This case-control study assesses data from a single center about the safety and effectiveness of COVID-19 vaccination among patients who received an orthotopic heart transplant.
Abstract
Importance
Orthotopic heart transplant (OHT) recipients are at increased risk for morbidity and mortality after SARS-CoV-2 infection. Although antibody response to COVID-19 vaccination is lower in solid organ transplant recipients, there has been no study assessing the safety and effectiveness of COVID-19 vaccination in OHT recipients.
Objective
To assess the safety and effectiveness of COVID-19 vaccination and associations with SARS-CoV-2 infection and clinical outcomes in a large population of adult OHT recipients.
Design, Setting, and Participants
This case-control study examined data from a US heart transplant program at a single center for all adult recipients of OHT who were followed up from January 15, 2021, through January 31, 2022.
Main Outcomes and Measures
The primary outcome was number of SARS-CoV-2 infections and related hospitalizations, intensive care unit (ICU) admissions, and deaths between vaccinated vs unvaccinated adult recipients of OHT.
Results
A total of 436 patients who received OHT were included in the study, of which 106 patients were infected with COVID-19. The mean (SD) age was 54 (17) years; 303 (69.5%) were men and 133 (30.5%) were women. There were 366 patients in the vaccinated cohort with 72 COVID-19 infections (19.7%), 15 hospitalizations (4.1%), 4 ICU admissions (1.1%), and 3 deaths (0.8%). There were 70 patients in the unvaccinated cohort with 34 COVID-19 infections (48.6%), 10 hospitalizations (14.3%), 3 ICU admissions (4.3%), and 3 deaths (4.3%). COVID-19 vaccination was associated with a lower risk of COVID-19 infection (risk ratio [RR], 0.41; 95% CI, 0.30-0.56), hospitalization (RR, 0.29; 95% CI, 0.14-0.61), and death (RR, 0.19; 95% CI, 0.05-0.82). Among the 366 vaccinated OHT recipients, there was no echocardiographic evidence of graft dysfunction, clinically significant rejection, or allosensitization at 6 months after they received the COVID-19 vaccine.
Conclusions and Relevance
Patients with OHT who are infected with SARS-CoV-2 are at greater risk of severe infection and death compared with immunocompetent individuals. COVID-19 vaccination was associated with fewer COVID-19 infections, hospitalizations, and deaths, with no heart transplant–specific adverse events. COVID-19 vaccination for all OHT recipients is of paramount importance.
Key Points
Question
Do COVID-19 vaccines provide protection against severe SARS-CoV-2 infection and death in heart transplant recipients?
Findings
In this case-control study, heart transplant recipients from a single center who were vaccinated against SARS-CoV-2 had significantly lower risk of COVID-19 infection, hospitalization, and death with no transplant-related safety concerns.
Meaning
Even though the immunogenic response to COVID-19 vaccination is lower in patients who receive a heart transplant, the vaccine appears to be safe and is associated with a lower risk of COVID-19 infection, hospitalization, and death, suggesting it is imperative that all heart transplant recipients obtain the COVID-19 vaccine.
Introduction
The ongoing COVID-19 pandemic has resulted in significant morbidity and mortality, particularly for patients with chronic medical conditions. Orthotopic heart transplant (OHT) recipients are at increased risk of SARS-CoV-2 infection because of chronic immunosuppression and frequent comorbid disease.1,2 SARS-CoV-2 infection in heart transplant recipients is associated with a high case fatality rate ranging from 10% to 35% and hospitalization rate ranging from 50% to 60%.2,3
The US Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for a a messenger RNA (mRNA) vaccine against COVID-19 on December 11, 2020. Transplant recipients were excluded from the initial safety studies of COVID-19 vaccines, and there was concern that transplant recipients may have suboptimal immunogenicity due to immunosuppression. Among solid organ transplant recipients who received the mRNA vaccines, investigators reported that an antibody response was found in only 14% to 17% after the first dose and 48% to 51% of transplant recipients after the second dose.4,5 Although the study did report that COVID-19 vaccines appear to be safe in transplant recipients, the implications of only partial antibody response to vaccination toward protection from COVID-19–related morbidity and mortality remain unknown.5 Therefore, we sought to assess the safety and effectiveness of COVID-19 vaccination in a large cohort of OHT recipients.
