Faculty Bibliography

BACKGROUND:Understanding immunogenicity and alloimmune risk following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in kidney transplant recipients is imperative to understanding the correlates of protection and to inform clinical guidelines. METHODS:We studied 50 kidney transplant recipients following SARS-CoV-2 vaccination and quantified their anti-spike protein antibody, donor-derived cell-free DNA (dd-cfDNA), gene expression profiling (GEP), and alloantibody formation. RESULTS:Participants were stratified using nucleocapsid testing as either SARS-CoV-2-naïve or experienced prior to vaccination. One of 34 (3%) SARS-CoV-2 naïve participants developed anti-spike protein antibodies. In contrast, the odds ratio for the association of a prior history of SARS-CoV-2 infection with vaccine response was 18.3 (95% confidence interval 3.2, 105.0, p < 0.01). Pre- and post-vaccination levels did not change for median dd-cfDNA (0.23% vs. 0.21% respectively, p = 0.13), GEP scores (9.85 vs. 10.4 respectively, p = 0.45), calculated panel reactive antibody, de-novo donor specific antibody status, or estimated glomerular filtration rate. CONCLUSIONS:SARS-CoV-2 vaccines do not appear to trigger alloimmunity in kidney transplant recipients. The degree of vaccine immunogenicity was associated most strongly with a prior history of SARS-CoV-2 infection.

Lung transplant is a life-saving treatment for carefully selected patients with respiratory failure related to the infection with coronavirus disease-2019. Despite a complex pretransplant medical course, the posttransplant outcomes are excellent when performed by experienced centers.

BACKGROUND:Baricitinib and dexamethasone have randomised trials supporting their use for the treatment of patients with COVID-19. We assessed the combination of baricitinib plus remdesivir versus dexamethasone plus remdesivir in preventing progression to mechanical ventilation or death in hospitalised patients with COVID-19. METHODS:In this randomised, double-blind, double placebo-controlled trial, patients were enrolled at 67 trial sites in the USA (60 sites), South Korea (two sites), Mexico (two sites), Singapore (two sites), and Japan (one site). Hospitalised adults (≥18 years) with COVID-19 who required supplemental oxygen administered by low-flow (≤15 L/min), high-flow (>15 L/min), or non-invasive mechanical ventilation modalities who met the study eligibility criteria (male or non-pregnant female adults ≥18 years old with laboratory-confirmed SARS-CoV-2 infection) were enrolled in the study. Patients were randomly assigned (1:1) to receive either baricitinib, remdesivir, and placebo, or dexamethasone, remdesivir, and placebo using a permuted block design. Randomisation was stratified by study site and baseline ordinal score at enrolment. All patients received remdesivir (≤10 days) and either baricitinib (or matching oral placebo) for a maximum of 14 days or dexamethasone (or matching intravenous placebo) for a maximum of 10 days. The primary outcome was the difference in mechanical ventilation-free survival by day 29 between the two treatment groups in the modified intention-to-treat population. Safety analyses were done in the as-treated population, comprising all participants who received one dose of the study drug. The trial is registered with ClinicalTrials.gov, NCT04640168. FINDINGS/RESULTS:Between Dec 1, 2020, and April 13, 2021, 1047 patients were assessed for eligibility. 1010 patients were enrolled and randomly assigned, 516 (51%) to baricitinib plus remdesivir plus placebo and 494 (49%) to dexamethasone plus remdesivir plus placebo. The mean age of the patients was 58·3 years (SD 14·0) and 590 (58%) of 1010 patients were male. 588 (58%) of 1010 patients were White, 188 (19%) were Black, 70 (7%) were Asian, and 18 (2%) were American Indian or Alaska Native. 347 (34%) of 1010 patients were Hispanic or Latino. Mechanical ventilation-free survival by day 29 was similar between the study groups (Kaplan-Meier estimates of 87·0% [95% CI 83·7 to 89·6] in the baricitinib plus remdesivir plus placebo group and 87·6% [84·2 to 90·3] in the dexamethasone plus remdesivir plus placebo group; risk difference 0·6 [95% CI -3·6 to 4·8]; p=0·91). The odds ratio for improved status in the dexamethasone plus remdesivir plus placebo group compared with the baricitinib plus remdesivir plus placebo group was 1·01 (95% CI 0·80 to 1·27). At least one adverse event occurred in 149 (30%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 179 (37%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·5% [1·6 to 13·3]; p=0·014). 21 (4%) of 503 patients in the baricitinib plus remdesivir plus placebo group had at least one treatment-related adverse event versus 49 (10%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 6·0% [2·8 to 9·3]; p=0·00041). Severe or life-threatening grade 3 or 4 adverse events occurred in 143 (28%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 174 (36%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·7% [1·8 to 13·4]; p=0·012). INTERPRETATION/CONCLUSIONS:In hospitalised patients with COVID-19 requiring supplemental oxygen by low-flow, high-flow, or non-invasive ventilation, baricitinib plus remdesivir and dexamethasone plus remdesivir resulted in similar mechanical ventilation-free survival by day 29, but dexamethasone was associated with significantly more adverse events, treatment-related adverse events, and severe or life-threatening adverse events. A more individually tailored choice of immunomodulation now appears possible, where side-effect profile, ease of administration, cost, and patient comorbidities can all be considered. FUNDING/BACKGROUND:National Institute of Allergy and Infectious Diseases.

