Impact of COVID-19 in Solid Organ Transplant Recipients

Lara Danziger-Isakov; Emily A. Blumberg; Oriol Manuel; Martina Sester

Disclosures

American Journal of Transplantation. 2021;21(3):925-937. 

In This Article

Treatment Strategies Including Immunosuppression-related Modifications

Given the high mortality associated with COVID-19 in hospitalized patients, and in particular for SOT recipients, several antiviral or immunomodulatory drugs have been given as compassionate use for therapy of COVID-19 since the beginning of the pandemic (Figure 2).

Figure 2.

Timeline of SARS-CoV-2 identification, selected announcements, and therapeutic milestones related with COVID-19. The yellow line shows the cumulative number of cases worldwide (source: John Hopkins Coronavirus research Center). COVID-19, coronavirus disease 19; FDA, Food and Drug Administration; HCQ, hydroxychloroquine; PEP, postexposure prophylaxis; RCTs, randomized clinical trials; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SOT, solid organ transplant; WHO, World Health Organization.

Antiviral Therapy

Antiviral drugs for SARS-CoV-2 were initially chosen based on observational data obtained during the SARS-CoV-1 and MERS-CoV outbreaks,[115,116] or in vitro activity against SARS-CoV-2.[117,118] The first series of cases of SOT recipients infected with SARS-CoV-2 showed that a significant percentage of patients were treated with hydroxychloroquine (ranging from 25% to 90%) and/or lopinavir/ritonavir (3%-50%).[17,75,84,89] None of these drugs have shown efficacy in clinical trials and are currently not recommended.[119,120]

The most promising antiviral drug tested for COVID-19 is remdesivir.[121] Remdesivir is an inhibitor of the viral RNA-dependent RNA polymerase with in vitro activity against SARS-CoV-2. EC50 of remdesivir in in vitro models against MERS-CoV and SARS-CoV-2 was 0.09 μM and 0.77 μM, respectively.[117,122] A double-blind placebo controlled trial including more than 1000 patients given 10 days of remdesivir treatment showed a significant reduction of time to recovery from 15 days in the placebo group to 10 days in the remdesivir group (rate ratio for recovery, 1.29; 95% CI, 1.12 to 1.49).[123] However, reduction of mortality was not statistically significant. The beneficial effect of remdesivir was predominantly seen in patients needing oxygen but was not apparent in those on mechanical ventilation or on ECMO. Of note, no significant toxicity has been observed in trials using remdesivir, or in case reports specifically in SOT recipients.[66] Drug-drug interaction with immunosuppression has not been described and is not anticipated. More recently, the Solidarity trial, a large international WHO-sponsored trial compared 2700 patients receiving remdesivir with the local standard of care with preprint preliminary results available[124] and noted no effect of remdesivir on mortality (10.9% vs. 11.1% with standard of care). A meta-analysis of all existent interventional data on remdesivir was included in the Solidarity publication and showed a risk ratio (RR) of death with remdesivir of 0.91 (95% CI 0.79–1.05, p = .20), being 0.80 (95% CI 0.63–1.01) in patients without mechanical ventilation. Thus it appears that remdesivir should be given early after the infection onset to reduce viral load and avoid the development of the cytokine storm phase in patients who may have risk factors for a worse outcome, a category that includes SOT recipients.[121]

Administration of convalescent plasma (CP) of infected patients has been approved for emergency use in the US based on observational data that includes an acceptable safety profile.[125] Although the first randomized clinical trial was underpowered and failed to show clear clinical benefit across all patients, it appears that CP is superior in reducing viral load and time to clinical improvement when administered early in the disease course rather than after the onset of life-threatening disease.[126] A more recent trial compared CP with standard of care in non-transplant patients (n = 464); no reduction in progression to severe disease or mortality was noted with CP,[127] perhaps due to the presence of similar neutralizing antibody titers in both study arms. Thus, it seems that sufficient antibody titers may be essential to confer clinical efficacy. Data on the use of CP in SOT recipients are limited to case reports.[128,129] Apart from antibody treatment with CP, several highly active monoclonal antibodies against SARS-CoV-2 are currently under evaluation.[130,131] An anti-spike neutralizing antibody named LY-CoV555 has shown a reduction in SARS-CoV-2 viral loads in outpatients with COVID-19 in a phase II trial.[132]

Immunomodulatory Therapy

The unique clinical course of COVID-19, with initial viral clearance followed by the development of a second clinical phase characterized by the release of inflammatory cytokines and coagulation factors, prompted the introduction of anti-inflammatory and immunomodulatory drugs for reducing the deleterious effects of the immune reaction to SARS-CoV-2. Given that interleukin-6 (IL-6) was elevated in patients with COVID-19, several studies assessed whether inhibiting IL-6 by blocking the IL-6 receptor with tocilizumab could have beneficial effects. In an uncontrolled study including 20 non-transplant patients with mild to moderate COVID-19 in China, a reduction in inflammatory parameters (including CRP) and clinical symptoms (fever, dyspnea) was observed after administration of tocilizumab; none of the patients died.[133,134] However, none of three recent randomized controlled trials having compared tocilizumab with standard of care and/or placebo in the general population has shown a reduction of mortality.[135–137] In SOT recipients, a Spanish cohort of kidney transplant recipients receiving tocilizumab for COVID-19 reported an overall mortality of 32%. However, tocilizumab was given to patients with more severe disease, so that the effect of tocilizumab on mortality cannot be assessed.[138] A case-control study involving 117 SOT recipients from New York showed that tocilizumab was not associated with a reduction of mortality.[139]

