key: cord-0748403-v78xl69t
authors: Sarrell, Bonnie Ann; Bloch, Karen; Chediak, Alissar El; Kumm, Kayla; Tracy, Kaitlyn; Forbes, Rachel C.; Langone, Anthony; Thomas, Lora; Schlendorf, Kelly; Trindade, Anil J.; Perri, Roman; Wright, Patty; Concepcion, Beatrice P.
title: Monoclonal antibody treatment for COVID‐19 in solid organ transplant recipients
date: 2021-11-17
journal: Transpl Infect Dis
DOI: 10.1111/tid.13759
sha: 6c8cd388a8719aba22233db1d4f83077c23a1d13
doc_id: 748403
cord_uid: v78xl69t

Solid organ transplant (SOT) recipients are at high risk for severe coronavirus disease 2019 (COVID‐19). Studies suggest that early intervention with monoclonal antibody (MAB) treatment directed against the SARS‐CoV‐2 spike protein may reduce the risk of emergency department visits or hospitalization for COVID‐19, especially in high‐risk patients. Herein we describe our single‐center experience of 93 SOT (50 kidney, 17 liver, 11 lung, 9 heart and 6 dual‐organ) recipients with mild to moderate COVID‐19 who were treated with bamlanivimab or casirivimab‐imdevimab per Emergency Use Authorization guidelines. Median age of recipients was 55 (IQR 44–63) years and 41% were diabetic. Median time from transplant to MAB was 64 (IQR 24–122) months and median time from onset of COVID‐19 symptoms to the infusion was 6 (IQR 4–7) days. All patients had a minimum 30 days of study follow up. The 30‐day hospitalization rate for COVID‐19 directed therapy was 8.7%. Infusion‐related adverse events were rare and generally mild. Biopsy‐proven organ rejection occurred in 2 patients and there were no graft losses or deaths. A comparator group of 72 SOT recipients diagnosed with COVID‐19 who were eligible but did not receive MAB treatment had a higher 30‐day hospitalization rate for COVID‐19 directed therapy (15.3%), although this difference was not statistically significant, after adjustment for age [OR 0.49 (95% CI 0.18‐1.32), p = 0.16]. Our experience suggests that MAB treatment, with respect to the available MAB formulations and circulating viral variants present during our study period, may provide favorable outcomes for mild to moderate COVID‐19 in SOT recipients. This article is protected by copyright. All rights reserved

Since its emergence in late 2019, the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has reached pandemic proportions and to date is responsible for over 219 million coronavirus disease 2019 (COVID- 19) cases and more than 4 million deaths. 1 Evidence suggests that patients with comorbidities such as older age, hypertension, coronary artery disease, diabetes, chronic kidney disease, obesity, chronic lung disease, dyslipidemia, and cancer may experience a more severe COVID-19 course. 2 In order to improve patient outcomes and to decrease the burden on the healthcare system, it is imperative to identify these high-risk patients and, if possible, to provide early interventions to decrease disease severity and progression.

Published data pertaining to outcomes of COVID-19 in solid organ transplant (SOT) recipients include single center case series, multicenter registries, and analyses utilizing matched controls. [3] [4] [5] [6] [7] [8] 21, 22 Some earlier reports suggested that transplant recipients may have more severe disease and worse outcomes. 3, 6 However, more recent studies utilizing matched cohorts have shown conflicting results. 8, 21, 22 It is therefore unknown how, or if, chronic immunosuppression affects the disease course. Immunosuppression may prevent an effective immune response to the virus and lead to more severe disease. However, it is also hypothesized that a dampened immune response could be protective against the exaggerated and injurious inflammatory response typical of severe COVID-19. 17 Whatever the effect of immunosuppression, transplant recipients often have comorbidities known to increase the risk of severe COVID-19. In addition, SOT recipients are more likely to shed SARS-CoV-2 for a prolonged period of time [19] [20] , and are less likely to develop an immune response to vaccination 16, 18 . Because of these features, SOT recipients are felt to be at high-risk for severe COVID-19, warranting proactive detection and treatment of COVID-19 in this patient population.

One of the treatments in the armamentarium against COVID- 19 and/or hospitalization (of note, the EUA for bamlanivimab monotherapy was revoked on April 16, 2021 and the combination of bamlanivimab/etesevimab on June 25, 2021). [9] [10] [11] Criteria for inclusion in the initial EUA active during the study period includes patients with a body mass index (BMI) ≥35, chronic kidney disease, diabetes mellitus, immunosuppressive disease or treatment, age ≥ 65 years, or age ≥55 years PLUS cardiovascular disease or hypertension or chronic respiratory disease. Monoclonal antibodies are authorized for infusion within 10 days of symptom onset and are not authorized for use in patients who are hospitalized for COVID-19 or have a new or increased oxygen requirement due to COVID-19.

