The solid organ transplant recipient with SARS-CoV-2 infection

Abstract

Purpose of review:

The COVID-19 pandemic is a major challenge to global health, particularly among vulnerable populations. Here we describe the emerging epidemiology and relevant data on treatment options for COVID-19. We discuss the implications of current knowledge for SOT recipients

Recent findings:

Risk factors and outcomes of COVID-19 among SOT recipients remain uncertain but recent data suggest similar outcomes to the general population. Case reports of donor derived SARS-CoV-2 infection are emerging. Few studies on treatment of COVID-19 among SOT recipients are available and therefore general recommendations are similar to the general population. Vaccine efficacy in the SOT population is uncertain.

Summary:

COVID-19 remains a significant threat to SOT recipients and studies on treatment and prevention specific to this population are urgently needed. While vaccines represent the greatest hope to control this pandemic, their efficacy in this immunocompromised population is uncertain.

Introduction

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified in Wuhan, China in December 2019 and subsequently designated as the causative agent of coronavirus disease 2019 (COVID-19). COVID-19 is now a global pandemic that by March 2021 has led to over 115 million cases and 2.5 million deaths worldwide.¹ Though the pathogenesis of COVID-19 remains incompletely understood, it causes a spectrum of clinical manifestations that range from asymptomatic infection to acute respiratory distress syndrome (ARDS) with septic shock and multiorgan failure.^2,3

The clinical aspects and impact of COVID-19 in solid organ transplant (SOT) patients are areas of intense investigation. While much remains to be determined, defining an effective and safe approach to COVID-19 in solid organ transplant (SOT) recipients is critical to the care of this vulnerable population.⁴ In this article, we aim to review the epidemiology, risk factors, clinical outcomes, and treatments for COVID-19 with a focus on the unique challenges among SOT patients. We will conclude with a discussion of preventative measures and prophylaxis against SARS-CoV-2 infection in SOT recipients.

Epidemiology

The exact prevalence of infection in the general population is unknown as the pandemic is ongoing and testing rates have been suboptimal. Seroprevalence surveys from the United States and Europe suggest that the rate of prior exposure to SARS-CoV-2 exceeds the incidence of reported cases by approximately 10-fold.^5,6 Based on experience with other respiratory viruses, there was initial concern about a disproportionate impact of COVID-19 in SOT recipients.^7,8 A study based out of Spain found that despite a similar epidemiological pattern, liver transplant recipients had almost double the risk of developing COVID-19 compared to age and gender-matched controls.⁹

A unique concern to transplant centers across the world has been the possibility of donor-derived SARS-CoV-2 infection. From March to May 2020, there were 8 potential donor-derived SARS-CoV-2 transmissions reported to the Organ Procurement and Transplantation Network. A public health investigation by the US Centers for Disease Control and Prevention (CDC) concluded that these infections likely occurred via community or healthcare exposure rather than transmission from an organ donor.¹⁰ Though the risk of organ-derived infection with SARS-CoV-2 remains undefined, the American Society of Transplantation has recommended testing all donors by nucleic acid test since May 2020.¹¹ A recent report of proven donor to recipient transmission of SARS-CoV-2 by lung transplantation despite a negative nasopharyngeal nucleic acid test from the donor highlights the risk of donor-derived COVID-19.¹² Post-transplant, one surgeon present during the procedure developed COVID-19 and sequence analysis of isolates from donor bronchoalveolar lavage fluid, the recipient, and the surgeon proved donor origin of the recipient and health-care worker infection.

Risk Factors and Outcomes

Comorbidities including advanced age, obesity, hypertension, diabetes mellitus, coronary artery disease, chronic kidney disease, and chronic lung disease are widely recognized risk factors for severe COVID-19.^3,13 However, the impact of chronic immunosuppression on outcomes from COVID-19 remains unknown. The unique contribution of a dysregulated immune response in SARS-CoV-2 morbidity and mortality led to discussions of a favorable effect of immunosuppression in SOT recipients who developed COVID-19.¹⁴ Reports based on transmission dynamics in Wuhan, China estimated a case fatality rate of 2–4% among the general population.¹⁵ A case fatality rate as high as 61.5% has been reported amongst patients with critical illness from COVID-19.¹⁶

Whether the net state of immunosuppression associated with SOT patients is protective against or a risk factor for severe COVID-19 remains uncertain. Early case reports from China described favorable outcomes among kidney and heart transplant recipients with COVID-19.^17,18 Subsequently, a study of 47 SOT recipients, when compared to a matched group of non-transplant patients with COVID-19, showed that transplant itself was not associated with increased morality.¹⁹ However, other studies from across Europe and North America have indicated worse outcomes in the SOT population.^20–22 A study of 482 SOT recipients from over 50 transplant centers found that the 28-day mortality from COVID-19 was 18.7% in the overall cohort and 20.5% among those hospitalized.²³ This study explored potential surrogates of immunosuppression (earlier time post-transplant, thoracic versus nonthoracic organ transplant, or receipt of augmented immunosuppression within the past 3 months) and did not find an association of these factors with mortality.

