key: cord-0769391-otu3ezo4
authors: Heldman, Madeleine R.; Kates, Olivia S.
title: COVID-19 in Solid Organ Transplant Recipients: a Review of the Current Literature
date: 2021-06-29
journal: Curr Treat Options Infect Dis
DOI: 10.1007/s40506-021-00249-6
sha: a9677bb9108749db5c0983f09b1a90b5da03c51b
doc_id: 769391
cord_uid: otu3ezo4

PURPOSE OF REVIEW: The approach to ongoing organ transplantation and management of COVID-19 in solid organ transplant recipients (SOTR) has evolved tremendously since the pandemic’s beginning. We summarize the current literature surrounding the virology of SARS-CoV-2, epidemiology of COVID-19 in transplant recipients, review the clinical features and complications of COVID-19 in SOTR, and discuss the safety and efficacy of current therapies and candidate vaccines in this population. RECENT FINDINGS: Despite initial suspensions in organ transplantation during early 2020, routine donor testing and de-crowding of hospitals have allowed transplant activity to resume at pre-pandemic rates. COVID-19-associated mortality in SOTR is similar to that of the general population, and lower than that of patients with end-organ disease awaiting transplant. The optimal approach to immunosuppression in SOTR with COVID-19 is unknown and disease severity may influence management decisions. Many vaccines in development are likely to be safe for immunocompromised hosts, though post-marketing investigations will be required to determine the efficacy in the SOTR. SUMMARY: Though there are multiple unique considerations in the care of SOTR with COVID-19, immunosuppression does not appear to have a detrimental impact on overall outcome. Organ transplantation remains a lifesaving intervention and can be safely performed despite a global pandemic.

The impact of the COVID-19 pandemic on the field of solid organ transplantation has been profound, from patients with organ transplants to patients on waiting lists to clinicians and transplant programs. Over the first year since the emergence of the novel coronavirus, SARS-CoV-2, in 2019, several key questions about COVID-19 in transplantation have arisen: How is the epidemiology of COVID-19 different for transplant recipients? What are the clinical manifestations and outcomes of COVID-19 in patients with organ transplants? What role does immunosuppression play in infection, morbidity, and mortality? What are the optimal strategies for treatment or prevention of COVID-19 among transplant recipients? How should transplant programs adapt to the novel global pandemic in order to deliver optimal care to their patients? This review will summarize current knowledge about COVID-19 in transplantation.

SARS-CoV-2 is a novel human beta-coronavirus of probable bat origin first recognized in Wuhan, China, in late 2019 [1] . All coronaviruses are large, enveloped, positive-sense RNA viruses with 4 homologous structural proteins: envelope, membrane, nucleocapsid, and spike. The spike protein of SARS-CoV-2 binds angiotensin-converting enzyme 2 (ACE2) on the human cell surface. The SARS-CoV-2 spike protein receptor-binding domain is hidden in the preactivation state, enabling immune evasion. Multiple host proteins including furin, TMPRSS2, and lysosomal proteases participate in SARS-CoV-2 entry into human cells by exposing the receptor-binding domain and facilitating endocytosis, leading to high-affinity binding to ACE2 and enhanced cell entry [2] . These unique properties of the cell entry molecular mechanism may contribute to infectivity and impaired immune clearance of the virus.

ACE2 is widely distributed in human tissue including in the lung, heart, kidney, central nervous system, and vascular endothelium [3] . SARS-CoV-2 has been detected in each of these tissues in clinical samples or at autopsy in a limited number of cases, although detection of intact virions by electron microscopy remains a technical challenge requiring specialized expertise [4] [5] [6] . Direct viral infection of non-lung tissues may contribute to organ-specific involvement and extra-pulmonary symptoms seen in COVID-19, including renal dysfunction, cardiomyopathy, vasculopathy, and more recently recognized neuropsychiatric effects [7] . The possibility of non-lung end organ involvement with SARS-CoV-2 has raised the question of whether SARS-CoV-2 could be transmitted through transplantation. In the USA, the Organ Procurement and Transplantation Network (OPTN) recommends that all potential deceased organ donors be screened for SARS-CoV-2 infection and that any potential donor who tests positive be deferred [8] . One case report describes inadvertent living liver transplantation from a donor with symptomatic SARS-CoV-2 infection at the time of donation, without transmission [9] .