SOT recipients meet the inclusion criteria for MAB treatment due to immunosuppressive therapy alone, and often have additional comorbidities. However, the efficacy and safety of monoclonal antibodies in transplant recipients have not been thoroughly described. Herein we report our single-center experience in the utilization of monoclonal antibodies for treatment of COVID-19 in SOT recipients. Our objectives were 1) to describe the 30-day hospitalization rate for COVID-19 directed therapy among patients treated with MAB compared to a similar group of patients who were eligible but did not receive MAB, 2) to describe the safety of MAB treatment including infusion-related adverse events, and 3) to describe other outcomes among patients treated with MAB and compare to patients who were eligible but did not receive MAB, including 30-day all-cause hospitalization and emergency department (ED visits), biopsy-proven organ rejection, kidney function, graft loss, and death..

We conducted a retrospective single-center cohort study of adult SOT recipients who were diagnosed with COVID-19 between November 22, 2020 and February 2, 2021 at Vanderbilt University Medical Center (VUMC), Nashville, TN.

Study inclusion criteria were: 1) age ≥18 years, 2) recipient of a kidney, pancreas, heart, liver, lung transplant including dual-organ recipients; and 3) positive SARS-CoV-2 PCR nasal or nasopharyngeal swab.

The treatment cohort was composed of patients who received MAB for treatment of COVID-19. Patients were identified by either active laboratory surveillance or by passive provider referral. A daily report was generated that identified all symptomatic outpatients with a positive SARS-CoV-2 polymerase chain reaction (PCR) test performed at VUMC. The PCR platforms utilized at VUMC were Roche 6800 COVID-19 cobas, Roche Liat cobas SARS-CoV-2, Cepheid Xpert® SARS-CoV-2 and CDC LDT. Review of the electronic medical record was performed to identify risk factors for progression to severe disease as specified in the EUA.

Of note, the EUA for MAB treatment is only approved for symptomatic patients. Patients were contacted to confirm the duration of symptoms and those who qualified for monoclonal antibody treatment were offered an infusion appointment. Additionally, VUMC providers were given information about the availability of monoclonal antibody treatment to allow referral of patients who tested positive for SARS-CoV-2 at another laboratory. In these cases, patients with a positive PCR test regardless of platform utilized met criteria for COVID-19 infection.

The comparator cohort was composed of patients who were diagnosed with COVID-19 in an outpatient setting and were eligible but did not receive MAB therapy. Patients who were hospitalized within <2 days between COVID-19 diagnosis and admission were excluded. The rationale is that it would have been unlikely for these patients to have had sufficient time to receive MAB in the ambulatory setting as all patients in the treatment cohort received MAB ≥2 days after initial COVID-19 diagnosis. The <2 day timeframe also likely captures patients who were more acutely ill and are therefore less comparable to the treatment cohort which excluded all seriously ill patients based on EUA criteria. In addition, if a patient attempted to get MAB treatment but was hospitalized before they could receive it, they were also excluded. Supplementary figure 1 demonstrates how the comparator group was determined.

At the time of data collection, all patients were at least 30 days past initial COVID-19 diagnosis and had the opportunity to meet the outcome of 30-day hospitalization. The Vanderbilt University Institutional Review Board (IRB#210132) approved the study.

Determination of which monoclonal antibody product was infused was made by pharmacy leadership depending on allocation and supply. At the time of the study, bamlanivimab and casirivimab-imdevimab were available at VUMC. The monoclonal antibody product that was highest in stock was used for a one-week period; no provision was made to allow patients, staff, or providers to choose a specific product. Vital signs were obtained at baseline and every fifteen minutes during and after the infusion. Initially, both monoclonal antibodies were infused over a 1-hour period. In January 2021 the US Food and Drug Administration revised the duration of infusion time for bamlanivimab, and subsequently patients who received this antibody completed the infusion over 30 minutes. Patients were observed for a minimum of 1-hour after the infusion to ensure there was no hypersensitivity reaction to the monoclonal antibody preparation. Patients were given contact information for the infusion clinic to report delayed adverse events.

Clinical characteristics were collected from the electronic medical record and tabulated in a REDCap database. These included demographic and baseline characteristics (age, sex, race, co-morbidities, kidney function), transplant characteristics (time from transplant, type of transplant, induction and maintenance immunosuppression, history of acute rejection), and data pertaining to the COVID-19 clinical and treatment course (presenting symptoms, treatment and interventions).

