Previous SARS-CoV-2 infection or a third dose of vaccine elicited cross-variant neutralising antibodies in vaccinated solid-organ transplant recipients.

Objectives: The SARS-CoV-2 pandemic poses a great threat to global health, particularly in solid organ transplant recipients (SOTRs). A 3-dose mRNA vaccination protocol has been implemented for the majority of SOTRs, yet their immune responses are less effective compared to healthy controls (HCs). Methods: We analyzed the humoral immune responses against the vaccine strain and variants of concern (VOC), including the highly mutated-omicron variant in 113 SOTRs, of whom 44 had recovered from COVID-19 (recovered-SOTRs) and 69 had not contracted the virus (COVID-naïve). In addition, 30 HCs, 8 of whom had recovered from COVID-19, were also studied. Results: Here, we report that three doses of the mRNA vaccine had only a modest effect in eliciting anti-viral antibodies against all viral strains in the fully vaccinated COVID-naive SOTRs (n = 47). Only 34.0% of this group of patients demonstrated both detectable anti-RBD IgG with neutralization activities against alpha, beta, and delta variants, and only 8.5% of them showed additional omicron neutralizing capacities. In contrast, 79.5% of the recovered-SOTRs who received two doses of vaccine demonstrated both higher anti-RBD IgG levels and neutralizing activities against all VOC, including omicron. Conclusion: These findings illustrate a significant impact of previous infection on the development of anti-SARS-CoV-2 immune responses in vaccinated SOTRs and highlight the need for alternative strategies to protect a subset of a lesser-vaccine responsive population.

A Randomized Double-Blinded Placebo Controlled Trial of Clazakizumab for the Treatment of COVID-19 Pneumonia With Hyperinflammation.

OBJECTIVES: We designed this study to test whether clazakizumab, a direct interleukin-6 inhibitor, benefits patients hospitalized with severe or critical COVID-19 disease accompanied by hyperinflammation. DESIGN: Multicenter, randomized, double-blinded, placebo-controlled, seamless phase II/III trial. SETTING: Five U.S. medical centers. PATIENTS: Adults inpatients with severe COVID-19 disease and hyperinflammation. INTERVENTIONS: Eighty-one patients enrolled in phase II, randomized 1:1:1 to low-dose (12.5 mg) or high-dose (25 mg) clazakizumab or placebo. Ninety-seven patients enrolled in phase III, randomized 1:1 to high-dose clazakizumab or placebo. MEASUREMENTS AND MAIN RESULTS: The primary outcome was 28-day ventilator-free survival. Secondary outcomes included overall survival, frequency and duration of intubation, and frequency and duration of ICU admission. Per Data Safety and Monitoring Board recommendations, additional secondary outcomes describing clinical status and status changes, as measured by an ordinal scale, were added. Bayesian cumulative proportional odds, logistic, and Poisson regression models were used. The low-dose arm was dropped when the phase II study suggested superiority of the high-dose arm. We report on 152 patients, 74 randomized to placebo and 78 to high-dose clazakizumab. Patients receiving clazakizumab had greater odds of 28-day ventilator-free survival (odds ratio [OR] = 3.84; p [OR > 1] 99.9%), as well as overall survival at 28 and 60 days (OR = 1.75; p [OR > 1] 86.5% and OR = 2.53; p [OR > 1] 97.7%). Clazakizumab was associated with lower odds of intubation (OR = 0.2; p [OR] < 1; 99.9%) and ICU admission (OR = 0.26; p [OR < 1] 99.6%); shorter durations of ventilation and ICU stay (risk ratio [RR] < 0.75; p [RR < 1] > 99% for both); and greater odds of improved clinical status at 14, 28, and 60 days (OR = 2.32, p [OR > 1] 98.1%; OR = 3.36, p [OR > 1] 99.6%; and OR = 3.52, p [OR > 1] 99.8%, respectively). CONCLUSIONS: Clazakizumab significantly improved 28-day ventilator-free survival, 28- and 60-day overall survival, as well as clinical outcomes in hospitalized patients with COVID-19 and hyperinflammation.

Effect of intensive versus limited monitoring on clinical trial conduct and outcomes: A randomized trial.

BACKGROUND: Regulatory agencies have endorsed more limited approaches to clinical trial site monitoring. However, the impact of different monitoring strategies on trial conduct and outcomes is unclear. METHODS: We conducted a patient-level block-randomized controlled trial evaluating the effect of intensive versus limited monitoring on cardiovascular clinical trial conduct and outcomes nested within the CoreValve Continued Access and Expanded Use Studies. Intensive monitoring included complete source data verification of all critical datapoints whereas limited monitoring included automated data checks only. This study's endpoints included clinical trial outcome ascertainment as well as monitoring action items, protocol deviations, and adverse event ascertainment. RESULTS: A total of 2,708 patients underwent transcatheter aortic valve replacement (TAVR) and were randomized to either intensive monitoring (n = 1,354) or limited monitoring (n = 1,354). Monitoring action items were more common with intensive monitoring (52% vs 15%; P < .001), but there was no difference in the percentage of patients with any protocol deviation (91.6% vs 90.4%; P = .314). The reported incidence of trial outcomes between intensive and limited monitoring was similar for mortality (30 days: 4.8% vs 5.5%, P = .442; 1 year: 20.3% vs 21.3%, P = .473) and stroke (30 days: 2.8% vs 2.4%, P = .458), as well as most secondary trial outcomes with the exception of bleeding (intensive: 36.3% vs limited: 32.0% at 30 days, P = .019). There was a higher reported incidence of cardiac adverse events reported in the intensive monitoring group at 1 year (76.7% vs 72.4%; P = .019). CONCLUSIONS: Tailored limited monitoring strategies can be implemented without influencing the integrity of TAVR trial outcomes.

