:
Although heart transplantation mortality may increase in the acute rejection phase concomitant with COVID-19, immunosuppressive dose reduction may not be necessary for all heart transplant patients with COVID-19.
Keywords: SARS-CoV-2, COVID-19, Heart Transplantation, Immunosuppressive Medication
Copyright
© 2022 The Author(s)
This is an open access article distributed under the terms of the Creative Commons Attribution License (
http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Introduction
The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) pandemic has posed unprecedented health challenges. Patients receiving solid organ transplantation require lifelong immunosuppression, thus more susceptible to COVID-19.1 There are few data on the prevalence and clinical features of COVID-19 in heart transplant patients. Heart transplant recipients have comorbidities such as diabetes mellitus (DM), hypertension (HTN), chronic kidney disease (CKD), obesity, coronary heart disease, coronary allograft vasculopathy (CAV), and chronic lung diseases, making them prone to severe diseases.2 While managing immunosuppressive medication in individuals with severe COVID-19 is uncertain,3 the relationship between COVID-19 and heart transplant rejection needs attention. Therefore, we evaluated the clinical outcomes of heart transplantation in patients with confirmed COVID-19.
Materials and Methods
Study design
We conducted observational research at Rajaie Heart Center (RHC), Iran. From February 2020 to September 2021, this research included all adult heart transplant patients with positive nasopharyngeal reverse transcriptase-polymerase chain reaction (RT-PCR) testing for SARS-CoV-2.
We gathered data from medical records on hospitalized patients and outpatients. Patients’ clinical and laboratory data, immunosuppression, and early antiviral treatments were documented.
Patients were classified as having a mild infection (requiring just outpatient treatment), a moderate infection (requiring admission to the general inpatient ward), or a severe disease (mechanical ventilation, intensive care unit (ICU) admission, or death).
Statistical analysis
Continuous variables were expressed as mean ± standard deviation. Categorical data were provided as frequency and were compared using the Chi-square test. Significance was defined as a two-sided p-value of < 0.05. SPSS software version 24 was used for analysis.
Results
The detailed characteristics of the patients are shown in Table 1. Table 2 summarizes on-admission characteristics, risk factors, and laboratory data. Although SARS-CoV-2 PCR was negative in five individuals, a chest computed tomography (CT) scan suggested COVID-19.
Table 1.
Characteristics of the patients.
|
Patients
|
Age, years after transplant
|
Admission
|
Risk factors
|
Symptoms
|
Immunosuppression therapy
|
Rejection in COVID-19 infection
|
COVID-19 treatment
|
Adverse effects
|
Immunosuppression dosage change
|
Intubation, Death
|
|---|
| 1 | 34, 4 | Yes | DM, CKD, Obesity | dyspnea, fever, nausea and vomiting | prednisolone, mycophenolate mofetil, sirolimus, cyclosporine | Yes | prednisolone, IVIG, ATG | No | increased prednisolone (methylprednisolone pulse) and mycophenolate mofetil* | No, No |
| 2 | 18, 2 | Yes | Obesity, DM, HTN | Myalgia and bone pain, fever | prednisolone, mycophenolate mofetil,
tacrolimus | No | remdesivir, dexamethasone | No | increased dexamethasone | No, No |
| 3 | 42, 5 | No | Obesity | fever, myalgia, and bone pain | prednisolone, mycophenolate mofetil,
tacrolimus | No | No | No | No | No, No |
| 4 | 32, 2 | Yes | HTN | dyspnea, myalgia and bone pain, fever | prednisolone, mycophenolate mofetil,
tacrolimus | No | remdesivir, dexamethasone | No | No | No, No |
| 5 | 31, 4 | Yes | No | fever, myalgia and bone pain | prednisolone, mycophenolate mofetil,
