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Vinay Nair, Nicholas Jandovitz, Kenar D Jhaveri, Ernesto Molmenti, COVID-19 and solid organ transplant outcomes, Nephrology Dialysis Transplantation, Volume 35, Issue 8, August 2020, Pages 1444–1446, https://doi.org/10.1093/ndt/gfaa207
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The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread out from a single city in China to most of the world. Patients found to be at higher risk for infection and adverse outcome include those with comorbid conditions and the elderly. Until recently, data on immunocompromised kidney transplant patients have been lacking. Given their diminished T-cell immunity, transplant recipients are expected to be at higher risk for severe bacterial and viral infections. This would suggest that they are at higher risk for infection and mortality from coronavirus disease 2019 (COVID-19). However, recent publications report great variations in the clinical course and mortality of COVID-19 in solid organ transplant recipients [1–9]. It is unclear whether these differences are related to study methods, treatment choices or variables associated with patient populations among different transplant centers. Studies with low to no mortality may support a beneficial immunosuppressive effect on the cytokine storm described with COVID-19, whereas those with high mortality rates may further enhance the deleterious association of immunosuppression and infections.
To better understand the true risk of COVID-19 in transplant recipients, we sought to collect and summarize existing experiences. We performed a PubMed search for all published manuscripts that included kidney transplantation and COVID-19. We excluded studies with fewer than five kidney transplant recipients, and those without data reported. We reviewed dates of publication, number of patients, types of solid organ transplantation including kidney transplantation, patient demographics, comorbid conditions, baseline immunosuppression, changes in immunosuppression, presenting symptoms, hospital course, treatments administered, follow-up time and patient mortality.
Of 13 articles from February to 1 May 2020, 4 were excluded for having fewer than five kidney transplant recipients. A summary of the nine analyzed manuscripts is detailed in Table 1. Two studies [6, 8] included kidney, non-kidney and combined kidney and other organ transplantations. Most studies included patients with a median age in the 50s with primary comorbidities of hypertension and diabetes (in addition to the primary organ failure). The majority of patients were male. COVID-19 diagnosis was confirmed via laboratory testing in all studies. Calcineurin inhibitors, antimetabolites and prednisone were among the types of immunosuppression used. The majority of patients included in the studies were on tacrolimus, mycophenolate and prednisone. The presenting symptoms were usually fever, cough and dyspnea, and less commonly diarrhea. Immunosuppression was either reduced or discontinued upon diagnosis in all studies. Not all authors reported on intensive care unit admission and intubation, potentially introducing a bias in the severity of illness.
