key: cord-1021340-utzaoav8
authors: Arya, Akanksha; Li, Michael; Aburjania, Nana; Singh, Pooja; Royer, Tricia; Moss, Sean; Belden, Katherine
title: COVID-19 in Solid Organ Transplantation: Disease Severity and Clinical Update
date: 2021-02-25
journal: Transplant Proc
DOI: 10.1016/j.transproceed.2021.02.014
sha: e6a498ecd8ba97af2f0719d881bc8c919e080e87
doc_id: 1021340
cord_uid: utzaoav8

Background Solid organ transplant (SOT) recipients are a complex, immunocompromised population in whom greater COVID-19 mortality has been reported as compared to the general population. Methods We examined a retrospective cohort of 58 SOT recipients with first-wave COVID-19, comparing patients with severe and non-severe illness. Additionally, SOT patients are compared to general first-wave COVID-19 patients. Results Organs transplanted included 38 kidneys, 8 livers, 5 hearts, 3 pancreas. Average SOT patient age was 57.4 years with 62% male, 46.6% African American, 36.2% white. Comorbidities included hypertension (86%), chronic kidney disease (86%), diabetes mellitus (50%), coronary artery disease (26%), COPD (14%). Twenty patients (34.5%) had severe COVID-19 and 38 (65.5%) non-severe disease. Severe disease was more common in older SOT patients with comorbidities and associated with cough, dyspnea, pneumonia, C-reactive protein > 10 mg/L, platelet count < 150/mcL. Gender, race, BMI, time from transplant, baseline immunosuppression and diagnosis month did not differ between those with severe vs non-severe COVID-19. Seventy percent of SOT patients were hospitalized vs 27.2% of general COVID-19 patients and SOT inpatients had a higher mechanical ventilation rate. While trending towards longer length of stay, higher ICU admission and greater inpatient mortality (19.5% vs 14.8%), these differences were not significant. Conclusions SARS-CoV-2 has greatly impacted SOT recipients. One-third of our SOT patients seen during the first wave had severe illness with associated standard risk factors for poor outcome. Compared to general first wave patients, more SOT recipients were hospitalized, although inpatient COVID-19 mortality did not significantly differ.

The ongoing COVID-19 pandemic is an outbreak of historic proportions. Currently, there are over 23 million cases and over 390,000 deaths reported in the United States alone, and over 94 million cases and 2 million reported deaths globally. 1, 2 The progression of the pandemic has generated an understanding of the varied clinical presentations of COVID-19 and factors that increase morbidity and mortality in the general population, including older age and comorbidities. [3] [4] [5] [6] [7] [8] [9] Solid organ transplant (SOT) patients are a complex, immunocompromised population for which the full impact of COVID-19 remains to be determined. Mortality in SOT patients has been reported to be higher than that in the general population with rates of 10-28% seen in symptomatic patients and up to 50-75% in those requiring intubation. [10] [11] [12] [13] SOT patients often have comorbidities, such as older age, obesity, diabetes, hypertension, renal dysfunction, cardiovascular disease and chronic lung disease, that lead to or are resultant of their organ transplants and also likely increase the risk for a more severe COVID-19 clinical course.

SOT patients are unique in their regular use of immunosuppressant medications, however, potentially impacting presentation, clinical course, and outcomes in COVID-19. A high proportion of transplant recipients infected during previous coronavirus outbreaks had severe disease. 14 It is currently unknown whether immunosuppressive therapy impacts susceptibility to the SARS-CoV-2 virus or the severity of inflammation in COVID-19.

Our study aims to describe the clinical features and clinical course of COVID-19 in SOT recipients seen in our region during the first COVID-19 wave in our region. We compare subgroups of SOT patients with severe and non-severe illness and also compare SOT patients to our healthcare system's general COVID-19 patients. Through reporting our findings, we aim to further the understanding of COVID-19 in the SOT patient population as transplant centers continue with patient care and transplantation surgery during the ongoing surge in COVID-19 cases anticipated through 2021.