tacrolimus, sirolimus | No | remdesivir, dexamethasone | No | decreased sirolimus | No, No |
| 6 | 51, 2 | Yes | HTN, DM, CKD | cough, fever, myalgia and bone pain | prednisolone, mycophenolate mofetil,
cyclosporine | No | remdesivir, dexamethasone | Yes (leukopenia) | decreased mycophenolate mofetil, GCSF added | No, No |
| 7 | 16, 2 | Yes | DM, Obesity, HTN | cough, dyspnea, fever | mycophenolate mofetil,
tacrolimus | Yes | methylprednisolone | No | increased tacrolimus and mycophenolate mofetil* | Yes, Yes† |
| 8 | 33, 2 | Yes | DM | abdominal pain, nausea and vomiting | prednisolone, mycophenolate mofetil,
tacrolimus | Yes | methylprednisolone | No | increased tacrolimus | No, Yes† |
| 9 | 45, 3 | Yes‡ | Obesity, HTN | atypical chest pain, fever, myalgia and bone pain | mycophenolate mofetil,
tacrolimus | No | prednisolone | No | increased tacrolimus | No, No |
| 10 | 43, 4 | Yes | Anemia, DM, CKD | fever, myalgia and bone pain, cough | mycophenolate mofetil,
cyclosporine | No | remdesivir, dexamethasone | Yes (leukopenia) | decreased mycophenolate mofetil, GCSF added | No, No |
| 11 | 30, 6 | Yes | DM, HTN, Obesity, CKD | fever, chills, myalgia and bone pain, weakness, dyspnea, nausea and vomiting | prednisolone, mycophenolate mofetil, cyclosporine, sirolimus | No | remdesivir, dexamethasone | Yes (creatinine rise, leukopenia) | Sirolimus discontinued, decreased mycophenolate mofetil, decreased cyclosporine | No, No |
| 12 | 23, 5 | Yes | CAV | weakness, abdominal pain, nausea and vomiting | prednisolone, mycophenolate mofetil, sirolimus | No | remdesivir, prednisolone | No | increased prednisolone | No, No |
| 13 | 42, 3 | Yes | Obesity | fever, myalgia and bone pain | prednisolone, mycophenolate mofetil,
tacrolimus | No | remdesivir, dexamethasone | Yes (leukopenia) | decreased mycophenolate mofetil, GCSF added | No, No |
| 14 | 39, 3 | Yes‡ | Obesity, DM | cough, fever, myalgia and bone pain, dyspnea, nausea and vomiting, abdominal pain | prednisolone, mycophenolate mofetil, tacrolimus, sirolimus | No | remdesivir, dexamethasone | Yes (leukopenia) | decreased sirolimus and mycophenolate mofetil | No, No |
| 15 | 33, 2 weeks | Yes | DM | No symptom | prednisolone, mycophenolate mofetil, tacrolimus | No | No | No | No | No, No |
| 16 | 39, 2 months | Yes | CKD | dyspnea | mycophenolate mofetil,
tacrolimus | Yes | IVIG, hydrocortisone, hydroxyl chloroquine | Yes (leukopenia, liver failure) | mycophenolate mofetil and tacrolimus discontinued | Yes, Yes |
| 17 | 37, 2 | Yes | Obesity | dyspnea, fever, myalgia and bone pain | prednisolone, mycophenolate mofetil,
tacrolimus | No | remdesivir, dexamethasone | Yes (leukopenia) | decreased mycophenolate mofetil, GCSF added | No, No |
| 18 | 39, 4 | No | DM | myalgia and bone pain, abdominal pain | prednisolone, mycophenolate mofetil,
tacrolimus | No | remdesivir | No | No | No, No |
| 19 | 35, 3 | No | No | cough | prednisolone, mycophenolate mofetil,
cyclosporine | No | No | No | decreased mycophenolate mofetil | No, No |
| 20 | 30, 3 | Yes | No | fever, myalgia and bone pain, cough | prednisolone, mycophenolate mofetil,
tacrolimus | No | dexamethasone | No | No | No, No |
| 21 | 33, 3 | Yes | Obesity | fever, myalgia and bone pain, cough | mycophenolate mofetil,
tacrolimus | No | remdesivir, dexamethasone | No | No | No, No |
| 22 | 34, 2 | Yes | HTN | fever, myalgia and bone pain, abdominal pain | prednisolone, mycophenolate mofetil,
tacrolimus | No | remdesivir, dexamethasone | No | decreased tacrolimus | No, No |
Abbreviations: ATG, anti-thymocyte globulin; CAV, coronary allograft vasculopathy; CKD, chronic kidney disease; DM, diabetes mellitus; HTN, hypertension; GCSF, granulocyte colony-stimulating factor; IVIG, intravenous immunoglobulin.
* increased mycophenolate mofetil dosage due to acute rejection.
†acute rejection.
‡experienced two episodes of COVID-19.
Table 2.