Methods
A single-center retrospective case-control study of 482 adult recipients of OHT was performed from March 23, 2020, through January 31, 2022. The Colorado Multiple Institutional Review Board approved the protocol for the retrospective review of medical records and analysis of echocardiographic studies.
On December 11, 2020, when the FDA issued the EUA for COVID-19 vaccines, all patients with OHT were encouraged by the transplant program to obtain vaccines as they were permitted by local public health authorities in prioritization schemes. Forty-six OHT recipients were infected with COVID-19 from March 23, 2020, to January 14, 2021 (before the availability and time frame for completing the vaccine series), and these patients were excluded from analysis. Starting January 15, 2021, the remaining 436 OHT recipients were divided into 2 groups, vaccinated and unvaccinated. The primary outcomes were number of COVID-19 infections and COVID-19–related hospitalizations, intensive care unit (ICU) admissions, and deaths. The diagnosis of COVID-19 was made through a positive test result using either a polymerase chain reaction test or an antigen test. Patients were considered vaccinated at 2 weeks after their second dose of mRNA vaccine (BNT162b2 [Pfizer-BioNTech] or mRNA-1273 [Moderna]) or 2 weeks after receiving the adenovirus vector vaccine (JNJ-78436735 [Johnson & Johnson]). In addition, a similar exploratory analysis was performed among OHT recipients who had not been infected with COVID-19 by August 12, 2021 (the date the FDA approved booster vaccine doses in patients who were immunocompromised), to determine the association between booster doses and COVID-19 infections and outcomes.
To assess heart transplant–specific vaccine safety, data were collected to assess cardiac graft function before and after COVID-19 vaccination as well as after COVID-19 infection, including echocardiographic parameters, B-type natriuretic peptide (BNP) levels, measures of allosensitization, and incidence of cellular and vascular rejection. Because patients with OHT are seen routinely every 6 months, these data were collected from the clinic visits immediately before and after vaccine administration.
The Fisher exact test (for categorical variables) and unpaired t test (for continuous variables) were used to compare differences between groups, and risk ratios with 95% CIs were calculated. Paired t tests were used to compare differences among measures of graft function before and after COVID-19 vaccination and infection. Statistical analysis was performed with Graph Pad Prism (version 9.2.0).
Results
Of the 482 total OHT recipients who were followed up from March 23, 2020, through January 14, 2021, 46 patients were infected with COVID-19 prior to vaccine availability. The individual case morbidity and mortality rate during this initial phase of the pandemic was high: 17 patients (37%) required hospitalization, 8 (17%) required ICU admission, and 7 (15%) died. These 46 patients were excluded from further analysis, leaving 436 OHT recipients who were followed up from January 15, 2021, until January 31, 2022. There were 366 patients in the vaccinated cohort and 70 patients in the unvaccinated cohort. Unvaccinated patients were younger, had better kidney function, and had slightly higher diastolic blood pressure but were otherwise similar in demographics, comorbidities, immunosuppression regimen, and cardiac medications (Table 1).
Table 1. Baseline Characteristics of Vaccinated vs Unvaccinated Heart Transplant Recipients.