Early infection appears to be dominated by viral replication. In later infection, host immune dysregulation appears to play a significant role in the pathogenesis of severe COVID-19 and respiratory failure, as well as delayed sequelae of COVID-19 [10] . Plasma cytokine levels indicate broad immune activation including type 1, 2, and 3 responses, with some evidence that a type 2 immune response may be more strongly associated with respiratory failure [11] . How transplant-related maintenance immunosuppression affects this complex pathophysiology is still incompletely understood and likely varies with the different phases of illness. Interestingly, while short-term application of glucocorticoids is shown to reduce the type 2 immune response, prior exposure to glucocorticoids is associated with a predisposition toward type 2 immunity, which may partially explain the therapeutic value of glucocorticoids despite some evidence in non-transplant populations that baseline steroid use is not protective [12] [13] [14] .

As of March 30, 2021, there have been over 127 million cases of COVID-19 diagnosed, and over 2.7 million deaths globally [15] . Seroprevalence studies suggest that confirmed case counts underestimate the true prevalence of COVID-19 by a factor of 10 [11] . Following its emergence in Wuhan, China, the early phases of the COVID-19 pandemic were defined by travel-associated local and regional outbreaks, with notable large outbreaks in Italy, Iran, Spain, and New York City, USA, from February through April 2020 [16] (Table 1) . During this period, concerns about unfavorable outcomes among organ transplant recipients, challenges with infection prevention and control, and reduced resource availability led to a decline in deceased donor organ transplantation by 51% in the USA and as high as 91% in France [17] . Such declines in transplantation were associated with increases in waitlist deaths [18, 19] . Despite the continued rise in cases, transplantation has returned to pre-2020 levels in many regions, reflecting the adaptability of the transplant community and increasing understanding of the risks of deferring transplantation for patients on waiting lists.

SARS-CoV-2 is spread primarily via respiratory droplets, with additional contributions from short-distance aerosols and contaminated surfaces [11] . Multiple epidemiologic studies have demonstrated higher incidence of COVID-19 among solid organ transplant recipients compared to the general population, which may be due to increased risk of exposure from frequent healthcare contacts, greater susceptibility to a lower infectious dose of SARS-CoV-2, greater likelihood of symptomatic rather than asymptomatic infection, or ascertainment bias due to increased alertness and testing in this population [20, 21] . Interestingly, studies in Italy and the UK reveal even higher incidence among patients on transplant waiting lists, again underscoring the risks of deferring transplantation during this pandemic [22, 23] .

Transplant recipients may also be more likely to transmit SARS-CoV-2. In the general population, peak viral shedding occurs prior to symptom onset and declines rapidly [11] . Among immunocompromised transplant patients, viral shedding may persist much longer and at lower cycle thresholds, corresponding to higher viral loads [24] . Although detection of viral RNA does not necessarily indicate transmissible live virus, altered viral kinetics in transplant recipients may have implications for infection prevention. Neutralizing antibodies to SARS-CoV-2 typically appear at approximately 2 weeks after symptom onset. The degree of protection and duration of natural immunity is not yet fully understood and may differ for transplant recipients. In one study of kidney No difference in mortality SOTR had a higher risk of hospitalization transplant recipients, antibodies to SARS-CoV-2 emerged within the second week after symptoms and persisted for 2 months for all patients [25] . Case reports describe non-immunosuppressed patients who have developed SARS-CoV-2 re-infection after seroconversion [26] . Although there are no case reports of re-infection in solid organ transplant recipients, one report does describe a patient who developed COVID-19 prior to liver transplantation and proceeded to seroconversion and negative SARS-CoV-2 nasopharyngeal swab PCRs. The patient received a deceased donor liver transplant from a donor who tested negative for SARS-CoV-2 on day 36 after symptom onset, day 15 after seroconversion. After transplant, the patient had return of positive nasopharyngeal swab PCR for SARS-CoV-2 that was genetically identical to the previous strain, as well as marked decline in neutralizing antibodies to a low-range titer [27] . This single case suggests that the process of transplantation, whether the stress of surgery, hemodilution, or immunosuppression, could potentially affect SARS-CoV-2 natural immunity that could theoretically predispose some transplant patients to reinfection, although actual cases of reinfection are not yet reported.