Table 1. Summary of COVID-19 in Transplantation Studies from February to May 2020
| Studies . | Zhang et al. [1] . | Zhu et al. [2] . | Banerjee et al. [3] . | Alberici et al. [4] . | Columbia University Kidney Transplant Program [5] . | Fernandez-Ruiz et al. [6] . | Akalin et al. [7] . | Pereira et al. [8] . | Nair et al. [9] . |
|---|---|---|---|---|---|---|---|---|---|
| Date accepted for publication | March 20 | March 23 | March 27 | April 3 | April 6 | April 16 | April 24 | April 24 | April 29 |
| Number of patients | 5 | 10 | 7 | 20 | 15 | 18 | 36 | 90 | 10 |
| Organ transplanted | Kidney | Kidney | Kidney | Kidney | Kidney | Kidney 8, liver 6, heart 4 | Kidney | Kidney 46, lung 17, liver 13, heart 9, heart-kidney 3, liver-kidney 1, pancreas-kidney 1 | Kidney |
| Age, years | 38 (38–47) | 50 (32–54) | 54 (45–69) | 59 (51–64) | 51 (28–72) | 71 (64–75) | 60 (32–77) | 57 (46–68) | 57 (47–67) |
| Male gender, % | 80 | 80 | 57 | 80 | 67 | 77.8 | 72 | 59 | 60 |
| Time from transplant | 352 days (170–929) | 6–12 months | 3 to ≥1 year | 13 years (9–20) | 4.1 years (3.2–9.8) | 9.3 years (6.3–16.5) | No info | 6.64 years (2.87–10.61) | 7.7 years (3.5–12.6) |
| Comorbidities, % | |||||||||
| HTN | 40 | 50 | 86 | 85 | – | 56 | 94 | 64 | 100 |
| DM | 20 | – | 43 | 15 | – | – | 69 | 46 | 80 |
| CKD | – | – | – | – | – | – | – | 63 | – |
| CLD | – | – | – | – | – | – | – | 19 | – |
| CHD | – | 20 | – | 15 | – | 17 | 17 | – | – |
| Cirrhosis | – | – | – | – | – | 28 | – | – | – |
| Baseline immuno suppression, % | |||||||||
| Tacrolimus | 80 | 90 | 86 | 95 | 93 | 56 | 97 | 86 | 90 |
| Cyclosporine | – | 10 | – | – | – | 17 | – | – | – |
| MMF/MPA | 100 | 90 | 71 | 70 | 80 | 61 | 86 | 72 | 100 |
| Prednisone | – | 70 | 71 | 65 | 67 | 67 | 94 | 59 | 70 |
| mTOR | – | – | – | 10 | – | 22 | – | 7 | 20 |
| Belatacept | – | – | – | – | 13 | – | – | 6 | – |
| Presenting symptoms, % | |||||||||
| Fever | – | 90 | 71 | 100 | 87 | 83 | 58 | 70 | 90 |
| Cough | 100 | 90 | 57 | 50 | 60 | 67 | 53 | 60 | 80 |
| Dyspnea | – | 90 | 86 | 5 | 27 | 61 | 44 | 43 | 30 |
| Diarrhea | – | 30 | 14 | 15 | 20 | 22 | 22 | 31 | 20 |
| Fatigue | 60 | 90 | – | – | 27 | – | – | 28 | 50 |
| ICU admission | 0 | – | 57 | 20 | – | 11 | – | 34 (23/68) | 50 |
| Intubation/ mechanical ventilation | 0 | 0 | 29 | 10 | 27 | 11 | 39 (11/28) | 35 (24/68) | 44 (4/9) |
| Immuno suppression reduced/ discontinued | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes |
| Treatment(s), % | |||||||||
| HCQ | – | – | – | 95 | 87 | 72,a 8 in combo with LPV/r | 86 (24/28) | 91 (62/68) | 100 (9/9) |
| Azithromycin | – | – | – | – | 60 | – | 46 (13/28) | 66 (45/68) | 100 (9/9) |
| Remdesivir | – | – | – | – | – | – | – | 3 (2/68) | – |
| Tocilizumab | – | – | – | 30 | 7 | 6 | 7 (2/28) | 21 (14/68) | – |
| Leronlimab | – | – | – | – | – | – | 21 (6/28) | – | – |
| Oseltamivir | 100 | 20 | 14 | – | – | – | – | – | – |
| Follow-up, days | 29 (27–31) | – | – | – | 7 (3–11) | 18 (14.5–22) | 21 (14–28) | 20 (14–24) | 25 (11–26) |
| Mortality | 0 | 10 | 14 | 25 | 7 | 28 | 28 | 24 | 30 |
| Studies . | Zhang et al. [1] . | Zhu et al. [2] . | Banerjee et al. [3] . | Alberici et al. [4] . | Columbia University Kidney Transplant Program [5] . | Fernandez-Ruiz et al. [6] . | Akalin et al. [7] . | Pereira et al. [8] . | Nair et al. [9] . |
