The impact of immunosuppression on SARS-CoV-2 infection in the presence of chronic immunosuppression is unknown. The clinical presentation is minor in the wide majority of the cases; however, it might have a progressive and severe clinical course causing pneumonia and acute respiratory distress syndrome, mainly in people older than 60 years or with the presence of comorbidities.1,2

Solid organ transplant recipients usually present an increased risk of complications due to respiratory viral infections associated with pharmacological immunosuppression, although little else about is known regarding the behavior of SARS-CoV-2 infection.3–6 In patients with SARS-CoV-2 infection and complicated clinical course, a severe hyperinflammatory state has been described7–9; this would suggest that the use of immunosuppression schemes could provide protection in solid organ transplant recipients. Expert opinions based on reports of previous coronavirus infections suggest, on one side that calcineurin inhibitors could be protective in severe hyperinflammatory states, and on the other side that they do not represent any impact.10–12 Series of cohorts, collecting experiences from different centers, have been published, most of them with patients receiving calcineurin inhibitor-based regimens; nevertheless, the analysis of the behavior with immunosuppression regimens free of calcineurin inhibitors, particularly with co-stimulation inhibitors and mTOR inhibitors is scarce. The most common practice in different centers at an overall level was to reduce or suspend antiproliferative drugs or mTOR inhibitors over the reduction or withdrawal of calcineurin inhibitors.13,14

The published series include a low number of renal transplant patients receiving belatacept, even more so when it is compared to the number of those receiving calcineurin inhibitors or mTOR inhibitors, which does not allow for comparisons between schemes.15–22 The drive mechanism of co-stimulation inhibitors and mTOR inhibitors suggests that they might play some role in inflammatory response modulation, compared with schemes based on calcineurin inhibitors in renal transplant recipients and COVID-19.23–27

In Colombia, the first case of COVID 19 was reported on March 6, 2020; as of mid-February, 2021, when vaccination started (and solid organ transplant recipients were prioritized), 2.2 million cases and 58 thousand cases had been confirmed. According to data from the national official registry, in 2019 there were 1844 renal transplant recipients in active follow-up in 11 transplant centers in the city of Bogotá. We undertook this observational study in 7 transplant centers in Bogota, Colombia in order to describe the clinical presentation, treatment, and outcomes in adult kidney transplant recipients diagnosed with COVID-19, and the possible association between severity of infection and calcineurin inhibitor-based and calcineurin inhibitor-free immunosuppression regimens, before vaccination started.

This is a multicenter retrospective study involving renal transplant recipients with COVID-19 confirmed by RT PCR via upper respiratory tract sampling. All cases confirmed between March 15, 2020 and February 4, 2021 were included in the analysis, and followed until March 4, 2021 for survival analysis. Demographic variables, comorbidities, body mass index (BMI), renal function, post-transplant time to infection, presenting symptoms, immunosuppression schemes, and chest X-ray imaging findings were collected. The clinical course included admission to hospital, immunosuppression adjustments, treatment strategies, mechanical ventilation, dialysis, and death. The patients were treated according to the local site's standard of care and adjustments in immunosuppressive drugs were made following recommendations of the Colombian Society of Nephrology.28 Each centers received approval from their institutional review board.

There is limited information regarding the impact of chronic immunosuppression on the outcomes of solid organ transplant recipients or the differences between each of immunosuppression strategy. In this study, clinical presentation of COVID-19 is similar to that reported in the overall population, with fever and cough as the most frequent symptoms.29 It is important to note that the presence of gastrointestinal symptoms (30.9%) is higher than that reported in the general population (5%–10%).30 This situation has been reported in other series with organ transplant patients in France (42%) and Spain (36.7%).15,31,32 However, we did not find an association with lower risk of death as was found in a series in Spain.31,32

The average overall case fatality rate in Colombia has been between 2.5 and 3% depending on the region.33 Multiple experiences have described a higher risk of complications and death in solid organ recipients compared to the overall population, a finding confirmed in our experience.15,32–36 In our series, the 30-day case-fatality rate was 17%; the risk of hospitalization was close to half of the patients (49.7%), and mechanical ventilation requirement was also higher (21.8%).

