Optimal management of COVID-19 in immunocompromised patients, particularly SOT recipients, poses a great challenge regarding the risk of more severe respiratory virus infection and higher rates of bacterial and fungal superinfections compared with their immunocompetent counterparts. The interactions between post-transplant-related medications with anti-viral drugs have made it more difficult to use the drugs commonly used in COVID-19 management. Moreover, clinical data regarding COVID-19 infection and its ideal treatment in the transplant population are limited. In this study, we aimed to evaluate different anti-viral and immunomodulatory regimens of COVID-19 treatment in transplant patients, since the declaration of the COVID-19 outbreak until now. Regarding the anti-viral regimens in our study, Lopinavir/Ritonavir showed a lower chance of patient survival with a higher hospitalization duration; while Remdesivir has decreased mortality rates and hospitalization periods in the hospital and ICUs.
In the early era of the COVID-19 pandemic, Lopinavir/Ritonavir was used to be prescribed commonly in patients infected with COVID-19, based on the results suggesting efficacy against another coronavirus. In our study, Lopinavir/Ritonavir not only increased the mortality rates but also notably prolonged the length of ICU stays, in which patients who took Lopinavir/Ritonavir stayed in ICU for 5.3 more days on average. Many studies reported similar results, discouraging the use of Lopinavir / Ritonavir in the transplant population. Circumventing the use of this drug is attributed to its adverse effects and interaction with immunosuppressants such as Tacrolimus and other medications used in the transplant population, such as fluoroquinolones to deal with Gram-negative infections. Furthermore, gastrointestinal upset (e.g., nausea and vomiting) is the most common adverse effect of this drug along with QT prolongation in combination with other drugs used in the COVID-19 treatment regimen. Moreover, a rise in liver enzymes was also reported in some cases. Concerning the reported effects, routine administration of Lopinavir/Ritonavir in transplant patients was discouraged.
After being approved by WHO in October 2020, Remdesivir use has been increased dramatically and multiple studies were published indicating its role in managing COVID-19 patients in the world, while there were also some studies reporting contrary efficacy results. Overall, there hasn’t been a conclusive study based on Remdesivir use in SOT COVID-19 patients up until now, while only some small or case-report studies on its efficacy in these patients have been published so far. For example, in a study by Duran et al, it has been suggested that early Remdesivir use in orthotopic heart transplant patients infected with SARS-CoV-2 would improve clinical outcomes in the patients. Our study confirmed that a 5-day regimen of Remdesivir will significantly decrease the mortality rates in transplant patients. Since this drug has no potential interactions with other immunosuppressive medications used in SOT patients' drug regimens, it seems that Remdesivir could be a promising anti-viral drug in managing transplanted COVID-19 patients. However, to establish a more precise conclusion, the results of larger multicenter studies with greater sample sizes should be analyzed. On the other hand, there is a concern about nephrotoxicity and elevation of hepatic enzymes occurrences after receiving Remdesivir, which is critical in decision making for liver or kidney transplant recipients. In a multi-center cohort study, it was reported that Remdesivir administration did not significantly increase the incidence of acute kidney injury, even in patients with GFRs lower than 30 ml/min. Additionally, in the "SIMPLE-Moderate trial" study (NCT04292730), a clinical trial to evaluate the efficacy and safety of a 5 or 10-day regimen of Remdesivir versus standard care, it was reported that hepatic enzyme elevation in the Remdesivir-receiving group was not higher than the control group. Our results suggest that a decrease in GFR or hepatic enzyme elevation is not significantly different between transplant patients who were treated with Remdesivir and patients treated with other anti-viral drugs. Similar results have also been reported in other studies performed on transplant patients. In conclusion, it seems that Remdesivir could be considered a promising anti-viral with appropriate efficacy and safety in transplant patients infected with SARS-CoV-2.