|---|---|---|---|---|---|---|---|---|---|
| Date accepted for publication | March 20 | March 23 | March 27 | April 3 | April 6 | April 16 | April 24 | April 24 | April 29 |
| Number of patients | 5 | 10 | 7 | 20 | 15 | 18 | 36 | 90 | 10 |
| Organ transplanted | Kidney | Kidney | Kidney | Kidney | Kidney | Kidney 8, liver 6, heart 4 | Kidney | Kidney 46, lung 17, liver 13, heart 9, heart-kidney 3, liver-kidney 1, pancreas-kidney 1 | Kidney |
| Age, years | 38 (38–47) | 50 (32–54) | 54 (45–69) | 59 (51–64) | 51 (28–72) | 71 (64–75) | 60 (32–77) | 57 (46–68) | 57 (47–67) |
| Male gender, % | 80 | 80 | 57 | 80 | 67 | 77.8 | 72 | 59 | 60 |
| Time from transplant | 352 days (170–929) | 6–12 months | 3 to ≥1 year | 13 years (9–20) | 4.1 years (3.2–9.8) | 9.3 years (6.3–16.5) | No info | 6.64 years (2.87–10.61) | 7.7 years (3.5–12.6) |
| Comorbidities, % | |||||||||
| HTN | 40 | 50 | 86 | 85 | – | 56 | 94 | 64 | 100 |
| DM | 20 | – | 43 | 15 | – | – | 69 | 46 | 80 |
| CKD | – | – | – | – | – | – | – | 63 | – |
| CLD | – | – | – | – | – | – | – | 19 | – |
| CHD | – | 20 | – | 15 | – | 17 | 17 | – | – |
| Cirrhosis | – | – | – | – | – | 28 | – | – | – |
| Baseline immuno suppression, % | |||||||||
| Tacrolimus | 80 | 90 | 86 | 95 | 93 | 56 | 97 | 86 | 90 |
| Cyclosporine | – | 10 | – | – | – | 17 | – | – | – |
| MMF/MPA | 100 | 90 | 71 | 70 | 80 | 61 | 86 | 72 | 100 |
| Prednisone | – | 70 | 71 | 65 | 67 | 67 | 94 | 59 | 70 |
| mTOR | – | – | – | 10 | – | 22 | – | 7 | 20 |
| Belatacept | – | – | – | – | 13 | – | – | 6 | – |
| Presenting symptoms, % | |||||||||
| Fever | – | 90 | 71 | 100 | 87 | 83 | 58 | 70 | 90 |
| Cough | 100 | 90 | 57 | 50 | 60 | 67 | 53 | 60 | 80 |
| Dyspnea | – | 90 | 86 | 5 | 27 | 61 | 44 | 43 | 30 |
| Diarrhea | – | 30 | 14 | 15 | 20 | 22 | 22 | 31 | 20 |
| Fatigue | 60 | 90 | – | – | 27 | – | – | 28 | 50 |
| ICU admission | 0 | – | 57 | 20 | – | 11 | – | 34 (23/68) | 50 |
| Intubation/ mechanical ventilation | 0 | 0 | 29 | 10 | 27 | 11 | 39 (11/28) | 35 (24/68) | 44 (4/9) |
| Immuno suppression reduced/ discontinued | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes |
| Treatment(s), % | |||||||||
| HCQ | – | – | – | 95 | 87 | 72,a 8 in combo with LPV/r | 86 (24/28) | 91 (62/68) | 100 (9/9) |
| Azithromycin | – | – | – | – | 60 | – | 46 (13/28) | 66 (45/68) | 100 (9/9) |
| Remdesivir | – | – | – | – | – | – | – | 3 (2/68) | – |
| Tocilizumab | – | – | – | 30 | 7 | 6 | 7 (2/28) | 21 (14/68) | – |
| Leronlimab | – | – | – | – | – | – | 21 (6/28) | – | – |
| Oseltamivir | 100 | 20 | 14 | – | – | – | – | – | – |
| Follow-up, days | 29 (27–31) | – | – | – | 7 (3–11) | 18 (14.5–22) | 21 (14–28) | 20 (14–24) | 25 (11–26) |
| Mortality | 0 | 10 | 14 | 25 | 7 | 28 | 28 | 24 | 30 |
All data presented as median (IQR) unless otherwise noted. CHD: coronary heart disease; CKD: chronic kidney disease; CLD: chronic lung disease; DM: diabetes; ICU: intensive care unit; HCQ: hydroxychloroquine; HTN: hypertension; LPV/r: lopinavir/ritonavir; MMF: mycophenolate mofetil; MPA: mycophenolic acid; mTOR: mammalian target of rapamycin; –, not recorded.