BACKGROUND:The COVID-19 pandemic has led to significant reductions in transplantation, motivated in part by concerns of disproportionately more severe disease among solid organ transplant (SOT) recipients. However, clinical features, outcomes, and predictors of mortality in SOT recipients are not well-described. METHODS:We performed a multi-center cohort study of SOT recipients with laboratory-confirmed COVID-19. Data were collected using standardized intake and 28-day follow-up electronic case report forms. Multivariable logistic regression was used to identify risk factors for the primary endpoint, 28-day mortality, among hospitalized patients. RESULTS:Four hundred eighty-two SOT recipients from >50 transplant centers were included: 318 (66%) kidney or kidney/pancreas, 73 (15.1%) liver, 57 (11.8%) heart, and 30 (6.2%) lung. Median age was 58 (IQR 46-57), median time post-transplant was 5 years (IQR 2-10), 61% were male, and 92% had ≥1 underlying comorbidity. Among those hospitalized (376 [78%]), 117 (31%) required mechanical ventilation, and 77 (20.5%) died by 28 days after diagnosis. Specific underlying comorbidities (age >65 [aOR 3.0, 95%CI 1.7-5.5, p<0.001], congestive heart failure [aOR 3.2, 95%CI 1.4-7.0, p=0.004], chronic lung disease [aOR 2.5, 95%CI 1.2-5.2, p=0.018], obesity [aOR 1.9, 95% CI 1.0-3.4, p=0.039]) and presenting findings (lymphopenia [aOR 1.9, 95%CI 1.1-3.5, p=0.033], abnormal chest imaging [aOR 2.9, 95%CI 1.1-7.5, p=0.027]) were independently associated with mortality. Multiple measures of immunosuppression intensity were not associated with mortality. CONCLUSIONS:Mortality among SOT recipients hospitalized for COVID-19 was 20.5%. Age and underlying comorbidities rather than immunosuppression intensity-related measures were major drivers of mortality.

Antibody responses among immunocompromised solid organ transplant recipients (SOT) infected with Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) may be diminished compared to the general population and have not been fully characterized. We conducted a cohort study at our transplant center to investigate the rate of seroconversion for SARS-CoV-2 IgG antibodies among SOT recipients who were diagnosed with Coronavirus disease 2019 (COVID-19) and underwent serum SARS-CoV-2 IgG enzyme-linked immunosorbent assay (ELISA) testing. The 61 patients who were included in the final analysis underwent initial SARS-CoV-2 IgG testing at a median of 62 days (Interquartile range 55.0-75.0) from symptom onset. Note that, 51 of 61 patients (83.6%) had positive SARS-CoV-2 IgG results, whereas 10 (16.4%) had negative IgG results. Six (60%) out of 10 seronegative patients underwent serial IgG testing and remained seronegative up to 17 weeks post-diagnosis. Use of belatacept in maintenance immunosuppression was significantly associated with negative IgG antibodies to SARS-CoV-2 both in univariate and multivariate analyses (Odds ratio 0.04, p = .01). In conclusion, the majority of organ transplant recipients with COVID-19 in our study developed SARS-CoV-2 antibodies. Further longitudinal studies of the durability and immunologic role of these IgG responses and the factors associated with lack of seroconversion are needed.

Purpose: The presentation of Coronavirus disease 2019 (COVID-19) ranges from mild illness to severe respiratory failure. Disease progression may differ in immunocompromised patients and immunocompetent hosts. Therefore, we aim to characterize COVID-19 clinical presentation and outcomes in solid organ transplant recipients (SOTRs) to identify initial clinical factors that may predict COVID-19 associated mortality.
Method(s): We prospectively reviewed baseline demographic and clinical characteristics among adult kidney, pancreas, liver, heart and lung transplant recipients diagnosed with COVID-19 between March 1, 2020 and May 5, 2020 at our transplant center in New York City. A series of chi-square and Fisher's exact tests were conducted to investigate the relationship between several predictor variables (baseline characteristics, symptoms at presentation, and baseline immunosuppression regimen) and 30-day mortality.
Result(s): 73 SOTRs (53 kidney, 8 liver, 7 heart, 3 lung, 2 heart/kidney) with SARSCoV-2 PCR-confirmed COVID-19 were included in the final analysis. Median age was 59 years (IQR 54-68) and 34.2% were female. Median time since transplant was 21 months (IQR 13-46.5). All patients were on baseline immunosuppresion as shown in table 1. The majority of patients were diagnosed in the Emergency Department. Most common presenting symptoms were cough (68.5%), gastrointestinal symptoms (54.8%) and dyspnea (45.2%) with median of 5 days from symptom onset to hospitalization. All patients had elevated inflammatory markers at time of diagnosis (median CRP 54 mg/L, median ferritin 704 ng/mL, median procalcitonin 0.11 ng/mL, median D-dimer 311 ng/mL). 84.1% of patients required supplemental oxygen, including intubation in 19.7%. 13 of 63 (21%) hospitalized patients died. Dyspnea on presentation was the only baseline or presenting patient factor found to be predictive of death (p =.004). When stratified by initial chest X-ray findings, dyspnea combined with abnormal chest X-ray predicted mortality (p=.021) while dyspnea with normal chest X-ray did not.
Conclusion(s): Presenting symptoms of dyspnea and radiographic signs of pneumonia on initial imaging predicted mortality among SOTRs with COVID-19 in our cohort. These findings can inform allocation of limited resources in COVID-19 management, including the triage and timing of COVID-19 directed therapies early in the illness course among different patient populations