Among solid organ transplant recipients with COVID-19, approximately half have fever at presentation, a majority have cough and dyspnea, one-third have upper respiratory symptoms, and between one-third and one-half have gastrointestinal symptoms [17, 20, 28, 29] . In one study, 5% of patients presented with gastrointestinal symptoms in the absence of any respiratory symptoms [17] . Even in patients with minimal or mild respiratory symptoms, radiographic evidence of pneumonia is very common, seen in over 80% of patients [17, 30] . Differing definitions of clinical criteria, particularly "fever," have led to a wide range in reported rates of some symptoms; however, when comparable definitions are considered, the symptom profile among solid organ transplant recipients with COVID-19 is essentially the same as for the general population [17] . During the early phases of the COVID-19 pandemic, solid organ transplant patients experienced high morbidity and mortality. In the USA, approximately 75% of solid organ transplant recipients diagnosed with COVID-19 required hospital admission. Of these, close to 40% required intensive care, close to 30% required mechanical ventilation, and 25% required vasopressor support [17, 28] . Mortality among hospitalized patients in large cohorts of solid organ transplant recipients with COVID-19 has ranged from 20 to 32% [17, 21, 23, [28] [29] [30] [31] [32] [33] . Although these outcomes are grave, mortality appears to be similar to hospitalized general population cohorts during the same time period [34] . In fact, one study found significantly lower mortality among liver transplant recipients than in a matched comparison cohort [21] . More recently, morbidity and mortality from COVID-19 appear to be declining in the general population, possibly due to increased testing and identification of mild cases, changing epidemiology with a higher proportion of young patients with fewer comorbidities, improvements in management, or resource availability [11] .

Risk factors for mortality among solid organ transplant recipients with COVID-19 include older age, underlying medical conditions such as obesity, chronic lung disease, congestive heart failure, or malignancy and features of severe COVID-19 at presentation such as leukopenia or radiographic evidence of pneumonia [17, 32] . In one large cohort study including 54 lung transplant recipients, lung transplantation was associated with an increased risk of mortality compared to non-lung transplant recipients in a univariable analysis; however, this study was not able to control for baseline comorbidities [33] . In another study including 30 lung transplant recipients, there was a trend toward increased mortality among lung transplant recipients in a univariable analysis, but no association between type of organ transplanted and mortality in a model adjusted for age and comorbidities [17] . To date, no study has demonstrated a significant independent relationship between the timing of transplant or recent induction immunosuppression with mortality from COVID-19. In addition, no specific maintenance immunosuppression regimen or drug has been shown to be associated with mortality among transplant recipients with COVID-19. However, in one study of liver transplant recipients, use of a mycophenolatecontaining maintenance immunosuppression regimen was associated with a composite endpoint of ICU admission, mechanical ventilation, or death [21] . In general, the preponderance of evidence supports that age and comorbidities, rather than immunosuppression-related factors, drive COVID-19 mortality among solid organ transplant recipients. Similar findings are reported for patients with inflammatory bowel disease and patients with malignancy [35] [36] [37] .