This was a retrospective cohort study of 58 SOT recipients diagnosed with first-wave COVID-19 in our healthcare system located in Philadelphia, PA and southern New Jersey including 4 multihospital locations. The primary study objective was to compare SOT recipients with severe and non-severe infection. A secondary objective was to compare SOT patients with COVID-19 to general COVID-19 patients in our healthcare system during the study period. The study protocol was reviewed and approved by our center's Institutional Review Board (IRB). Patients without an active transplant or a new diagnosis of COVID-19 were excluded. Given incomplete data with automated extraction, manual chart review was performed to identify COVID-19 symptoms, comorbidities, presence of bacteremia, COVID-19 management, graft dysfunction.

Analysis was performed on available data. All data points were not available for each patient and the adjusted number of patients for each variable is noted. Continuous data are presented as mean value with calculated standard deviation and t-test performed against severe disease status for the primary outcome. Categorical data are presented as proportions with Chi-square test performed against severe disease status for the primary outcome. A p-value below 0.05 was considered as significant. Testing was not performed when the total N was less than 9.

Given our sample size, two to four independent variables were estimated in multivariable models with the binary outcome variable of severe disease. Variables from the multivariable regression models with a p-value less than 0.1 on analysis were considered significant. The signs of estimated parameters with the smallest p-values are reported from ten multivariable models to understand risk factor correlation with outcome. Given our sample size, true correlation effects (or odds ratios) could not be controlled for all confounding factors. dyspnea (37%), fatigue (20.4%), diarrhea/vomiting (18.5%), pharyngitis (9.3%) and loss of taste or smell (3.7%). One-third of patients presented with a WBC <4/L, 42% had a platelet count <150/mcL and 47% had a CRP >10 mg/L. Acute kidney injury was reported in 46.3% of cases.

Seventy percent of patients were hospitalized with an average inpatient length of stay of 11.1 days and 34% readmitted within 3 months of discharge. Total mortality for our patient population was 17.2% with 2 patients expiring outside of the hospital; 1 at home and 1 in a long-term care facility.

Severe vs non-severe COVID-19

Twenty patients (34.5%) had severe disease and 38 (65.5%) had non-severe disease. As shown in Table 1 , there were no significant differences in patient gender, race, type of transplant, time from transplant, baseline immunosuppressive therapy or month of diagnosis between patients with severe and non-severe COVID-19. Patients with severe disease were older than those with nonsevere disease having an average age of 64.5 vs. 53.7 years, with a p-value of 0.0042. Severe disease affected only 1 out of 11 patients less than 50 years but 8 out of 12 in those greater than 71 years.

Patients with severe disease were more likely to have hypertension (100% vs 78.9%, with a p-value of 0.0271) and/or COPD (25% vs 7.9%, with a p-value of 0.0726). Table 2 , those with severe illness were more likely to present with cough (84.2% vs 25.7%, with a p-value <0.0001) and/or dyspnea (57.9% vs 25.7%, with a p-value <0.0171) and to receive a diagnosis of pneumonia (100% vs. 42%, with a p-value <0.0001). They were also more likely to have a C-reactive protein >10 mg/L (84.6% vs 23.8%, with a p-value of 0.0007) and/or a platelet count <150/mcL (64.7% vs 28.6%, with a p-value of 0.0088). Sixty-five percent of patients received an adjustment in immunosuppressive therapy, more commonly those with severe illness (84.2% vs 55.6%, with a p-value of 0.0412). Twenty-seven (46.6%) patients received antiviral therapy with severely ill patients more likely to receive Remdesivir (31.6%) and convalescent plasma (31.6%). Ten patients were treated with corticosteroids initiated for COVID-19, nine of whom had severe illness. Severely ill patients had a significantly longer hospital length of stay (average 19 days) than those admitted and non-severely ill (average 5 days), with a p-value of 0.0003. Critical illness included those admitted to the ICU (12 patients), mechanically ventilated (10 patients) and on ECMO (2 patients). Mortality was 17.2% in the total SOT cohort, 19.5% in those hospitalized and 50% in those patients with severe infection. Table 3 , most multivariable analysis results were consistent with bivariable analyses although kidney as the transplanted organ was marginally negatively correlated with severe disease and a BMI value 30 kg/m 2 or higher was negatively correlated with severe disease.

Age greater than 71, COPD, a diagnosis of pneumonia, and CRP greater than 10 mg/l were positively correlated with severe disease.