On-admission characteristics, risk factors, and laboratory data.
|
Variables
|
Mean±SD
|
| Age (years) | 34.95 ± 8.97 |
| BMI (kg/m2) | 26.23 ± 5.2 |
| Years after transplant | 3.09 ± 1.57 |
| Hypertension* | 7 (31.8%) |
| Chronic kidney disease* | 5 (22.7%) |
| Obesity (BMI > 25)* | 10 (45.4%) |
| Diabetes Mellitus * | 10 (45.4%) |
| Mycophenolate mofetil use * | 22 (100%) |
| Tacrolimus use * | 16 (72.7%) |
| Cyclosporine use * | 5 (22.7%) |
| Sirolimus use * | 5 (22.7%) |
| Ejection fraction (%) | 42.5 ± 1.2 |
| FBS (mg/dL) | 125.55 ± 47.2 |
| Albumin (g/L) | 36.9 ± 11.46 |
| D-dimer (μg/mL) | 1.10 ± 1.5 |
| Troponin (ng/dL) | 0.67 ± 1.35 |
| Pro-BNP (pg/mL) | 342.5 ± 608.62 |
| CRP (mg/dL) | 32.22 ± 44.37 |
| WBC (cell/mm3) | 7449.47 ± 6211.51 |
| Hemoglobin (g/dL) | 12.52 ± 2.73 |
| Platelet (103/mm3) | 175.94 ± 56.83 |
| Blood urea nitrogen (mg/dL) | 17.84 ± 8.54 |
| Creatinine (mg/dL) | 1.23 ± 0.49 |
| AST (IU/L) | 33.52 ± 31.72 |
| ALT (IU/L) | 41.68 ± 57.78 |
| ALP (IU/L) | 147.76 ± 75.04 |
| LDH (IU/L) | 571.1 ± 309.81 |
| Bilirubin (mg/dL) | 1.72 ± 1.59 |
Abreviations: ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate transaminase; BMI, body mass index; BNP, brain natriuretic peptide; CRP, c-reactive protein; FBS, fasting blood sugar; IU, international unit; LDH, lactate dehydrogenase; SD, standard deviation; WBC, white blood cell.
-All values are reported as mean ± SD unless otherwise stated.
* Number (%).
Fever (16 (72.7%)) was the most common symptom in our patients. A summary of the patents’ outcomes is demonstrated in Table 3. Three patients (13.6%) died in this research (Table 3), one with severe gastrointestinal complications (patient 8) and suspicion of acute rejection. He died of sudden cardiac death one day after discharge. Another patient suspected of acute rejection and experiencing cough and dyspnea was treated with methylprednisolone. Three days after discharge, he was readmitted with COVID-19 to the ICU and ultimately expired (patient 7). The last patient, with early COVID-19 after the transplant, had a severe clinical course with sepsis and multiple end-organ failures, which led to death (patient 16) (Table 1).
Table 3.
Patients’ outcomes and adverse events.
|
Variables
|
Number of patients, n (%)
|
| Hospitalized patients | 19 (86.36%) |
| Fever | 16 (72.7%) |
| Myalgia and bone pain | 15 (68.2%) |
| Cough | 7 (31.8%) |
| Dyspnea | 7 (31.8%) |
| Abdominal pain | 5 (22.7%) |
| Positive troponin | 5 (22.7%) |
| Positive Pro-BNP (Pro-BNP > 125ng/dl) | 6 (27.3%) |
| Moderate to severe right ventricular dysfunction | 6 (27.3%) |
| Pericardial effusion | 2 (9%) |
| Change in immunosuppression therapy | 16 (72.7%) |
| Steroid treatment for COVID-19 | 18 (81.8%) |
| Remdesivir use | 13 (59%) |
| GCSF due to leukopenia | 4 (18.2%) |
| Rejection during COVID-19 infection | 4 (18.1%) |
| Intubation and ICU admission | 2 (9%) |
| Death | 3 (13.6%) |
Abreviations: GCSF, granulocyte colony-stimulating factor; ICU, intensive care unit.
Due to severe leukopenia, immunosuppressive discontinuation and mycophenolate mofetil dosage reduction was required in 2 (9%) and 7 (31.8%) patients, respectively (Table 1).
The COVID-19 risk factors were not significantly different between survivors and non-survivors (Table 4).
Table 4.