Table 1. Summary of COVID-19 in Transplantation Studies from February to May 2020
| Studies . | Zhang et al. [1] . | Zhu et al. [2] . | Banerjee et al. [3] . | Alberici et al. [4] . | Columbia University Kidney Transplant Program [5] . | Fernandez-Ruiz et al. [6] . | Akalin et al. [7] . | Pereira et al. [8] . | Nair et al. [9] . |
|---|---|---|---|---|---|---|---|---|---|
| Date accepted for publication | March 20 | March 23 | March 27 | April 3 | April 6 | April 16 | April 24 | April 24 | April 29 |
| Number of patients | 5 | 10 | 7 | 20 | 15 | 18 | 36 | 90 | 10 |
| Organ transplanted | Kidney | Kidney | Kidney | Kidney | Kidney | Kidney 8, liver 6, heart 4 | Kidney | Kidney 46, lung 17, liver 13, heart 9, heart-kidney 3, liver-kidney 1, pancreas-kidney 1 | Kidney |
| Age, years | 38 (38–47) | 50 (32–54) | 54 (45–69) | 59 (51–64) | 51 (28–72) | 71 (64–75) | 60 (32–77) | 57 (46–68) | 57 (47–67) |
| Male gender, % | 80 | 80 | 57 | 80 | 67 | 77.8 | 72 | 59 | 60 |
| Time from transplant | 352 days (170–929) | 6–12 months | 3 to ≥1 year | 13 years (9–20) | 4.1 years (3.2–9.8) | 9.3 years (6.3–16.5) | No info | 6.64 years (2.87–10.61) | 7.7 years (3.5–12.6) |
| Comorbidities, % | |||||||||
| HTN | 40 | 50 | 86 | 85 | – | 56 | 94 | 64 | 100 |
| DM | 20 | – | 43 | 15 | – | – | 69 | 46 | 80 |
| CKD | – | – | – | – | – | – | – | 63 | – |
| CLD | – | – | – | – | – | – | – | 19 | – |
| CHD | – | 20 | – | 15 | – | 17 | 17 | – | – |
| Cirrhosis | – | – | – | – | – | 28 | – | – | – |
| Baseline immuno suppression, % | |||||||||
| Tacrolimus | 80 | 90 | 86 | 95 | 93 | 56 | 97 | 86 | 90 |
| Cyclosporine | – | 10 | – | – | – | 17 | – | – | – |
| MMF/MPA | 100 | 90 | 71 | 70 | 80 | 61 | 86 | 72 | 100 |
| Prednisone | – | 70 | 71 | 65 | 67 | 67 | 94 | 59 | 70 |
| mTOR | – | – | – | 10 | – | 22 | – | 7 | 20 |
| Belatacept | – | – | – | – | 13 | – | – | 6 | – |
| Presenting symptoms, % | |||||||||
| Fever | – | 90 | 71 | 100 | 87 | 83 | 58 | 70 | 90 |
| Cough | 100 | 90 | 57 | 50 | 60 | 67 | 53 | 60 | 80 |
| Dyspnea | – | 90 | 86 | 5 | 27 | 61 | 44 | 43 | 30 |
| Diarrhea | – | 30 | 14 | 15 | 20 | 22 | 22 | 31 | 20 |
| Fatigue | 60 | 90 | – | – | 27 | – | – | 28 | 50 |
| ICU admission | 0 | – | 57 | 20 | – | 11 | – | 34 (23/68) | 50 |
| Intubation/ mechanical ventilation | 0 | 0 | 29 | 10 | 27 | 11 | 39 (11/28) | 35 (24/68) | 44 (4/9) |
| Immuno suppression reduced/ discontinued | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes |
| Treatment(s), % | |||||||||
| HCQ | – | – | – | 95 | 87 | 72,a 8 in combo with LPV/r | 86 (24/28) | 91 (62/68) | 100 (9/9) |
| Azithromycin | – | – | – | – | 60 | – | 46 (13/28) | 66 (45/68) | 100 (9/9) |
| Remdesivir | – | – | – | – | – | – | – | 3 (2/68) | – |
| Tocilizumab | – | – | – | 30 | 7 | 6 | 7 (2/28) | 21 (14/68) | – |
| Leronlimab | – | – | – | – | – | – | 21 (6/28) | – | – |
| Oseltamivir | 100 | 20 | 14 | – | – | – | – | – | – |