The primary outcome of interest was hospitalization for COVID-19-directed therapies within 

Descriptive statistics were used to compare important clinical characteristics between groups. Categorical variables were presented as frequencies (percentages) and continuous variables were presented as medians (IQR). Wilcoxon rank sum test and chi-square test were utilized when appropriate to compare groups. Logistic regression was utilized to quantify the association of MAB therapy with the outcome of hospitalization for COVID-19 directed therapy and all-cause hospitalization ED visits within 30 days of COVID-19 diagnosis, adjusted for age. A p-value of <0.05 was considered statistically significant. All analyses were performed using STATA SE version 15.0 (StataCorp, College Station, TX).

A total of 165 SOT recipients were included in the study with 93 patients comprising the MAB treatment cohort and 72 patients comprising the comparator cohort. Patient and transplant characteristics of both cohorts are summarized in Table 1 . Among the MAB treatment cohort, there were 50 (54%) kidney-alone, 9 (10%) heart-alone, 17 (18%) liveralone, 11 (12%) lung-alone, and 6 (6%) dual-organ recipients with a median time from transplant to MAB therapy of 64 (IQR 24-122) months. Median age was 55 (IQR 43-63) years and majority were male (60%) and white (77%). Comorbidities included hypertension in 88 patients (95%) and diabetes in 38 (41%). The majority of patients received induction immunosuppression at the time of transplant. Alemtuzumab induction was utilized solely for kidney-alone transplant recipients. The most common agents patients for maintenance immunosuppression were tacrolimus (87%), mycophenolate mofetil or mycophenolic acid (64%) and prednisone (58%). The comparator cohort was similar to the MAB treatment cohort except that in the MAB treatment cohort, more patients were hypertensive (88% versus 81%), there was a greater proportion of lung transplant recipients (8% versus 3%), and there was a lesser proportion of heart transplant recipients (15% versus 22%). None of the patients included in the study had a record of COVID-19 vaccination prior to COVID-19 diagnosis.

Among the MAB treatment cohort, patients' symptoms attributed to COVID-19 prior to the infusion are listed in Table 2 . The most common symptoms were cough (82%), congestion (76%), fatigue (75%), headache (68%) and myalgias (61%). (positive PCR test) to the infusion was 3 (IQR 2-5) days. Among the three patients who were hospitalized and did not receive COVID-19 directed treatment, one was admitted for acute kidney injury, one was admitted for nausea and vomiting, and one was asymptomatic and diagnosed with COVID-19 during pre-operative screening for a surgical resection of an aggressive parotid tumor. In addition to the hospitalizations noted, 1 patient in the comparator cohort was seen in the ED without being admitted. He presented with fever and sore throat 17 days after being diagnosed with COVID-19 and was found to have Streptococcal pharyngitis for which he was prescribed antibiotics and subsequently discharged home (Supplementary table 7 

Adverse events related to monoclonal antibody infusion were uncommon. Immediate infusion reactions, defined as occurring within 1 hour of the infusion, were rare and mild except in one patient who experienced an anaphylactic-type reaction which required termination of the infusion after seven minutes and responded to antihistamines and intravenous steroids without further escalation of care. Three patients experienced intravenous infiltration, one patient was asymptomatic but demonstrated heart rate variability between 40-130 beats/minute during the infusion, and one patient felt flushed and experienced palpitations a few minutes after starting the infusion --symptoms resolved quickly after the infusion was paused and did not recur after the infusion was resumed. Among the comparator cohort, as noted above, two patients died within 30 days of COVID-19 diagnosis. There were no acute rejection episodes nor death-censored graft losses.

Serum creatinine values for the comparator cohort at baseline and at 30±7 after COVID-19 diagnosis were similar; baseline median serum creatinine was 1.24 (IQR 1.04-1.57) mg/dL (100% of patients had a baseline serum creatinine) and follow up median serum creatinine was 1.20 (IQR 1.02-1.53) mg/dL (97% of patients had a follow-up serum creatinine).

To our knowledge, this study describes the largest cohort of SOT recipients treated with MAB therapy for COVID-19 and demonstrates that among high-risk, immunosuppressed outpatients infected with COVID-19, MAB therapy is associated with low risk of hospitalizations for COVID-19, and a favorable safety profile. Our cohort of patients was diverse in terms of organs transplanted and exhibited multiple risk factors for severe COVID-19 including older age, overweight/obesity, hypertension, diabetes mellitus, and coronary artery disease.