Disseminated strongyloidiasis and hyperinfection syndrome can cause significant morbidity and mortality after transplantation. Screening and treatment prior to transplantation can reduce or prevent this disease. Targeted screening of transplant candidates, based on assessed risk, fails to identify all who would benefit. We implemented universal serology-based screening for Strongyloides at our transplant center, located in a non-endemic area. Of 200 transplant candidates who were evaluated for cardiothoracic transplant from January 2018 to June 2019, 169 were screened serologically and 21 (12.4%) were seropositive. Among seropositive patients, 57% reported travel to an endemic region, 38% were born outside the USA, 38% had eosinophilia, 5% had history of gram-negative bacteremia. We estimate that universal screening for strongyloidiasis could identify an average of 17 additional candidates for preventive treatment for every 200 transplant candidates.

Purpose: During the COVID 19- pandemic, there is no consensus on management strategies for treating infected heart transplant patients. The outcomes of these patients vary by institution. We report our center experience and management strategies to date.
Method(s): All patients who received heart transplantation, from January 4th 2018 to September 25th 2020 and were diagnosed with SARS-CoV-2 were included and full chart review was performed.
Result(s): There were 113 heart transplants at our institution by September 2020. A total of 13 (12%) patients were infected with SARS-CoV-2: 9 (69%) isolated heart, 3 heart -kidney (23%) and 1 heat- lung (8%). The median (IQR) time from transplant to diagnosis was 10 (5-16) months. The mean age was 57 years and 50% were male; 50% were of Hispanic ethnicity. The main presenting symptoms were fever (43%), cough (86%) and SOB (43%). Chest x-ray was abnormal in all patients. We evaluated all patients and 79% were hospitalized and 21% were closely monitored as outpatients. None of our patients were hospitalized at outside institutions. Two (14%) required intubation and none required V-V ECMO support. The immunotherapy was modified in all patients: MMF and prednisone were discontinued, tacrolimus dose was reduced. COVID19 treatment was: 71% received hydroxychloroquine, 50% azithromycin, 15% remdesevir, 7% convalescent plasma. All hospitalized patients received anticoagulation. One patient had 2R/3A rejection within 30 days prior to diagnosis. Graft function was maintained in all patients with median LVEF% 65 (59-65%) except one patient who had received thymoglobulin 2 weeks prior to COVID 19 infection (LVEF 30%). The patient had a prolonged intubation but ultimately recovered and was discharged from the hospital. The one death (7.1%) was a heart - kidney recipient who concomitantly presented with pseudomonas sepsis and severe neutropenia. The remaining patients have all been discharged home.
Conclusion(s): We present our single center experience in managing COVID 19 infected heart transplant patients. We implemented uniform management strategies by incorporating aggressive reduction of immunosuppression, frequent scheduled contacts with infected outpatients and making sure all infected patients requiring hospitalization were treated at a transplant center.
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Solid organ transplant (SOT) candidates and recipients are at risk of significant morbidity and mortality from infection, including those circulating in the community from unexpected outbreaks. In late 2018-summer of 2019, a measles outbreak occurred in the New York City area, with a total of 649 cases reported. We developed a systematic three-part approach to address measles risk in our adult SOT program through: 1) identification of non-immune adults living in outbreak ZIP codes, 2) education focused on risk reduction for patients from outbreak ZIP codes and 3) risk reduction for non-immune patients. All waitlisted or previously transplanted patients residing in outbreak areas received a measles patient education handout. The electronic medical record of patients born in or after 1957 was reviewed for serologic evidence of measles immunity. Measles immunity testing was performed in patients without documentation of immunity. Patients who tested non-immune were offered MMR vaccination or intravenous immunoglobulin depending on their transplant phase and risk profile. Thus, we demonstrate successful implementation of a systematic risk assessment during a large measles outbreak to identify and protect at-risk SOT patients. As vaccine hesitancy persists, our strategies may be increasingly relevant to transplant centers and those caring for immunocompromised patients.