| Follow-up, days | 29 (27–31) | – | – | – | 7 (3–11) | 18 (14.5–22) | 21 (14–28) | 20 (14–24) | 25 (11–26) |
| Mortality | 0 | 10 | 14 | 25 | 7 | 28 | 28 | 24 | 30 |
| Studies . | Zhang et al. [1] . | Zhu et al. [2] . | Banerjee et al. [3] . | Alberici et al. [4] . | Columbia University Kidney Transplant Program [5] . | Fernandez-Ruiz et al. [6] . | Akalin et al. [7] . | Pereira et al. [8] . | Nair et al. [9] . |
|---|---|---|---|---|---|---|---|---|---|
| Date accepted for publication | March 20 | March 23 | March 27 | April 3 | April 6 | April 16 | April 24 | April 24 | April 29 |
| Number of patients | 5 | 10 | 7 | 20 | 15 | 18 | 36 | 90 | 10 |
| Organ transplanted | Kidney | Kidney | Kidney | Kidney | Kidney | Kidney 8, liver 6, heart 4 | Kidney | Kidney 46, lung 17, liver 13, heart 9, heart-kidney 3, liver-kidney 1, pancreas-kidney 1 | Kidney |
| Age, years | 38 (38–47) | 50 (32–54) | 54 (45–69) | 59 (51–64) | 51 (28–72) | 71 (64–75) | 60 (32–77) | 57 (46–68) | 57 (47–67) |
| Male gender, % | 80 | 80 | 57 | 80 | 67 | 77.8 | 72 | 59 | 60 |
| Time from transplant | 352 days (170–929) | 6–12 months | 3 to ≥1 year | 13 years (9–20) | 4.1 years (3.2–9.8) | 9.3 years (6.3–16.5) | No info | 6.64 years (2.87–10.61) | 7.7 years (3.5–12.6) |
| Comorbidities, % | |||||||||
| HTN | 40 | 50 | 86 | 85 | – | 56 | 94 | 64 | 100 |
| DM | 20 | – | 43 | 15 | – | – | 69 | 46 | 80 |
| CKD | – | – | – | – | – | – | – | 63 | – |
| CLD | – | – | – | – | – | – | – | 19 | – |
| CHD | – | 20 | – | 15 | – | 17 | 17 | – | – |
| Cirrhosis | – | – | – | – | – | 28 | – | – | – |
| Baseline immuno suppression, % | |||||||||
| Tacrolimus | 80 | 90 | 86 | 95 | 93 | 56 | 97 | 86 | 90 |
| Cyclosporine | – | 10 | – | – | – | 17 | – | – | – |
| MMF/MPA | 100 | 90 | 71 | 70 | 80 | 61 | 86 | 72 | 100 |
| Prednisone | – | 70 | 71 | 65 | 67 | 67 | 94 | 59 | 70 |
| mTOR | – | – | – | 10 | – | 22 | – | 7 | 20 |
| Belatacept | – | – | – | – | 13 | – | – | 6 | – |
| Presenting symptoms, % | |||||||||
| Fever | – | 90 | 71 | 100 | 87 | 83 | 58 | 70 | 90 |
| Cough | 100 | 90 | 57 | 50 | 60 | 67 | 53 | 60 | 80 |
| Dyspnea | – | 90 | 86 | 5 | 27 | 61 | 44 | 43 | 30 |
| Diarrhea | – | 30 | 14 | 15 | 20 | 22 | 22 | 31 | 20 |
| Fatigue | 60 | 90 | – | – | 27 | – | – | 28 | 50 |
| ICU admission | 0 | – | 57 | 20 | – | 11 | – | 34 (23/68) | 50 |
| Intubation/ mechanical ventilation | 0 | 0 | 29 | 10 | 27 | 11 | 39 (11/28) | 35 (24/68) | 44 (4/9) |
| Immuno suppression reduced/ discontinued | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes |
| Treatment(s), % | |||||||||
| HCQ | – | – | – | 95 | 87 | 72,a 8 in combo with LPV/r | 86 (24/28) | 91 (62/68) | 100 (9/9) |
| Azithromycin | – | – | – | – | 60 | – | 46 (13/28) | 66 (45/68) | 100 (9/9) |
| Remdesivir | – | – | – | – | – | – | – | 3 (2/68) | – |
| Tocilizumab | – | – | – | 30 | 7 | 6 | 7 (2/28) | 21 (14/68) | – |
| Leronlimab | – | – | – | – | – | – | 21 (6/28) | – | – |
| Oseltamivir | 100 | 20 | 14 | – | – | – | – | – | – |