One of the challenging and controversial issues in managing COVID-19 among transplant patients is the use of immunomodulatory drugs. Pereira et al. confirmed the positive effect of high-dose steroid therapy in the case of lung transplantation after the first several days of the illness. (34) Liu et al. confirmed the beneficial use of corticosteroids in an infected case of a liver transplant, but they recommended low doses of steroids. (35) Zhu et al. also believed that appropriate doses of IV corticosteroids during a short period will not only protect the allograft from acute rejection, but also decrease the alveolar exudation and improve systemic symptoms due to its anti-inflammatory effects. On the other hand, several studies discouraged widespread use of corticosteroid medications, and even advised to discontinue or reduce the dose of steroids in transplant patients. They adduced to the potential negative effect of early corticosteroids administration in reducing pathogen clearance, while increasing viral shedding subsequent to immune response inhibition. Observational studies showed that corticosteroid treatment was linked to higher mortality rates and nosocomial infections for influenza and delayed virus clearance for SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV); however, there is limited data regarding SARS-CoV-2 (36). Also, corticosteroids have been associated with an increased risk of bacterial and fungal superinfections (37–41).
Our results showed no significant improvement following the administration of high doses of corticosteroids based on the hospitalization period and mortality rates. Nevertheless, patients treated with high doses of corticosteroids experienced more episodes of bacterial superinfections, however not statistically significant.
One of the controversial issues of immunomodulator therapy is the administration of interleukin-6, such as Tocilizumab, in COVID-19 management. Earlier, extensive studies were conducted regarding using Tocilizumab in the management of COVID-19 patients, of which some showed promising results in decreasing mortality rates. Further, published results of several clinical trials regarding the evaluation of the efficacy of Tocilizumab, such as the COVINTOC study, showed that the combination of the drug with standard care has achieved higher success in decreasing the risks of requiring mechanical ventilation or death, compared to the combination of a placebo and standard care. The subjects were hospitalized due to COVID-19 pneumonia and did not receive mechanical ventilation when enrolled in the study. However, the TOCIVID study showed no difference between the two groups in the total risk of death by any cause. (42)
Various studies have been conducted regarding the efficacy of Tocilizumab in transplant patients, each with different and contrary results. Some have reported lower mortality rates after using a combination of Tocilizumab with Hydroxychloroquine in COVID-19 patients who had received a kidney transplant or had received a liver transplant and required dialysis. However, retrospective studies have reported no significant decrease in mortality risk after using this drug, while also describing it as a safe drug to use for SOT patients.
Our results indicate that patients who were treated with Tocilizumab experienced a significantly lower duration of hospitalization duration in the hospital and ICUs and also lower mortality rates, however, without significantly affecting the need for mechanical ventilation. The risk of complication occurrences after drug administration was not higher than other therapy groups. The most probable reason behind diverse results between these studies is the basic differences in studies design; in which some studies were case reports, while some had a more extensive pool of patients. On the other hand, some of the studies, in the process of analyzing mortality rates among the groups who had not been treated with Remdesivir or Tocilizumab, have matched the patients based on critical mortality risk factors such as age, transplant type, and immunosuppressive regimen, while several considered this factor in their clinical trial. Also, there are differences in the onset of Tocilizumab administration and its enrolling requirements. In some studies, Tocilizumab was combined with high doses of corticosteroids and the drug administration had been started prior to intubation, while in some studies, the therapy had been started after patient intubation. Also, while some studies restricted mortality rates to its occurrence during hospitalization, several had followed up on the patients the mortality rates for 30 days after dismissing dates. (43)
Our study had several limitations. The retrospective method may include the risk of having false-positive results as well as overestimation. Due to this, it seems that designing a clinical trial to analyze the results related to the administration of anti-viral and immunomodulator drugs in transplant patients is critical. Our study only includes the results during the hospitalization period, and the patients haven’t been followed up after being discharged. For example, 28-day mortality and long-term complications were not evaluated. Another limitation was that there was no control group including the non-transplant infected patients. Therefore, the unique features of the transplant patient in terms of clinical symptoms, response to medications, and potential adverse effects of drugs could not be measured. Also, one of the factors influencing the reduction of mortality throughout the study timeline has been the more experienced medical staff in the field of management of patients with COVID-19, but it is somewhat difficult to assess the effect of this factor alone. Finally, in our study, some patients received multiple agents, and therefore the impact of each agent is difficult to tease out.