Eight patients (8.7%) treated with MAB therapy required a hospital admission and received COVID-19-directed treatment within 30 days after COVID-19 diagnosis, compared to 11 patients (15%) who did not receive MAB therapy. This difference however did not reach statistical significance. There was also no significant statistical difference when all-cause hospital admissions and ED visits were evaluated as the outcome. It is interesting to note that none of the 22 patients who received casirivimab-imdevimab were hospitalized, and that all 8 patients hospitalized in the MAB treatment group received bamlanivimab monotherapy which is no longer available for EUA use due to concerns for reduced efficacy with the emergence of SARS-CoV-2 viral variants. We do not have data on the specific variants that infected our patients, but speculate whether these hospitalized patients could Prior studies of COVID-19 in SOT recipients have reported much higher hospitalization rates of 84% and 75%. 5, 6 However, these studies were conducted earlier in the global course of COVID-19 when outpatient testing was not as readily available, so are likely skewed toward sicker patients and may have missed the mild-to-moderate outpatient cases like those reported here. However, even among 41 kidney transplant recipients with confirmed or suspected COVID-19 initially managed as outpatients in New York City, Husain and colleagues 7 reported a 32% hospitalization rate. The 8.7%-15% hospitalization rate observed in our patient population is notably higher than the 0.9-1.6% rate reported in the BLAZE-1 (Blocking Viral Attachment and Cell Entry with SARS-CoV-2 Neutralizing Antibodies) study. 12 The BLAZE-1 study evaluated the efficacy and adverse effects of bamlanivimab monotherapy, bamlanivimab-etesevimab, or placebo in outpatients diagnosed with mild to moderate COVID-19. In this study, 387 out of 577 (67%) patients had at least 1 risk factor for severe COVID-19, although there is no documentation of inclusion/exclusion of SOT recipients. One of the study's secondary endpoints was the proportion of patients with COVID-19 related hospitalization, ED visit, or death at day 29. The rates of COVID-19 related hospitalizations or ED visits were lower in the monotherapy (1.6%) and combination therapy (0.9%) groups compared to placebo (5.8%). One possible reason for lower rates of hospitalization/ED visits in BLAZE-1 compared to our experience is the inclusion of lower risk patients in BLAZE-1; all of our patients were considered high risk, while BLAZE-1 was composed of only 67% high risk patients with no data available to determine what proportion of these were SOT recipients.

More recent studies describing the use of MAB treatment include a retrospective casecontrol study by Kumar et al which showed that the use of bamlanivimab for 218 ambulatory patients with mild-to-moderate COVID-19 led to a lower 30-day hospitalization rate compared to a control group of 185 patients who did not receive MAB treatment (7.3% vs 20%); 27% of the patients in this study were immunosuppressed (HIV, malignancy, autoimmune disease, or transplant). 13 in 73 SOT recipients; of these patients, 12.3% were hospitalized and none experienced intubation, rejection, or death. 15 Earlier administration of MAB also appeared to be more efficacious in this study. The 30-day hospitalization rate in our cohort of SOT patients treated with MAB is similar to these more recent studies, with the benefit of having a SOT comparator group that shows similar hospitalization rate to the study by Kumar et al. 13 Overall, our study suggests that MAB treatment, with respect to the available formulations and circulating viral variants present during our study period, may have favorable outcomes and minimal adverse events. Similar to the BLAZE-1 study, adverse events related to monoclonal antibody infusion in our study were uncommon. 12 Immediate infusion reactions were rare and mild other than one patient who experienced an anaphylactic-type reaction which responded to therapy but required termination of the infusion. Admittedly, the delayed reactions may have been unreliable since there was no active follow-up of patients following infusion. These delayed reactions could have also been related to the COVID-19 infection rather than the therapy.

Other important outcomes in our patient population treated with MAB included acute rejection, kidney function, graft loss, and death. We observed only 2 episodes of biopsyproven acute rejection within 30 days of MAB therapy. Whether these episodes of acute rejection were related to COVID-19, MAB therapy, immunosuppression adjustments, or none of these factors is unknown. Kidney function was stable and excellent at approximately 1-month post-COVID-19or MAB therapy which is relevant to all of our patients since acute kidney injury is a common complication of COVID-19. There were no events of graft loss or death. No deaths were reported in the MAB trials, although mortality has been reported to be up to 20-30% in other studies describing outcomes of COVID-19 in SOT recipients. 5, 12, 14, 15 This comparison in mortality outcomes between our patient cohort and those previously reported in SOT recipients infected with COVID-19 must however be taken in the context that our cohort had only mild to moderate symptoms prior to MAB therapy, and our patients were well enough to present for outpatient testing rather than to the ED or hospital.