The reported incidence of acute kidney injury (AKI) in hospitalized patients with COVID-19 ranges from 0.5 to 50%, with lower incidences reported in China compared to Europe and the USA [38] [39] [40] . High FiO2 requirements, mechanical ventilation, vasopressor use, advanced age, male sex, Black race and underlying hypertension, diabetes mellitus, or chronic kidney disease are risk factors for AKI in the setting of COVID-19 [38, 39, 41, 42] .

Solid organ transplant recipients with COVID-19 are at particularly high risk for kidney injury due to high prevalence of underlying chronic kidney disease, diabetes mellitus, hypertension, and calcineurin inhibitor (CNI) use. In a multicenter study of 482 SOTR with COVID-19, 44% of hospitalized patients developed AKI and 15% required renal replacement therapy [17] . Smaller studies directly comparing SOT recipients versus non-SOT controls show trends towards higher incidences of AKI requiring RRT in SOT recipients, even when controlling for underlying CKD [31, 43] . Diarrhea, present in nearly half of SOTR with COVID-19 [17] , reduces efflux pump expression from intestinal epithelial cells, leading to toxic CNI troughs [44] . Treatment of COVID-19 using ritonavir or cobicistat-boosted protease inhibitors may lead to substantial increases in CNI levels and resulting nephrotoxicity by impairing cytochrome P450 drug metabolism [45] .

Allograft dysfunction in COVID-19 must be differentiated from allograft rejection, as heart, lung, kidney, and liver injuries are well-described sequelae of SARS-CoV-2 infection in the non-SOT population. Cytomegalovirus (CMV) and other viral infections enhance alloantigen reactivity, raising the question as to whether SOTR with COVID-19 are at risk for allograft rejection [46] . Any reduction immunosuppression in response to diagnosis of a viral illness would further the risk of rejection. Literature regarding allograft rejection in COVID-19 is currently limited, though biopsy-proven kidney and liver rejection has been reported [47] [48] [49] [50] . In a series of 482 SOTR with COVID-19 followed for 28 days, acute cellular rejection (ACR) occurred in 6 patients (1.3%) and antibodymediated rejection occurred in one patient [17] . Thus, allograft rejection in COVID-19 appears to be rare, though ascertaining the true incidence of biopsyproven rejection in patients with COVID-19 may be limited by reluctance to perform invasive procedures for infection control purposes.

Patients with COVID-19 may have viral, bacterial, or fungal infections at any time during their course of illness. Injury to the respiratory tract epithelium and loss of ciliary function predisposes individuals with influenza and other respiratory viruses to secondary pulmonary infections. In large, single-center studies of the general population, secondary infections occurred in 3-5% of hospitalized patients with COVID-19 [51, 52] , though smaller studies and metaanalyses suggest that the true incidence in patients surviving the initial phase of illness may be higher [53] . The largest cohort study of hospitalized SOTR with COVID-19 to date demonstrates a similar, but slightly higher, incidence of secondary infection; 8% and 6.1% developed bacterial pneumonia and bloodstream infections during hospitalization, respectively [17] . Bacterial pathogens were most common; two patients were diagnosed with Aspergillus pneumonia, and one patient each was diagnosed with Cryptococcus and Pneumocystis pneumonia [17] . Pulmonary aspergillosis in both immunocompetent and immunocompromised patients with COVID-19 has been reported and is associated with poor outcomes [54] .

Effective pharmacotherapy for COVID-19 remains limited and data on treatment efficacy is SOTR is sparse. Current treatment strategies focus on [1] inhibiting viral entry and replication and [2] mitigating an overactive immune response to the virus. Remdesivir, a broad-spectrum antiviral which inhibits viral RNAdependent RNA polymerase, has received emergency use authorization from the Food and Drug administration (FDA). This approval was based on data from the Adaptive COVID-19 Treatment Trial-1 (ACTT-1), a large randomized, placebo-controlled trial demonstrating a trend toward improved survival in severely ill patients and improved respiratory status in hypoxemic patients not requiring intubation [17, 55] . However, preliminary results of the SOLIDARITY trial, a multinational randomized control trial, do not suggest that remdesivir has any impact on mortality. Seven percent of patients in the ACTT-1 trial were classified as having an immune deficiency, but details of these immune compromising states were not reported [55] . Early anti-viral therapy lessens influenza disease severity in solid organ transplant recipients [56] ; the impact of timely remdesivir administration in SOTR with COVID-19 has not been delineated.