Concerns about unfavorable outcomes from COVID-19 led to changes in immunosuppression management and a substantial decrease in transplant surgeries at many centers around the world. By April 2020, the overall rate of organ transplantation had fallen by 51% in the United States, by 87% in Spain, and by 91% in France.²⁴ Logistical challenges that have unfavorably influenced transplant activity include travel restrictions, stretching of available resources, unclear risk of infection in immunosuppressed hosts, and evolving guidelines on testing and transplantation. A study comparing COVID-19 patients waitlisted for kidney transplant with those post-kidney transplant found that waitlist status was independently associated with mortality.²⁵ Efforts to build organizational flexibility at transplant centers and to encourage dialogue between providers have helped the transplant community to continue to provide its live-saving services to patients.^26,27

Treatment

A variety of agents have emerged as potentially beneficial for the treatment of COVID-19, but few have shown conclusive results via randomized controlled trials (RCTs). In October 2020, the United States Food and Drug Administration (FDA) approved remdesivir for the treatment of hospitalized children ≥ 12 years and adults regardless of disease severity.²⁸ While some agents under consideration have a clear antiviral mechanism of action, others are postulated to have immunomodulatory activity. Unfortunately, there have been no specific therapeutic or randomized studies among SOT recipients. Table 1 outlines a general approach to managing SOT recipients with COVID-19 based on disease severity.

Table 1:

Illness categories and corresponding treatment approaches for SOT recipients with COVID-19.

Patient presentation	Symptoms, Indication	Therapy Options
Mild illness	Symptoms of upper and/or lower respiratory tract infection in patients who have no hypoxia (SpO2 > 94%)	• Supportive care • For outpatients, consider monoclonal antibodies • Avoid corticosteroids if no oxygen requirement • Consider no change in chronic immunosuppression
Moderate illness	SpO2 <94% on room air or requiring supplemental oxygen	• Hydroxychloroquine should not be used for treatment of COVID-19 • Dexamethasone (or equivalent steroid) 6mg daily for 10 days or upon discharge, whichever comes first • Remdesivir 200 mg ×1 dose, then 100mg daily for 5 days • Consider reducing or holding anti-metabolite
Severe illness	Requiring mechanical ventilation or ECMO	• Dexamethasone as above • Consider remdesivir on a case by case basis, as remdesivir has not been shown to be associated with clinical improvement in patients requiring mechanical ventilation of ECMO • Consider tocilizumab on a case by case basis such as rapidly worsening oxygen requirements and admission to the ICU within 24 hours • Reduce or hold anti-metabolite

SpO2 = peripheral oxygen saturation, ICU = intensive care unit

Remdesivir

Remdesivir is a nucleotide analog prodrug that acts as an inhibitor of the viral RNA-dependent RNA polymerase shown to exhibit broad-spectrum antiviral activity.^29,30 Given past evidence of activity against SARS-CoV-1 and Middle East respiratory syndrome-related coronavirus, there was interest in its use as a therapeutic agent for SARS-CoV-2 in the early stages of the pandemic.^31,32

Initial in vitro studies showed that remdesivir inhibited SARS-CoV-2.³³ The Adaptive COVID-19 Treatment Trial (ACTT-1) was a multinational, randomized, double-blinded, placebo-controlled trial that formed the basis for incorporating this drug into major treatment algorithms.³⁴ This trial evaluated 1,062 hospitalized patients randomized 1:1 to receive remdesivir or placebo for up to 10 days. Patients were eligible if they had radiographic evidence of infiltrates or peripheral oxygen saturation of 94% or less on ambient air or if they required supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). ACTT-1 found that the remdesivir arm was associated with reduced time to recovery (10 versus 15 days) and that the benefit was greatest in the subgroup who required oxygen support but who were not intubated. There was a nonsignificant trend towards improved mortality by 15 days of 6.7% and 11.9% in the remdesivir and placebo groups, respectively. There were no observed benefits in the patients who were mechanically ventilated or on ECMO. The authors do not specifically mention whether SOT recipients were included in the study, but 6.9% of overall participants had an immune deficiency which did not include cancer.

An additional multinational, randomized, open-label trial investigating a 5 versus 10-day course of remdesivir for patients with COVID-19 has also been published.³⁵ Eligible patients were those who had to have radiographic evidence of pulmonary infiltrates and either an oxygen saturation of 94% or less while they were breathing ambient air or were receiving supplemental oxygen. 397 hospitalized patients were randomized to either a 5-day or 10-day course of remdesivir. The trial found that there were no significant differences in clinical outcomes between these groups. Though SOT patients were included in the study, the exact number has not been released.