Kidney allograft biopsy findings after COVID-19.

COVID-19 has been associated with acute kidney injury and published reports of native kidney biopsies have reported diverse pathologies. Case series directed specifically to kidney allograft biopsy findings in the setting of COVID-19 are lacking. We evaluated 18 kidney transplant recipients who were infected with SARS-CoV-2 and underwent allograft biopsy. Patients had a median age of 55 years, six were female, and five were Black. Fifteen patients developed COVID-19 pneumonia, of which five required mechanical ventilation. Notably, five of 11 (45%) biopsies obtained within 1 month of positive SARS-CoV-2 PCR showed acute rejection (four with arteritis, three of which were not associated with reduced immunosuppression). The remaining six biopsies revealed podocytopathy (n = 2, collapsing glomerulopathy and lupus podocytopathy), acute tubular injury (n = 2), infarction (n = 1), and transplant glomerulopathy (n = 1). Biopsies performed >1 month after positive SARS-CoV-2 PCR revealed collapsing glomerulopathy (n = 1), acute tubular injury (n = 1), and nonspecific histologic findings (n = 5). No direct viral infection of the kidney allograft was detected by immunohistochemistry, in situ hybridization, or electron microscopy. On follow-up, two patients died and most patients showed persistent allograft dysfunction. In conclusion, we demonstrate diverse causes of kidney allograft dysfunction after COVID-19, the most common being acute rejection with arteritis.

Perspectives on COVID-19 vaccination among kidney and pancreas transplant recipients living in New York City.

PURPOSE: Solid organ transplant recipients are at increased risk of morbidity and mortality from coronavirus disease 2019 (COVID-19), but limited vaccine access and vaccine hesitancy can complicate efforts for expanded vaccination. We report patient perspectives and outcomes from a vaccine outreach initiative for a vulnerable population of transplant recipients living in New York City. METHODS: This was a retrospective review of qualitative perspectives from a COVID-19 vaccine outreach initiative. In the outreach effort, kidney and pancreas transplant recipients under care at the transplant center at NewYork-Presbyterian Hospital were initially contacted electronically with educational material about vaccination followed by telephone outreach to eligible unvaccinated patients. Calls were used to schedule vaccine appointments for patients who agreed, answer questions, and assess attitudes and concerns for patients not yet ready to be vaccinated, with conversational themes recorded. RESULTS: Of the 1,078 patients living in the 5 New York City boroughs who had not reported receiving COVID-19 vaccination, 320 eligible patients were contacted by telephone. Of these, 210 patients were scheduled for vaccination at our vaccine site (including 13 who agreed to vaccination after initially declining), while 110 patients were either not ready or not interested in being vaccinated. The total number of patients willing to be vaccinated was 554 when also including those already vaccinated. Unwillingness to be vaccinated was associated with younger age (median age of 47 vs 60 years, P < 0.001), Black race (P = 0.004), and residence in Bronx or Brooklyn counties (P = 0.018) or a zip code with a medium level of poverty (P = 0.044). The most common issues raised by patients who were ambivalent or not interested in vaccination were regarding unknown safety of the vaccines in general, a belief that there was a lack of data about the vaccines in transplant recipients, and a lack of trust in the scientific process underlying vaccine development, with 34% of the patients contacted expressing vaccine hesitancy overall. CONCLUSION: Our qualitative summary identifies determinants of COVID-19 vaccine hesitancy in a diverse transplant patient population, supporting the need for transplant centers to implement tailored interventions to increase vaccine acceptance in this vulnerable population.

Prevalence and predictors of SARS-CoV-2 antibodies among solid organ transplant recipients with confirmed infection.