| Variable | Heart transplant recipients, No. (%) | P value | |
|---|---|---|---|
| Vaccinated (n = 366) | Unvaccinated (n = 70) | ||
| Demographicsa | |||
| Age, mean (SD), y | 56 (16) | 45 (18) | <.01 |
| Men | 255 (70) | 48 (69) | .88 |
| Women | 111 (30) | 22 (31) | .88 |
| African American and Black | 28 (8) | 4 (6) | .80 |
| Asian | 11 (3) | 1 (1) | .70 |
| Hispanic and Latinx | 43 (12) | 7 (10) | .84 |
| Native Hawaiian | 6 (2) | 1 (1) | .99 |
| White | 278 (76) | 57 (81) | .36 |
| Time from transplant, mean (SD), y | 14 (10) | 12 (9) | .12 |
| Comorbidities | |||
| Hypertension | 284 (78) | 53 (76) | .76 |
| Diabetes | 124 (34) | 18 (26) | .21 |
| Pulmonary disease | 73 (20) | 12 (17) | .74 |
| Obstructive sleep apnea | 69 (19) | 9 (13) | .31 |
| Obesity | 87 (24) | 20 (29) | .45 |
| Chronic kidney disease stage ≥3 | 245 (67) | 31 (49) | <.01 |
| Clinical characteristics, mean (SD) | |||
| Height, cm | 166.9 (22.4) | 172.6 (70) | .10 |
| Weight, kg | 78.4 (20.6) | 84.7 (43.1) | .29 |
| Body mass indexb | 26.6 (5.8) | 26.9 (5.8) | .61 |
| Heart rate, bpm | 89 (16) | 87 (15) | .20 |
| Blood pressure, mm Hg | |||
| Systolic | 125 (16) | 125 (15) | .43 |
| Diastolic | 78 (10) | 83 (11) | <.01 |
| Left ventricular ejection fraction, % | 61.6 (7.3) | 61.3 (6.6) | .85 |
| Glomerular filtration rate, mL/min/1.73 m2 | 53 (19) | 61 (20) | .02 |
| Immunosuppression medications | |||
| Glucocorticoids | 95 (26) | 11 (16) | .07 |
| Calcineurin inhibitor | 333 (91) | 66 (94) | .48 |
| Mycophenolate | 300 (82) | 58 (83) | .99 |
| mTOR inhibitor | 117 (32) | 14 (20) | .05 |
| Cardiac medications | |||
| Aspirin | 347 (95) | 66 (94) | .77 |
| Statin | 340 (93) | 60 (86) | .06 |
| ACE inhibitor, ARB, or ARNI | 256 (70) | 48 (69) | .89 |
| Anticoagulant | 40 (11) | 3 (4) | .12 |
| COVID-19 vaccine | |||
| BNT162b2 (Pfizer-BioNTech) | 201 (55) | NA | NA |
| mRNA-1273 (Moderna) | 155 (42) | NA | NA |
| JNJ-78436735 (Johnson & Johnson) | 10 (3) | NA | NA |
| Booster dose receivedc | 198 (54) | NA | NA |
Abbreviations: ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor–neprilysin inhibitor; bpm, beats per minute; mTOR, mammalian target of rapamycin; NA, not applicable.
Race and ethnicity data were collected from electronic health records.
Calculated as weight in kilograms divided by height in meters squared.
Booster includes any additional dose of a vaccine after the initial vaccine series was completed.
There were 106 patients infected with COVID-19, at a median time after transplant of 11.4 years (range, 7 months to 34 years). Among the 366 patients in the vaccinated cohort, there were 72 COVID-19 infections (19.7%), with 15 hospitalizations (4.1%), 4 ICU admissions (1.1%), and 3 deaths (0.8%). Among the 70 patients in the unvaccinated cohort, there were 34 COVID-19 infections (48.6%), and the morbidity and mortality rate was high, with 10 (14.3%) requiring hospitalization, 3 (4.3%) requiring ICU admission, and 3 deaths (4.3%). The vaccinated cohort of patients with OHT was less likely to have a COVID-19 infection, hospitalization, or death (Table 2).
Table 2. COVID-19 Infections and Outcomes Among Vaccinated and Unvaccinated Heart Transplant Recipients.
| Variable | Heart transplant recipients, No. (%) | Risk ratio (95% CI) | |
|---|---|---|---|
| Vaccinated (n = 366) | Unvaccinated (n = 70) | ||
| COVID-19 infections | 72 (19.7) | 34 (48.6) | 0.41 (0.30-0.56)a |
| COVID-19 hospitalizations | 15 (4.1) | 10 (14.3) | 0.29 (0.14-0.61)a |
| ICU admissions | 4 (1.1) | 3 (4.3) | 0.26 (0.07-1.01) |
| Deaths | 3 (0.8) | 3 (4.3) | 0.19 (0.05-0.82)b |
Abbreviation: ICU, intensive care unit.
P < .001 for comparison of vaccinated vs unvaccinated patients.
P < .05 for comparison of vaccinated vs unvaccinated patients.