Convalescent plasma from donors who have recovered from SARS-CoV-2 infection provides passive immunity with the goal of preventing viral entry and nucleic acid assembly. The US Food and Drug Administration (FDA) has issued an emergency use authorization for use for convalescent plasma, but data supporting its efficacy are limited to small reports [57, 58] . For solid organ transplant recipients, convalescent plasma offers the advantage of avoiding the potential for nephrotoxicity and drug-drug interactions, and immunosuppression does not preclude participation in clinical trials. Several anti-spike protein monoclonal antibodies have been authorized for emergency use. Administration of a monoclonal antibody shortly after exposure provides passive immunity and may dampen disease severity [59] .

Several other drugs with antiviral activity have been explored. Despite initial enthusiasm for chloroquine and hydroxychloroquine, these agents have not been proven to be effective in treating COVID-19 [60, 61] , leading to revocation of an FDA-issued emergency use authorizations [61] . Several other agents, including azithromycin, ivermectin, HIV protease inhibitors, and ribavirin, demonstrate in vitro activity against SARS-CoV-2 or other coronaviruses, but grounded evidence supporting their clinical use in either the general or immunocompromised population is lacking [57] .

Anti-inflammatory agents used to inhibit an overactive immune response have shown mixed results. The corticosteroid dexamethasone was shown to decrease mortality in patients with severe COVID-19 requiring supplemental oxygen in a large, randomized, open labeled control trial (RECOVERY) [62] , though methylprednisolone did not demonstrate such benefit in a phase IIb double-blinded study [63] . Monoclonal antibodies directed against interleukin 6 (IL-6), the IL-6 receptor, and interleukin-1β are under investigation but are not recommended for use outside of clinical trials [64, 65] . Janus kinase (JAK) inhibitors including baracitinib and ruxolitinib are currently under investigation for use in COVID-19, as these agents have in vitro antiviral properties and interfere with cytokine signaling [66] . Whether the addition of dexamethasone or other anti-inflammatory therapies benefits solid-organ transplant patients who are immunosuppressed at presentation is unclear, as immunosuppression precluded enrollment in many large-scale, randomized studies. Concerns that dexamethasone, in combination with other immunosuppressants, may increase the risk of co-infections and prolong shedding of live virus further complicate management decisions in SOTR with COVID-19 ( Table 2 ).

The optimal management of immunosuppression in patients with COVID-19 is unknown. Decreasing or withdrawing immunosuppression to promote viral clearance is an intuitive management strategy employed for treatment of severe viral infections in SOTR. However, the hyper-inflammatory response characteristic of severe COVID-19 has introduced a hypothesis that immunosuppression may be protective against severe disease and the observed benefits of dexamethasone support a role for immune modulation in disease management [62] . Indeed, solid organ transplant recipients with sepsis and bacteremia have improved outcomes compared to controls, suggesting that immunosuppression may curb the detrimental effects of hypercytokinemia [68] . However, there is little evidence that the immunosuppression used in the post-transplant setting impacts cytokine profiles in COVID-19. IL-6 and CRP levels, both evidence of cytokine release and predictors of poor outcomes in COVID-19 [69] , were similar among SOTR and non-SOTR in a multicenter analysis [31] . In vitro suggestions that mycophenolate and tacrolimus have direct activity against coronaviruses provided an initial argument in favor of continuing fulldose immunosuppression, but in vivo evidence of benefit is lacking [70] .