In comparison to general COVID-19 patients at our healthcare system during the study period, SOT patients with COVID-19 were more likely to be male (62% vs. 45% with a p-value of 0.0094) and/or Hispanic (13.8% vs. 4.9% with a p-value of 0.0018), as shown in Table 4 . Seventy percent of SOT recipients were admitted to the hospital with COVID-19 as compared to 27.2% of general patients, with a p-value <0.00001. Inpatient progression measures were examined for SOT and general COVID-19 inpatients. SOT patients had a higher mechanical ventilation rate (24.4% vs. 14.3%, with a p-value of 0.070). They trended towards a longer average inpatient length of stay (11.1 vs. 8.7 days), a higher ICU admission rate (29.3% vs. 24.3%), and a higher inpatient mortality rate (19.5% vs. 14.8%) without a significant difference in comparison to general patients.

This paper provides a profile analysis of 58 SOT patients diagnosed with COVID-19 between March and September, 2020, comparing those with and without severe infection. SOT patients are also compared to general COVID-19 patients.

The Centers for Disease Control identifies organ transplant recipients as at increased risk of severe COVID-19. 15 Reported mortality in SOT patients has been higher than in the general population with rates of 10-28% in symptomatic patients and up to 50-75% in those requiring intubation. 10-13, [16] [17] [18] Notably, seventy percent of our SOT patients were hospitalized as compared to 27 .2% of general COVID-19 patients in our healthcare system. This difference likely reflects a lower threshold for hospitalization in SOT recipients as well as concerning clinical markers. A greater percentage of our SOT patients required mechanical ventilation than general patients, while the inpatient metric comparisons of length of stay, need for ICU admission and inpatient mortality (19.5% in SOT patients and 14.8% in general patients) did not significantly differ. Once hospitalized for COVID-19, progression in SOT patients may be similar to the general population. One-third of our SOT recipients were readmitted to the hospital within three months of discharge, however, speaking to frailty and an often-complicated recovery. Mortality in general patients has declined with progression of the pandemic likely in part due to improved management. 19, 20 Accordingly, only one patient in our series with a fatal outcome was admitted after June 1, 2020. Fifteen of our patients recovered at home with supportive care and further investigation into the heterogeneity of COVID-19 in immunocompromised hosts is warranted.

The risk of severe COVID-19 in SOT patients is likely multifactorial with the direct contribution of immunosuppression challenging to assess. Other centers have not found transplantrelated immunosuppression surrogates to contribute to increased COVID-19 morbidity and mortality while age and medical comorbidities have been independently associated with worse outcomes. 13, 17, 18 Most SOT related factors did not correlate with severity of infection differences among our transplant recipients. Time from transplant, baseline immunosuppressive therapy, and graft dysfunction did not differ between those with severe and non-severe infection. Better general health in kidney transplant recipients may explain the observed negative correlation of kidney as the transplanted organ with severe disease on multivariable analysis.