Comparison of the risk factors in COVID-19 non-survivors and survivors.
|
Risk factors
|
COVID-19 non-survivors (n=3), n (%)
|
COVID-19 survivors (n=19), n (%)
|
P
Value
|
| Diabetes mellitus | 2 (66.7%) | 9 (47.36%) | 0.534 |
| Hypertension | 1 (33.3%) | 6 (31.57%) | 0.951 |
| Obesity | 1 (33.3%) | 9 (47.36%) | 0.650 |
| Chronic kidney disease | 1 (33.3%) | 4 (21%) | 0.222 |
The analyses were performed using the Chi-square test. P value < 0.05
Discussion
COVID-19 is more common in solid organ transplant recipients compared to the general population. This increased prevalence is probably due to increased susceptibility to infections due to their chronic use of immunosuppressants.4
Our study’s mortality rate (13.6%) was lower compared to previous studies (29.7%, 28.75%, and 22.7% in the studies by Bottio et al, Rivinius et al and Singhvi et al respectively).4-6 This could be due to the higher prevalence of risk factors or older patients in the mentioned studies.
Pereira et al evaluated 90 individuals undergoing solid organ transplantation with COVID-19, 9 of whom were heart transplant recipients. Overall, 76% of patients were hospitalized, and 18% died. The mortality rate was similar, but ICU admission was lower than ours, possibly because their study was conducted in the early days of COVID-19, in which the appropriate treatments were not widely known.7
In the present study, only 2 patients (9%) required immunosuppressive discontinuation due to sepsis and severe leukopenia, while 7 patients (31.8%) required mycophenolate mofetil dosage reduction due to leukopenia. Even though we did not reduce the dosage in other patients, we witnessed a reduced death rate. As a result, maintaining antimetabolite dosage in individuals without leukopenia seems reasonable. Discontinuation of these medicines solely due to COVID-19, without adverse effects or complications, is not recommended.
Conclusion
As RHC is a large tertiary heart transplant center, we had a high rate of COVID-19 in our transplant patients. Our patients were younger than in other studies, and the other risk factors were less prevalent. This may explain why our patients had lower rates of mortality and ICU admission
Acknowledgements
We would like to thank the participants of this study.
Author Contributions
Conceptualization: Sepideh Taghavi.
Methodology: Sepideh Taghavi, Nasim Naderi, Hoda Raffiei Jelodar.
Validation: Marzieh Mirtajaddini, Ahmad Amin.
Formal Analysis: Hoda Raffiei Jelodar, Ali Rafati.
Investigation: Leili Valizadeh, Razieh Omidvar, Monireh Kamali.
Resources: Sepideh Taghavi, Marzieh Mirtajaddini, Nasim Naderi.
Data Curation: Monireh Kamali, Soroush Naseh, Leili Valizadeh, Razieh Omidvar.
Writing—Original Draft Preparation: Sepideh Taghavi, Hoda Raffiei Jelodar, Ali Rafati.
Writing—Review and Editing: Ali Rafati, Nasim Naderi, Ahmad Amin, Soroush Naseh.
Supervision: Sepideh Taghavi.
Project Administration: Hoda Raffiei Jelodar.
Funding Acquisition: not applicable.
Funding
None.
Ethical Approval
The RHC’s ethics review committee approved this study with the ethics code IR.RHC.REC.1400.076. We adhered to the declaration of Helsinki in this investigation. All patient records were kept confidential.
Competing Interests
The authors declare no conflict of interest.
References
- Infection in solid-organ transplant recipients. N Engl J Med 2007; 357(25):2601-14. doi: 10.1056/NEJMra064928 [Crossref]
- COVID-19 in hospitalized lung and non-lung solid organ transplant recipients: a comparative analysis from a multicenter study. Am J Transplant 2021; 21(8):2774-84. doi: 10.1111/ajt.16692 [Crossref]
- Systematic review of immunosuppressant guidelines in the COVID-19 pandemic. Ther Adv Drug Saf 2021; 12:2042098620985687. doi: 10.1177/2042098620985687 [Crossref]
- COVID-19 in heart transplant recipients: a multicenter analysis of the Northern Italian outbreak. JACC Heart Fail 2021; 9(1):52-61. doi: 10.1016/j.jchf.2020.10.009 [Crossref]
- COVID-19 among heart transplant recipients in Germany: a multicenter survey. Clin Res Cardiol 2020; 109(12):1531-9. doi: 10.1007/s00392-020-01722-w [Crossref]
- Challenges in heart transplantation during COVID-19: a single-center experience. J Heart Lung Transplant 2020; 39(9):894-903. doi: 10.1016/j.healun.2020.06.015 [Crossref]
- COVID-19 in solid organ transplant recipients: initial report from the US epicenter. Am J Transplant 2020; 20(7):1800-8. doi: 10.1111/ajt.15941 [Crossref]