Unlike other respiratory viruses, SARS-CoV-2 viral burden peaks early after infection prior to development of prominent symptoms [71] , and severe illness develops late in the course when viral replication has diminished. Thus, reducing immunosuppression in early COVID-19 to promote viral clearance may prevent progression to severe disease is an intuitive approach. Because lymphopenia portends a poor prognosis in COVID-19 [69] , limiting exposure to lymphotoxic immunosuppressive agents (e.g., mycophenolate) is logical. Reducing immunosuppression (RIS), particularly antimetabolites, has demonstrable impacts on controlling DNA viruses in SOTR [72] . Evidence supporting RIS for lower respiratory viral infections is less robust, though, as discussed above, withdrawal of maintenance mycophenolate was associated with a trend toward less severe COVID-19 disease in a cohort of liver transplant recipients in Spain [21] . Holding or reducing antimetabolites has become a common practice in the management of SOTR with COVID-19, while adjustments to calcineurin inhibitors are less common [17, 28, 43, 46] . Addition of dexamethasone in severe disease provides additional protection against allograft rejection.

Vaccines are powerful tools for controlling pandemic respiratory viruses [73] . In December 2020, two vaccines containing messenger RNA encoding the SARS-CoV-2 spike protein (mRNA-1273 (Moderna) and BNT162b2 (Pfizer/BioNTech)) were authorized for emergency use in many countries based on promising efficacy data from phase III trials in immunocompetent adults [74, 75] . Replication-defective adenoviral vaccines containing the DNA version of the SARS-CoV-2 spike protein and vaccines that contain whole-inactivated SARS-CoV-2 virus or recombinant spike proteins are platforms that have also been authorized for use or in advanced phases of clinical trials [76]. These major vaccine platforms do not contain any replication-competent SARS-CoV-2 RNA and therefore do not pose any risk of SARS-CoV-2 infection in immunocompromised hosts. There is a theoretical risk that any vaccine may elicit systemic immune response and subsequent rejection. This became a major concern after a high incidence of de novo anti-HLA antibodies was observed in kidney transplant recipients who received the 2009 influenza A(H1Na1)pdm09 vaccine. However, a thorough investigation was unable to identify any association between vaccination and acute rejection and multiple professional organizations agree that the potential benefits of SARS-CoV-2 vaccination far exceed any theoretical risks [76] .

While the SARS-CoV-2 platforms in current use do not have major safety concerns for SOT recipients, it is unknown whether these vaccines will be sufficiently immunogenic and effective in immunocompromised populations. Solid organ transplant recipients on immunosuppressive agents are precluded from participating in SARS-CoV-2 vaccine trials. SOTR mount weaker antibody responses to inactivated, polysaccharide, and conjugated vaccines compared to healthy controls and preliminary data suggests that SOT recipients may mount weaker humoral responses to mRNA SARS-CoV-2 vaccines compared to healthy controls [67, 77] . Large epidemiologic studies assessing the real-world effectiveness of vaccines in preventing both severe infection and asymptomatic transmission in SOT recipients are desperately needed.

Our understanding of the SARS-CoV-2 virology and COVID-19 disease has grown tremendously over the past 9 months. Outcomes of COVID-19 in SOTR appear to mirror those in the general population, though how to best balance the protective and deleterious aspects of immunosuppression remains uncertain. Dedicated efforts are needed to understand the efficacy of novel treatments and vaccines in solid organ transplant recipients and immunocompromised hosts. Despite continued uncertainty about the management of COVID-19 after transplantation, the risks of deferring transplantation for patients on waiting lists must be appreciated, and we commend transplant programs around the world for their work to continue to deliver this life-saving therapy under extraordinarily challenging circumstances.

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The authors thank Dr. Ajit P. Limaye, Dr. Cynthia E. Fisher, Dr. Robert M. Rakita, and Dr. Erika D. Lease for their tireless commitment to teaching and contagious enthusiasm for infectious disease management in solid organ transplantation. 

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