Remdesivir is generally well-tolerated and without a significant difference in rate of adverse effects compared to placebo. Concern has been raised regarding the relationship between remdesivir in patients with renal dysfunction and transaminase elevations. For example, exclusion criteria in ACTT-1 included transaminase elevations more than five times the upper limited of normal, renal impairment with an estimated glomerular filtration rate less than 30 mL/min, or renal replacement therapy.³⁴ There are no known drug interactions between remdesivir and any of the commonly used immunosuppressive agents prescribed to SOT patients.³⁶ Although there is a paucity of data evaluating its safety among SOT recipients, it has been widely used in transplant centers.

Corticosteroids

SARS-CoV-2 infection can cause a systemic inflammatory response leading to lung injury and multisystem organ dysfunction. In the early stages of the pandemic, it was proposed that the potent anti-inflammatory effects of corticosteroids could mitigate these deleterious effects. Conflicting results on the benefit and safety of corticosteroids in other viral pneumonias led to early recommendations by the World Health Organization (WHO) against their routine use in the management of COVID-19.

However, the subsequent release of new trial data from the RECOVERY trial led to the widespread adoption of corticosteroids in the treatment of severe COVID-19. Hospitalized patients were eligible if they had clinically suspected or laboratory-confirmed SARS-CoV-2 infection and no medical history that might put them at substantial risk if they were to participate in the trial.³⁷ A total of 2,104 patients were assigned to receive dexamethasone for up to 10 days. Following randomization, the 28-day mortality was lower in the dexamethasone arm compared to the standard care arm (22.9% vs 25.7%, respectively; p < 0.001). While there was no survival benefit among participants who did not require oxygen therapy, the survival benefit was greatest among participants who required mechanical ventilation at randomization. Also, the risk of progression to mechanical ventilation was lower in the dexamethasone arm than in the standard of care arm. Guideline recommendations from the US National Institutes of Health and the Infectious Diseases Society of America now recommend dexamethasone for treatment of severe COVID-19.^38,39

As with remdesivir, there are no studies on corticosteroids among SOT recipients. This, compounded by the fact that corticosteroids are extensively used as part of chronic immunosuppression, makes it difficult to contextualize this therapy in this population. Nevertheless, most transplant centers have incorporated dexamethasone in the COVID-19 treatment algorithm for SOT recipients.

Monoclonal Antibodies

A significant proportion of individuals with COVID-19 produce neutralizing antibodies to SARS-CoV-2, with higher antibody titers observed in those with severe disease.⁴⁰ The neutralizing activity of COVID-19 patient plasma is correlated with magnitude of antibody response to SARS-CoV-2 spike (S) protein. Thus, monoclonal antibodies targeting the S protein are potential therapeutics for COVID-19.

In a randomized controlled phase 2 trial including 577 outpatients with mild to moderate disease, bamlanivimab and combination bamlanivimab-etesevimab were compared to placebo.⁴¹ By day 29, there were trends towards lower combined rates of emergency department visits or hospitalizations in both treatment arms compared with placebo, but only combination therapy resulted in a small, statically significant reduction. An interim analysis from a randomized controlled phase 1 and 2 trial comparing two doses of casirivimab plus imdevimab to placebo suggested a potential clinical benefit of casirivimab-imdevimab for outpatient with mild to moderate COVID-19.⁴² In a post-hoc analysis submitted to the FDA, 8/434 participants (2%) in the casirivimab-imdevimab arm versus 10/231 participants (4%) in the placebo arm were hospitalized or had emergency department visits within 28 days of treatment.

The FDA issued emergency use authorizations for bamlanivimab and for combination casirivimab-imdevimab for non-hospitalized patients with COVID-19 not requiring supplemental oxygen (or without increased oxygen requirement if on chronic supplemental oxygen).^43,44

Other Therapeutic Agents

Convalescent plasma (CP) provides passive immunity in the form of neutralizing antibodies collected from screened donors. There are currently insufficient data from well-controlled, adequately powered RCTs to fully evaluate the efficacy and safety of CP. Data from trials have failed to demonstrate a consistent benefit from CP among patients with COVID-19. An efficacy analysis of 3,082 participants which assessed outcomes by low-, medium-, and high-titer plasma was performed. After adjusting for baseline characteristics, the 30-day morality in the low- and high-titer groups was not statistically different (29% and 25%, respectively).⁴⁵ A separate post-hoc analysis found that in patients aged <80 years who were not intubated and who were treated within 72 hours of COVID-19 diagnosis, 7-day mortality was lower among patients who received high-titer plasma compared to low-titer plasma (6.3% vs 11.3%, respectively; p=0.008).⁴⁶ CP does not interact with any immunosuppressive medications prescribed to SOT patients and evidence for the use of CP to treat COVID-19 in SOT patients is limited to case reports.⁴⁷