The strengths of our study include the largest cohort of SOT recipients reported to date to have received MAB therapy, along with granular efficacy and safety data provided and the presence of a comparator group. Although we did not detect a significant difference in our primary outcome between the MAB treatment group and the comparator group, our experience demonstrates the feasibility of MAB administration for the management of COVID-19 in high-risk SOT recipients in an outpatient setting, and an overall acceptable adverse profile.

The study has the inherent limitations of a retrospective observational study including, but not limited to, the possibility of missing data related to patient characteristics and outcomes if not reported in the electronic medical record, patients that are not included in the study because we were unaware of their SARS-CoV-2 infection, and the need to retrospectively identify a comparator group potentially leading to selection bias. The comparator arm was not matched due to the small sample size of potential comparators, although we did note that important baseline characteristics between both groups were similar. The study followup was relatively short and hospitalizations at outside facilities may have been missed.Importantly, Bamlanivimab, either as monotherapy or in combination with etesevimab, is no longer authorized for use given concerns for reduced efficacy with the emergence of SARS-CoV-2 viral variants. Despite this, we believe that our experience utilizing MAB therapy is still clinically relevant. Our study suggests that MAB therapy appears to be a safe and possibly effective treatment during our study period, and could still be beneficial in the future as long as the effectiveness of different MAB formulations against SARS-CoV-2 variants is monitored and treatments adjusted accordingly. Importantly, our study includes patients who received casirivimab-imdevimab which is still in use currently. A prospective study utilizing currently approved MAB therapy is needed to confirm the findings of our study. We do not have data about the specific viral variants which infected our patients, but note that this cohort was infected prior to the wide circulation of the delta variant.

In conclusion, our experience supports the hypothesis that MAB therapy appears to be a safe option for the management of COVID-19 in high-risk SOT recipients in an outpatient setting. Our MAB treatment group had an overall lower 30-day hospitalization rate than a comparator group of patients who were eligible but did not receive MAB treatment which is encouraging, though this was not statistically significant and the retrospective nature of the data collection makes it difficult to draw any firm conclusions about outcome differences.

We believe our findings are timely and informative to the transplant community as we continue to explore the best approach in preventing severe COVID- 19 Values are expressed as frequencies (percentages) for categorical variables and medians (interquartile ranges) for continuous variables; *not mutually exclusive; a chronic obstructive pulmonary disease; b coronary artery disease; c monoclonal antibody; d simultaneous pancreas-kidney; e simultaneous liver-kidney; f simultaneous heart-kidney, g mycophenolate mofetil, h mycophenolic acid, i emergency department Renal replacement therapy 0 (0) 1 (9.1)

Lymphocyte count, x10 3 

COVID-19 United States Cases by County -Johns Hopkins Coronavirus Resource Center

Prognostic factors for severity and mortality in patients infected with COVID-19: A systematic review

This article is protected by copyright. All rights reserved

COVID-19 and kidney transplantation: Results from the TANGO International Transplant Consortium

Outcomes of critically ill solid organ transplant patients with COVID-19 in the United States

COVID-19 in solid organ transplant: A multicenter cohort study

COVID-19 in solid organ transplant recipients: Initial report from the US Epicenter

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US Food and Drug Administration. Coronavirus (COVID-19) update: FDA authorizes monoclonal antibodies for treatment of COVID-19

Effect of Bamlanivimab as Monotherapy or in Combination With Etesevimab on Viral Load in Patients With Mild to Moderate COVID-19: A randomized Clinical Trial

Real-World Experience of Bamlanivimab for COVID-19: A Case-Control Study

This article is protected by copyright. All rights reserved

Casirivimab-Imdevimab for Treatment of COVID-19

Monoclonal Antibody Therapy for COVID-19 in Solid Organ Transplant Recipients. Open Forum Infectious Diseases

Three Doses of an mRNA COVID-19 Vaccine in Solid-Organ Transplant Recipients

COVID-19 and Calcineurin Inhibitors: Should They Get Left Out in the Storm?

Antibody response to 2-dose SARS-CoV-2 mRNA vaccine series in solid organ transplant recipients

Viral shedding prolongation in a kidney transplant patient with COVID-19 pneumonia

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Inpatient COVID-19 outcomes in solid organ transplant recipients compared to non-solid organ

The project described utilized REDCap which is supported by CTSA award No. UL1TR000445 from the National Center for Advancing Translational Sciences. Its contents are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the National Institutes of Health. There is no funding for this study to declare.

The authors of this manuscript have no conflicts of interest to disclose as described by Transplant Infectious Disease.