Razonable, Raymund R.

ImportanceEvidence on the effectiveness and safety of COVID-19 therapies across a diverse population with varied risk factors is needed to inform clinical practice.ObjectiveTo assess the safety of neutralizing monoclonal antibodies (nMAbs) for the treatment of COVID-19 and their association with adverse outcomes.Design, Setting, and ParticipantsThis retrospective cohort study included 167 183 patients from a consortium of 4 health care systems based in California, Minnesota, Texas, and Utah. The study included nonhospitalized patients 12 years and older with a positive COVID-19 laboratory test collected between November 9, 2020, and January 31, 2022, who met at least 1 emergency use authorization criterion for risk of a poor outcome.ExposureFour nMAb products (bamlanivimab, bamlanivimab-etesevimab, casirivimab-imdevimab, and sotrovimab) administered in the outpatient setting.Main Outcomes and MeasuresClinical and SARS-CoV-2 genomic sequence data and propensity-adjusted marginal structural models were used to assess the association between treatment with nMAbs and 4 outcomes: all-cause emergency department (ED) visits, hospitalization, death, and a composite of hospitalization or death within 14 days and 30 days of the index date (defined as the date of the first positive COVID-19 test or the date of referral). Patient index dates were categorized into 4 variant epochs: pre-Delta (November 9, 2020, to June 30, 2021), Delta (July 1 to November 30, 2021), Delta and Omicron BA.1 (December 1 to 31, 2021), and Omicron BA.1 (January 1 to 31, 2022).ResultsAmong 167 183 patients, the mean (SD) age was 47.0 (18.5) years; 95 669 patients (57.2%) were female at birth, 139 379 (83.4%) were White, and 138 900 (83.1%) were non-Hispanic. A total of 25 241 patients received treatment with nMAbs. Treatment with nMAbs was associated with lower odds of ED visits within 14 days (odds ratio [OR], 0.76; 95% CI, 0.68-0.85), hospitalization within 14 days (OR, 0.52; 95% CI, 0.45-0.59), and death within 30 days (OR, 0.14; 95% CI, 0.10-0.20). The association between nMAbs and reduced risk of hospitalization was stronger in unvaccinated patients (14-day hospitalization: OR, 0.51; 95% CI, 0.44-0.59), and the associations with hospitalization and death were stronger in immunocompromised patients (hospitalization within 14 days: OR, 0.31 [95% CI, 0.24-0.41]; death within 30 days: OR, 0.13 [95% CI, 0.06-0.27]). The strength of associations of nMAbs increased incrementally among patients with a greater probability of poor outcomes; for example, the ORs for hospitalization within 14 days were 0.58 (95% CI, 0.48-0.72) among those in the third (moderate) risk stratum and 0.41 (95% CI, 0.32-0.53) among those in the fifth (highest) risk stratum. The association of nMAb treatment with reduced risk of hospitalizations within 14 days was strongest during the Delta variant epoch (OR, 0.37; 95% CI, 0.31-0.43) but not during the Omicron BA.1 epoch (OR, 1.29; 95% CI, 0.68-2.47). These findings were corroborated in the subset of patients with viral genomic data. Treatment with nMAbs was associated with a significant mortality benefit in all variant epochs (pre-Delta: OR, 0.16 [95% CI, 0.08-0.33]; Delta: OR, 0.14 [95% CI, 0.09-0.22]; Delta and Omicron BA.1: OR, 0.10 [95% CI, 0.03-0.35]; and Omicron BA.1: OR, 0.13 [95% CI, 0.02-0.93]). Potential adverse drug events were identified in 38 treated patients (0.2%).Conclusions and RelevanceIn this study, nMAb treatment for COVID-19 was safe and associated with reductions in ED visits, hospitalization, and death, although it was not associated with reduced risk of hospitalization during the Omicron BA.1 epoch. These findings suggest that targeted risk stratification strategies may help optimize future nMAb treatment decisions.

AbstractBackgroundCurrent guidelines recommend immunomodulators, tocilizumab or baricitinib, for the management of severe coronavirus disease‐2019 (COVID‐19) in patients with increasing oxygen requirements. Given their immunosuppressive effects, there is a concern for higher rates of infection among transplant recipients.MethodsA retrospective cohort study of transplant patients with severe COVID‐19 between April 2020 and January 2022 was performed at the Mayo Clinic. The primary outcome was incidence of secondary infections after COVID‐19 diagnosis. Secondary outcomes were 90‐day mortality, ventilatory days, and thromboembolic events.ResultsA total of 191 hospitalized transplant patients were studied, including 77 (40.3%) patients who received an immunomodulator. Overall, 89% were solid organ transplant recipients, with kidney as the most common transplanted organ (50.3%). The majority (89.0%) required oxygen supplementation on admission, and 39.8% of these patients required mechanical ventilation during the hospital course. There was no significant difference in the incidence of secondary infections between those who received or did not receive an immunomodulator (p = .984). Likewise, there was no difference in 90‐day mortality between patients who received or did not receive an immunomodulator (p = .134). However, higher mortality was observed among patients that developed a secondary infection (p < .001).ConclusionThe use of immunomodulators in transplant patients with severe COVID‐19 was not significantly associated with an increased risk of secondary infections. Secondary infections were associated with higher risk of all‐cause mortality. Future studies of larger cohorts are needed to explore the effect of immunomodulators on survival among transplant patients with COVID‐19. image