Age over 60, history of diabetes and dyspnea at initial presentation were risk factors for mortality in our cohort, as has been described in the overall population.37 Time to renal transplantation of less than 6 months was not associated with a lower probability of survival although there is a trend in our cohort, which has been described in registries from New York and Spain, probably associated with a higher burden of early.32,36 Obesity has been previously reported as a risk factor for mortality in solid organ transplant recipients15 but we did not confirm this in our series. On the other hand, we found differences between immunosuppression schemes, with steroids and calcineurin inhibitors as important risk factors for mortality.

In the Brescia cohort, after adjusting with a multivariate model, tacrolimus was associated with risk of death (OR 6.9; 95% CI: 0.99–67, p=.07) although these results could be a consequence of the characteristics of the population studied39; however; in the Spanish Registry tacrolimus showed higher mortality in kidney transplant recipients in the first 6 months after transplantation, probably associated with maximum effect of immunosuppression.32

The capacity of CNI to inhibit viral replication through inhibition of immunophilin pathways independent of their immunosuppressive effect could potentially reduce viral replication of SARS-CoV-2.9,40,41 The role in the prophylaxis of graft rejection in a scenario with reduced immunosuppression burden were probably the reasons that positioned CNI as the preferred maintenance immunosuppressants in patients with COVID-19.15,20,35,36

Most studies in patients with solid organ transplants and COVID-19 describe few patients with immunosuppression schemes free of tacrolimus or cyclosporine; fact, which does not allow for comparisons. In our country, the most commonly used immunosuppression scheme is tacrolimus and mycophenolic acid with or without steroids in 69% and 88% of renal transplant recipients, respectively.38

Our search identified 15 publications totaling 1785 cases; 1532 (85.8%) were receiving CNI, 218 (12.2%) mTOR inhibitors, and 29 (1.6%) belatacept.10,15–17,19,31,35,39,42–45 A Spanish study of 414 renal transplant recipients, of which 82.6% were receiving tacrolimus and 23% mTOR inhibitors, would be the series with the highest number of cases with CNI-free schemes reported to date (n=94). It describes a trend toward a higher probability of recovery in the latter group (patients with COVID-19 mortality vs. recovery: mTOR inhibitors p=.069, tacrolimus p=.941).31

Since the clinical behavior in patients with severe COVID-19 could be explained by an excessive activation of the immune system,46 the use of drugs that manage to reduce the mortality of patients with severe COVID-19 could be explained by their activity on the immune system.46

The use of medications that potentially decrease an exaggerated immune response seems reasonable as a treatment strategy to reduce the risk of complications or reduce the likelihood of progression from mild to severe disease. SARS-CoV-2 causes excessive activation of the mTOR signaling pathway in in vitro models; proper functioning of this pathway is necessary for T-cell differentiation. Overactivation of the mTOR pathway can cause an imbalance leading to a reduced accumulation of regulatory T cells and an increased TH1747 response, a scenario that has been described in patients with severe COVID-19.48,49

mTOR inhibitors inhibit the proliferation of effector T cells and stimulate the accumulation of regulatory T cells.50 Consistent with these observations, mTOR inhibitors could reduce immune-mediated damage and clinical manifestations during SARS-CoV-2 infection. Nonetheless, in published series in solid organ transplant recipients with SARS-CoV-2 infection, mTOR inhibitors were reduced or discontinued in the vast majority of cases.15,35

In line with current evidence, a reduced level of peripheral regulatory T cells in patients with severe COVID-19 could be part of the reasons for an overactive immune system,49 the expansion of regulatory T cells through immunoregulatory molecules including CTLA4 may explain the role of the immunosuppressant belatacept in a hypothetical control of inflammation in renal transplant recipients with COVID-19.23,24

Our series includes a large number of cases with immunosuppression schemes free of CNI, with a higher risk of death in those who received CNI. It is important to note that there is no apparent benefit associated with the use of CNI above other immunosuppressants and it seems necessary to carry out further clinical studies that allow us to evaluate outcomes and immunosuppression in renal transplant recipients with COVID-19.

Design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication are the responsibility of the authors alone. The authors of this manuscript have no conflicts of interest to disclose.