Steroids have been evaluated for treatment of COVID-19. The Recovery trial including more than 11000 patients in several arms, compared the efficacy of dexamethasone 6 mg once daily with the standard of care alone for treatment of COVID-19.[140] Patients on dexamethasone had an overall 17% decrease in mortality (rate ratio, 0.83; 95% CI, 0.75–0.93). This effect was particularly seen in patients who received oxygen (rate ratio, 0.82; 95% CI, 0.72–0.94) and those on mechanical ventilation (rate ratio, 0.64; 95% CI, 0.51–0.81), but not in patients not receiving oxygen (rate ratio, 1.19; 95% CI, 0.91–1.55).[140] A recent meta-analysis of seven randomized controlled trials confirmed the beneficial effect of steroids on reducing COVID-19 mortality (OR, 0.66; 95% CI, 0.53–0.82).[141] These data indicate that steroids should be used in all patients with COVID-19 who need oxygen and/or mechanical ventilation. In SOT recipients, increasing the dose of prednisone or adding dexamethasone as part of the modulation of immunosuppressive therapy may be recommended in case of advanced disease.

Clinical trials are currently testing other immunomodulatory drugs such as Janus kinase inhibitors (baricitinib),[142] IL-1 blockers (anakinra),[143] and anti-C5 inhibitors (eculizumab) among many others.[144]

Management of Immunosuppression and Risk of Rejection

Modification of the immunosuppressive regimen is part of the therapeutic prescription in SOT recipients who develop a viral infection. Transplant physicians usually suspend antimetabolites and/or reduce calcineurin inhibitors dosing in case of severe viral infection, such as CMV disease or influenza, in an attempt to restore antiviral immunity and consequently increase viral clearance.[145] However, in patients with COVID-19 modulation of immunosuppression is a more pressing challenge, as most of the severe manifestations of COVID-19 are consequence of the imbalanced host response consisting of low expression of interferons and high expression of pro-inflammatory cytokines.[146] Theoretically, maintenance of immunosuppression with inhibition of T cell immunity may have beneficial effects on reducing this inflammatory response.[147] However, the potential benefit of immunosuppression in patients with COVID-19 is counterbalanced by the high number of comorbidities present in SOT recipients.[75,84] Experience in cohorts of SOT recipients showed that calcineurin inhibitors were held in 18%-29% of patients and antimetabolites were held in 66%-88% of patients during the clinical course of COVID-19.[17,84,95] It has been hypothesized that belatacept, by blocking the costimulatory signal, may prevent a severe clinical course of COVID-19; however, reports of both mild and severe cases of COVID-19 in SOT patients receiving belatacept have been published.[63,148] Despite the lack of strong evidence on optimal immunosuppression management in SOT recipients,[149,150] a stepwise reduction of immunosuppression according to the severity of the clinical presentation may be appropriate. In asymptomatic patients and patients not requiring hospitalization, modification of immunosuppression may be deferred. In patients needing low-flow oxygen, a dose reduction of the metabolite and/or reduction of calcineurin inhibitors or mTOR inhibitor levels may be necessary, especially in patients receiving other immunomodulatory drugs. In more severe cases, including those requiring ICU admission with mechanical ventilation and/or ECMO, some centers have applied a more significant immunosuppression reduction strategy, with temporary discontinuation of all immunosuppressive drugs, except steroids. This strategy needs to be balanced with a potential increased risk for the development of acute rejection and/or graft loss, particularly in life-saving transplants. However, other experts propose continuation of calcineurin inhibitors (particularly cyclosporine) during advanced disease to control the inflammatory phase.[149]

Another matter of concern is a potential increase in acute rejection rates due to administration of less potent immunosuppressive regimens for transplant recipients transplanted during the pandemic. Data from the Scientific Registry of Transplant Recipients showed a reduction in the use of ATG induction after March 2020 as compared to previous months, despite the fact that ATG was associated with a reduction in acute rejection rates and had no effect on mortality.[151] In addition, suboptimal posttransplant follow-up with concerns in drug compliance during lockdown may additionally result in increased rejection risk.[152] However, few studies have assessed the rates of acute rejection associated with COVID-19 itself or due to modulation of immunosuppression during infection. While a significant rate of AKI has been reported in kidney transplant recipients, the actual incidence of acute rejection has not been systematically reported, mostly due to the absence of allograft biopsies performed.[153] In a multicenter cohort involving 482 patients, only seven episodes of rejection were observed (six cellular and one humoral rejection).[17] Other studies in kidney and heart recipients with COVID-19 did not report diagnosis of rejections, despite reduction or withholding of immunosuppression in significant proportions of patients.[15,94] Increased doses of steroids administered during COVID-19 may partially explain the observed low rates of acute rejection. In any case, the complex management of immunosuppression during the course of infection should be discussed in a multidisciplinary approach by transplant physicians, ICU doctors, and transplant infectious diseases specialists.

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