Among the patients with OHT who received the COVID-19 vaccine, at 6 months postvaccination there were no significant changes in mean (SD) left ventricular ejection fraction (prevaccine, 57% [18%], vs postvaccine, 57% [17%]), left ventricular wall thickness (prevaccine, 10 [2] mm, vs postvaccine, 10 [2] mm), and BNP levels (prevaccine, 139 [322] pg/mL, vs postvaccine, 117 [163] pg/mL). No patients developed allograft rejection or increases in levels of panel reactive antibody or donor-specific antibody. Similarly, among the 72 patients who were infected with COVID-19 after receiving the vaccine, the mean (SD) left ventricular ejection fraction (pre–COVID-19 infection/vaccine, 58% [10%], vs post–infection/vaccine, 61% [9%]), wall thickness (pre–infection/vaccine, 10 [2] mm, vs post–vaccine/infection, 10 [2] mm), and BNP levels (pre–infection/vaccine, 161 [178] pg/mL, vs post–infection/vaccine, 128 [97] pg/mL) were unchanged compared with the baseline prevaccine measures. There were no cases of rejection or allosensitization.
By August 12, 2021, there were 356 vaccinated patients with OHT who had not been infected with COVID-19. These patients were followed up until January 31, 2022, in an exploratory analysis of the association of a COVID-19 booster dose with outcomes. Among this cohort, 193 patients received a booster dose at a mean (SD) of 30 (30) days after August 12, 2021, and 163 patients did not. There were no apparent differences in COVID-19 infections, hospitalizations, ICU admissions, or death associated with receipt of a booster dose (Table 3).
Table 3. COVID-19 Infections and Outcomes Among Heart Transplant Recipients Who Did and Did Not Receive a Booster Dose.
| Variable | Heart transplant recipients, No. (%) | Risk ratio (95% CI) | |
|---|---|---|---|
| Booster (n = 193) | No booster (n = 163) | ||
| COVID-19 infections | 38 (19.7) | 24 (14.7) | 1.34 (0.84-2.13) |
| COVID-19 hospitalizations | 6 (3.1) | 5 (3.1) | 1.01 (0.33-3.08) |
| ICU admissions | 2 (1.0) | 2 (1.2) | 0.84 (0.15-4.75) |
| Deaths | 1 (0.5) | 2 (1.2) | 0.42 (0.06-3.20) |
Abbreviation: ICU, intensive care unit.
Discussion
Despite data suggesting that patients receiving solid organ transplant have a less robust antibody response to COVID-19 vaccines and the need for booster doses,4,5,6 this large observational study shows that COVID-19 vaccination is associated with fewer symptomatic SARS-CoV-2 infections, hospitalizations, and deaths. The individual case-fatality rate among unvaccinated OHT recipients during the initial months of the pandemic prior to vaccine availability was 15% in this cohort. Despite the development of newer COVID-19 treatments, among unvaccinated patients with OHT, the case-fatality rate in this cohort of 9% is much higher than that observed among vaccinated OHT recipients (4% in this cohort) and the general population. This suggests that a strategy of only treating COVID-19 infections after they are acquired by OHT recipients is unlikely to be sufficient to lessen the burden of COVID-19 in this population.
In addition, despite theoretical safety concerns for vaccination resulting in immune activation and subsequent organ rejection or myocarditis, we found no evidence of allograft dysfunction, clinically significant rejection, or allosensitization in this large cohort of vaccinated patients with OHT. The combination of these findings support professional society and individual transplant center recommendations that OHT recipients receive COVID-19 vaccines.7
Limitations
There are several limitations to this study. This was a single-center analysis, and there have been temporal and geographic differences in COVID-19 transmission rates, strains, and incidence since the start of the pandemic. In addition, patients received their vaccines at varying time points throughout the study but were included in the vaccinated cohort for purposes of analysis once they were fully vaccinated, even if that occurred toward the end of the follow-up period. This method of analysis would have only decreased the association of vaccination with beneficial outcomes. Furthermore, because booster vaccines were only recently approved, we were unable to show a beneficial association of booster doses with outcomes, though this lack of benefit may be related to shorter exposure times after booster administration, a small sample size, and changing viral variants. Further, we did not include any patients who received the COVID-19 vaccine before their OHT to know if pretransplant vaccination prior to immunosuppression confers a greater immune response and subsequent higher level of protection from infection.
Conclusions
Patients with OHT who are infected with SARS-CoV-2 are at greater risk of severe infection and death compared with immunocompetent individuals. In this study, COVID-19 vaccination was associated with fewer symptomatic COVID-19 infections, hospitalizations, and deaths, with no heart transplant–specific adverse events. In light of more infectious COVID-19 variants and ongoing high rates of transmission, COVID-19 vaccination for all OHT recipients is of paramount importance.
References
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