| Follow-up, days | 29 (27–31) | – | – | – | 7 (3–11) | 18 (14.5–22) | 21 (14–28) | 20 (14–24) | 25 (11–26) |
| Mortality | 0 | 10 | 14 | 25 | 7 | 28 | 28 | 24 | 30 |
All data presented as median (IQR) unless otherwise noted. CHD: coronary heart disease; CKD: chronic kidney disease; CLD: chronic lung disease; DM: diabetes; ICU: intensive care unit; HCQ: hydroxychloroquine; HTN: hypertension; LPV/r: lopinavir/ritonavir; MMF: mycophenolate mofetil; MPA: mycophenolic acid; mTOR: mammalian target of rapamycin; –, not recorded.
All studies published after March 2020 utilized hydroxychloroquine in the majority of COVID-19-positive transplant recipients. Azithromycin, remdesivir, leronlimab, lopinavir/ritonavir, darunavir, oseltamivir and tocilizumab were also used. All studies described hospitalized patients. A third of the reports also included outpatients [3, 6, 7]. The median [interquartile range(IQR)] follow-up time was ∼3 weeks for most studies (7–29 days). Mortality ranged from 0% to 30%.
All studies (except Study [1]) that reported patient mortality under 20% did not report follow-up data or reported a median follow-up <10 days. In general, larger studies also tended to have a higher mortality. At the time of our analysis, we observed a higher mortality among more recent reports.
In summary, the available literature suggests that presentation of COVID-19 in transplant recipients is similar among transplant centers around the world. Immunosuppression strategies are also similar and revolve around reducing immunosuppression. Treatment strategies vary; however, all studies utilized some antiviral or anti-inflammatory agent. Differing outcomes may therefore be related to small number of cases, potentially varying acuities of illness, and short (or not reported) follow-up periods being associated with lower mortality. Given that the cytokine storm occurs later in the course of COVID-19, it is plausible that mortality may increase with follow-up. When excluding short or missing follow-up, recent mortality appears to be between 20% and 30%, which suggests that transplant recipients have a higher mortality than the non-immunocompromised population.
It is of utmost importance to understand these risks before proceeding with transplantation in the current era of COVID-19. Factors to be considered include the potential for improved survival and enhanced quality of life, the risk of SARS-CoV-2 infection in the transplant population when compared with in-center dialysis, and the increased morbidity and mortality associated with COVID-19 in the setting of transplantation. Ongoing studies reporting multi-center data may provide us with more robust information.
CONFLICT OF INTEREST STATEMENT
KDJ is a consultant for Astex pharmaceuticals and Natera. All other authors have no conflict of interests to declare.
REFERENCES
The Columbia University Kidney Transplant Program.
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