It remains uncertain whether immunocompromised patients including solid organ transplant (SOT) recipients will have a robust antibody response to SARS-CoV-2 infection. We enrolled all adult SOT recipients at our center with confirmed SARS-CoV-2 infection who underwent antibody testing with a single commercially available anti-nucleocapsid antibody test at least 7 days after diagnosis in a retrospective cohort. Seventy SOT recipients were studied (56% kidney, 19% lung, 14% liver ± kidney, and 11% heart ± kidney recipients). Thirty-six (51%) had positive anti-nucleocapsid antibody testing, and 34 (49%) were negative. Recipients of a kidney allograft were less likely to have positive antibody testing compared to those who did not receive a kidney (p = .04). In the final multivariable model, the years from transplant to diagnosis (OR 1.26, p = .002) and baseline immunosuppression with more than two agents (OR 0.26, p = .03) were significantly associated with the antibody test result, controlling for kidney transplantation. In conclusion, among SOT recipients with confirmed infection, only 51% of patients had detectable anti-nucleocapsid antibodies, and transplant-related variables including the level and nature of immunosuppression were important predictors. These findings raise the concern that SOT recipients with COVID-19 may be less likely to form SARS-CoV-2 antibodies.

STS-ACC TVT Registry of Transcatheter Aortic Valve Replacement.

The STS-ACC TVT Registry (Society of Thoracic Surgeons-American College of Cardiology Transcatheter Valve Therapy Registry) from 2011 to 2019 has collected data on 276,316 patients undergoing transcatheter aortic valve replacement (TAVR) at sites in all U.S. states. Volumes have increased every year, exceeding surgical aortic valve replacement in 2019 (72,991 vs. 57,626), and it is now performed in all U.S. states. TAVR now extends from extreme- to low-risk patients. This is the first presentation on 8,395 low-risk patients treated in 2019. In 2019, for the entire cohort, femoral access increased to 95.3%, hospital stay was 2 days, and 90.3% were discharged home. Since 2011, the 30-day mortality rate has decreased (7.2% to 2.5%), stroke has started to decrease (2.75% to 2.3%), but pacemaker need is unchanged (10.9% to 10.8%). Alive with acceptable patient-reported outcomes is achieved in 8 of 10 patients at 1 year. The Registry is a national resource to improve care and analyze TAVR's evolution. Real-world outcomes, site performance, and the impact of coronavirus disease 2019 will be subsequently studied. (STS/ACC Transcatheter Valve Therapy Registry [TVT Registry]; NCT01737528).

Tocilizumab for severe COVID-19 in solid organ transplant recipients: a matched cohort study.

The safety and efficacy of tocilizumab for the treatment of severe respiratory symptoms due to COVID-19 remain uncertain, in particular among solid organ transplant (SOT) recipients. Thus, we evaluated the clinical characteristics and outcomes of 29 hospitalized SOT recipients who received tocilizumab for severe COVID-19, compared to a matched control group who did not. Among a total of 117 total SOT recipients hospitalized with COVID-19, 29 (24.8%) received tocilizumab. The 90-day mortality was significantly higher among patients who received tocilizumab (41%) compared to those who did not (20%, P = .03). When compared to control patients matched by age, hypertension, chronic kidney disease, and administration of high dose corticosteroids, there was no significant difference in mortality (41% vs 28%, P = .27), hospital discharge (52% vs 72%, P = .26), or secondary infections (34% vs 24%, P = .55). Among patients who received tocilizumab, there was also no difference in mortality based on the level of oxygen support (intubated vs not intubated) at the time of tocilizumab initiation. In this matched cohort study, tocilizumab appeared to be safe but was not associated with decreased 90-day mortality. Larger randomized studies are needed to identify whether there are subsets of SOT recipients who may benefit from tocilizumab for treatment of COVID-19.

COVID-19 in pancreas transplant recipients.

Coronavirus disease 2019 (COVID-19) has become a pandemic since first being described in January 2020. Clinical manifestations in non-transplant patients range from asymptomatic infection to severe pneumonia with acute respiratory distress syndrome, multiorgan system failure, and death. Limited reports in kidney transplant recipients suggest similar characteristics in that population. We report here the first case series of COVID-19 infection occurring in pancreas transplant recipients.

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

Solid organ transplant recipients may be at a high risk for SARS-CoV-2 infection and poor associated outcomes. We herein report our initial experience with solid organ transplant recipients with SARS-CoV-2 infection at two centers during the first 3 weeks of the outbreak in New York City. Baseline characteristics, clinical presentation, antiviral and immunosuppressive management were compared between patients with mild/moderate and severe disease (defined as ICU admission, intubation or death). Ninety patients were analyzed with a median age of 57 years. Forty-six were kidney recipients, 17 lung, 13 liver, 9 heart, and 5 dual-organ transplants. The most common presenting symptoms were fever (70%), cough (59%), and dyspnea (43%). Twenty-two (24%) had mild, 41 (46%) moderate, and 27 (30%) severe disease. Among the 68 hospitalized patients, 12% required non-rebreather and 35% required intubation. 91% received hydroxychloroquine, 66% azithromycin, 3% remdesivir, 21% tocilizumab, and 24% bolus steroids. Sixteen patients died (18% overall, 24% of hospitalized, 52% of ICU) and 37 (54%) were discharged. In this initial cohort, transplant recipients with COVID-19 appear to have more severe outcomes, although testing limitations likely led to undercounting of mild/asymptomatic cases. As this outbreak unfolds, COVID-19 has the potential to severely impact solid organ transplant recipients.