Tocilizumab, an anti-IL-6 receptor blocker. has also emerged as an important but uncertain therapeutic option. New results from the RECOVERY trial show that, compared to usual care, tocilizumab reduced 28-day mortality among hospitalized patients with severe COVID-19 from 33% to 29% (p=0.007).⁴⁸ Participants who received tocilizumab had an increased probability of discharge alive within 28 days (47% vs 54%, p<0.0001). An ongoing international, multicenter, open-label trial found that among patients admitted to the ICU, those who received tocilizumab had a higher median number of organ support-free days (10 vs 0 days). Improved 90-day survival was also noted among patients who received either tocilizumab or sarilumab (hazard ratio 1.61, 95% CI 1.25–2.08).⁴⁹ However, a small single-center matched cohort study found no benefit from tocilizumab among SOT patients with severe disease.⁵⁰ A matched case-control study of tocilizumab for severe COVID-19 in SOT recipients found no change in secondary infections (34% vs 24%, p=0.55).⁵⁰ Further studies are needed in this therapeutic area.

Management of immunosuppression

There are no studies on the management of chronic immunosuppression in SOT recipients with COVID-19. Based on experience with other infections, there was initial consensus on reducing or holding antimetabolites.⁵¹ One European study found that tacrolimus was associated with improved survival among liver transplant recipients.⁵² Further studies are also needed to better guide management of chronic immunosuppression during COVID-19.

Prevention

The possibility of more severe outcomes from COVID-19 in SOT recipients highlights the need for preventative strategies against SARS-CoV-2. Other than general prevention measures, vaccines offer the potential for greatest impact in this pandemic.^{53, 54} In December 2020, the FDA issued Emergency Use Authorization for two mRNA vaccines, BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna). Large, placebo-controlled trials have shown these vaccines are 94–95% efficacious in preventing COVID-19 after participants completed a two-dose series.^55,56 However, a study of antibody response in SOT recipients at a median of 20 days after the first dose of mRNA (52% Pfizer, 48% Moderna) found a poor antispike antibody response, suggesting that SOT patients may remain at higher early risk for COVID-19 despite vaccination.⁵⁷ These data are preliminary and more studies are critical to this area of investigation. A replication-incompetent chimpanzee adenovirus vector vaccine ChAdOx1 nCoV-19/AZD1222 (University of Oxford, AstraZeneca) has been found to be 70.4% effective in preventing symptomatic COVID-19 starting 14 days after the second dose.⁵⁸ Most recently, the FDA issued emergency use authorization for the single dose Ad26.COV2.S vaccine (Johnson & Johnson) which was shown to be 66.9% effective in preventing moderate to severe COVID-19.⁵⁹ However, the efficacy of COVID-19 vaccines are unknown in SOT patients and there is some concern that immunogenicity may be reduced in this population, in particular among those having recently received T- or B-cell ablative therapy. In the past, some have been concerns about the possibility of vaccines triggering episodes of rejection. At this time, there is no indication that this might be the case with the COVID-19 vaccines currently available. A careful evaluation of the risks, benefits, and timing of COVID-19 vaccination should be considered on case-by-case basis. Further studies in the efficacy and safety of these vaccines in the SOT population are urgently needed.

Conclusions

Our understanding of COVID-19 has progressed significantly, and treatment approaches have been rapidly defined. The production and scale-up of effective vaccines against SARS-CoV-2 represents an unprecedented global effort. Nevertheless, further studies are urgently needed on various fronts, including understanding the role of chronic immunosuppression on SARS-CoV-2 pathogenesis, identifying risk factors for severe COVID-19 in SOT recipients, refining treatment and optimal timing of treatment initiation, and how to equitably vaccinate entire populations, including SOT recipients.

Key Points.

• COVID-19 remains a major threat to global health, in particular to vulnerable populations

• Solid organ transplant recipients are at risk for poor outcomes in COVID-19, although this risk seems comparable those individuals with similar co-morbidities

• While treatment data are emerging, there is a marked gap in transplant specific knowledge of the impact of specific antiviral agents and immunomodulatory therapies in the solid organ transplant population.

• The management of immunosuppression in solid organ transplant recipients with COVID-19 remains uncertain but most experts recommend reducing or stopping anti-metabolites in those with moderate to severe disease.

• Vaccines for COVID-19 have the greatest potential impact in controlling this pandemic but data on safety and efficacy are lacking.