Advanced age, comorbidities, racial and ethnic minority identification and male sex have been shown to increase COVID-19 morbidity and mortality in the general population. 5, [21] [22] [23] [24] In contrast to the 2009 influenza A (H1N1) pandemic in which the elderly had less severe illness, lack of preexisting or cross-reactive adaptive immunity to SARS-CoV-2 in the general population has contributed to its impact on older adults. [25] [26] [27] Longstanding systemic health and social inequities have contributed to the disproportionate burden of COVID-19 experienced by Americans of color, those of lower socioeconomic status and those residing in population dense regions. 22, 28, 29 A majority of our SOT patients with COVID-19 had demographic or medical risk factors for worse outcomes. Those with severe infection had an increased prevalence of hypertension and/or COPD and were significantly older than those with non-severe infection. We did not observe BMI or nonwhite race to be associated with severity of COVID-19 or clustering of cases by zip code. Transplant recipients are well connected to the healthcare system given their chronic conditions. This could potentially increase SARS-CoV-2 exposure given frequent contact with healthcare facilities while also facilitating support when confronted with infection. Differences in demographics as well as high rates of comorbidities reflect the SOT population's risk factors for organ failure requiring a transplant as well as increased risk for COVID-19 complications. 15, 22, 30, 31 In spite of the potential for confounding medication toxicity and organ rejection, available literature has demonstrated that SOT patients exhibit symptoms and laboratory abnormalities similar to general patients. 3, 6, 9, [12] [13] [14] [15] 29 Presentation similar to general patients allows clinicians to use similar illness-scripts and case definitions when determining which SOT patients require further investigation for COVID-19 and those at higher risk for progression. Our SOT patients with severe COVID-19 presented more often with cough, dyspnea, a diagnosis of pneumonia, higher CRP values and lower platelet counts. Only two patients reported loss of taste or smell, both of whom had a non-severe clinical course as has been portended in other cases. 38 Acute kidney injury, found in 46% of our patients, is likely multifactorial in COVID-19, especially in severe illness, with the roles of hypotension, viral mediated nephrotoxicity, complement deposition and microvascular thrombosis contributing. 39, 40 As T-cell immunity, a key component of the immune response to viral pathogens, is hampered by immunosuppressive transplant therapy, reduction of maintenance immunosuppression strategies in COVID-19 are understandable and were used in the majority of our patients. Presentation with lymphopenia in many COVID-19 patients indirectly supports this approach. 41 However, cytokine release syndrome with amplification of viral cytopathic lung injury has been proposed as an underlying mechanism for severe COVID-19, supported by increases in IL-6 and other inflammatory markers. 27, [42] [43] [44] Improved mortality in patients treated with corticosteroids supports this proposed mechanism and suggests potential benefits of immunosuppression. 45 Considerations include the potential for a lower antibody response, a more rapid decline in antibody titer, reduced protection post-transplant, and immune stimulation. 69 While acknowledging these gaps in knowledge, the benefits of vaccination in SOT recipients are thought to outweigh the risks. Transplant candidates should optimally receive vaccination two or more weeks prior to transplantation. Unvaccinated transplant recipients should delay vaccination for one to six months after transplant including three months after antithymocyte globulin therapy. Vaccination is recommended after COVID-19 recovery with the option to postpone for up to 90 days. 70, 71 While our study demonstrates that SOT patients face morbidity and mortality from COVID-19, the impact of the pandemic on the operation of transplant centers also harms patients awaiting transplant. Over 113,000 patients are on the US national transplant waiting list. A patient is added to the waitlist every nine minutes, and seventeen patients die every day waiting for a transplant. 72, 73 Early in the pandemic, transplant surgery was markedly reduced throughout the United States due to concerns about safety and lack of center capacity. 48, 74, 75 In communities with circulating SARS-CoV-2, transplant centers must weigh resource availability, in particular intensive care resources, with the need for continuation of organ transplantation. Per the Centers for Medicare and Medicaid Services, organ transplants are considered Tier 3b procedures that should not be postponed in high acuity or unhealthy patients. 76 Strategies for donor and candidate screening, appropriate personal protective equipment, general COVID-19 prevention practices and the use of telemedicine have allowed centers to continue patient care and resume organ transplantation at levels similar to prior years. 23, 77 Living donors and candidates should be counseled on prevention strategies, the need to report COVID-19 symptoms and contacts and self-quarantine as feasible. SARS-CoV-2 organ transplant testing recommendations have been developed by the American Association for the Study of Liver Diseases, the International Society for Heart and Lung Transplantation, the American Society for Transplantation and the Association of Organ Procurement Organizations, as outlined in Table 5 . [78] [79] [80] [81] [82] [83] Additional considerations for transplant centers include COVID-19 related renal dysfunction in potential kidney donors, non-lung organ utilization in SARS-CoV-2 positive donors and the roles of antigen and antibody testing.

Our study has several limitations including a small sample size and that 70% of patients were kidney transplant recipients limiting full extrapolation to other organs. In addition, some data points were not available for all patients or the general COVID-19 cohort and longer term follow up could identify additional outcomes.

In summary, SOT recipients in our healthcare system have been significantly impacted by the SARS-CoV-2 pandemic. The majority of those infected required hospitalization and over onethird had a severe clinical course. Once hospitalized for COVID-19, however, outcomes were similar for SOT and general patients. Risk factors for severe infection in SOT recipients appear to be similar to those in the general population, in particular including advanced age and comorbidities, while the contribution of immunosuppressive therapy remains to be determined. As circulation of SARS-CoV-2 continues, with an unknown impact of variant viral strains, transplant centers will experience ongoing straining of resources, facing similar challenges to those seen in the spring of 2020. However, the challenges confronting organ transplant recipients and transplant centers are now faced with improved access to testing, best practices on infection control, expanded treatment interventions, SARS-CoV-2 vaccines, and a growing body of literature contributing to understanding SARS-CoV-2 infection in this specialized patient population. 

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