AbstractBackgroundPre‐exposure prophylaxis with tixagevimab‐cilgavimab (tix‐cil) may be associated with cardiovascular adverse events. Also, in vitro studies have reported a reduced activity of tix‐cil against emerging SARS‐CoV‐2 Omicron subvariants. Our study aimed to report the real‐world outcomes of tix‐cil prophylaxis in orthotopic heart transplant (OHT) recipientsMethodsWe retrospectively studied all OHT recipients who received one dose of tix‐cil (150–150 mg or 300–300 mg) at Mayo Clinic in Arizona, Florida, and Minnesota, between February 5, 2022 and September 8, 2022. We collected data on cardiovascular adverse events and breakthrough COVID‐19 following tix‐cil administration.ResultsOne hundred sixty‐three OHT recipients were included. The majority were male (65.6%), and the median age was 61 years (IQR 48, 69). During the median follow‐up of 164 days (IQR 123, 190), one patient presented an episode of asymptomatic hypertensive urgency that was managed with outpatient antihypertensive treatment optimization. Twenty‐four patients (14.7%) experienced breakthrough COVID‐19 at the median of 63.5 days (IQR 28.3, 101.3) after tix‐cil administration. The majority (70.8%) completed the primary vaccine series and received at least one booster dose (70.8%). Only one patient with breakthrough COVID‐19 required hospitalization. All patients survived.ConclusionsIn this cohort of OHT recipients, no patients developed severe cardiovascular events related to tix‐cil. The high incidence of breakthrough COVID‐19 could be due to the reduced activity of tix‐cil against current circulating SARS‐CoV‐2 Omicron variants. These results emphasize the need for a multimodal prevention strategy against SARS‐CoV‐2 in these high‐risk patients. image

Abstract Coronavirus disease 2019 (COVID-19) convalescent plasma (CCP) is a safe and effective treatment for COVID-19 in immunocompromised (IC) patients. IC patients have a higher risk of persistent infection, severe disease, and death from COVID-19. Despite the continued clinical use of CCP to treat IC patients, the optimal dose, frequency/schedule, and duration of CCP treatment has yet to be determined, and related best practices guidelines are lacking. A group of individuals with expertise spanning infectious diseases, virology and transfusion medicine was assembled to render an expert opinion statement pertaining to the use of CCP for IC patients. For optimal effect, CCP should be recently and locally collected to match circulating variant. CCP should be considered for the treatment of IC patients with acute and protracted COVID-19; dosage depends on clinical setting (acute vs protracted COVID-19). CCP containing high-titer severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies, retains activity against circulating SARS-CoV-2 variants, which have otherwise rendered monoclonal antibodies ineffective.

AbstractBackgroundDecisions to transplant organs from severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) nucleic acid test‐positive (NAT+) donors must balance risk of donor‐derived transmission events (DDTE) with the scarcity of available organs.MethodsOrgan Procurement and Transplantation Network (OPTN) data were used to compare organ utilization and recipient outcomes between SARS‐CoV‐2 NAT+ and NAT– donors. NAT+ was defined by either a positive upper or lower respiratory tract (LRT) sample within 21 days of procurement. Potential DDTE were adjudicated by OPTN Disease Transmission Advisory Committee.ResultsFrom May 27, 2021 (date of OTPN policy for required LRT testing of lung donors) to January 31, 2022, organs were recovered from 617 NAT+ donors from all OPTN regions and 53 of 57 (93%) organ procurement organizations. NAT+ donors were younger and had higher organ quality scores for kidney and liver. Organ utilization was lower for NAT+ donors compared to NAT– donors. A total of 1241 organs (776 kidneys, 316 livers, 106 hearts, 22 lungs, and 21 other) were transplanted from 514 NAT+ donors compared to 21 946 organs from 8853 NAT– donors. Medical urgency was lower for recipients of NAT+ liver and heart transplants. The median waitlist time was longer for liver recipients of NAT+ donors. The match run sequence number for final acceptor was higher for NAT+ donors for all organ types. Outcomes for hospital length of stay, 30‐day mortality, and 30‐day graft loss were similar for all organ types. No SARS‐CoV‐2 DDTE occurred in this interval.ConclusionsTransplantation of SARS‐CoV‐2 NAT+ donor organs appears safe for short‐term outcomes of death and graft loss and ameliorates the organ shortage. Further study is required to assure comparable longer term outcomes. image

Abstract Background Immunomodulators have been shown to improve the outcomes of patients with severe COVID-19. However, it is not known if tocilizumab or baricitinib use would be beneficial in transplant patients who are already receiving immunomodulating agents. Moreover, augmented immunomodulation may increase risk of opportunistic infection. There are few studies analyzing the outcomes and complications of these medications in this population. Methods This is a detailed review of the medical records of all transplant patients who received tocilizumab or baricitinib for COVID-19 indication at our multi-state transplant center from April 2020 to March 2022. Results A total of 57 transplant patients received tocilizumab (n=48) or baricitinib (n=9) for management of COVID-19. Baseline characteristics are in Table 1. 60% had received at least one dose of COVID-19 vaccine. At diagnosis, all patients were lymphopenic (median 0.4 x109 cells/L) with high CRP (median 76.8mg/L) and elevated IL-6 levels (median 145.5pg/ml.). The majority had reduction in transplant immunosuppression (75%) and received remdesivir (86%) and dexamethasone (90%). Majority were admitted to the ICU (68%), including 40% who required invasive mechanical ventilation (Table 2). Almost a third developed bacterial or fungal superinfection. Bacterial infections include respiratory cultures with Klebsiella spp, MRSA, P. aeruginosa, Enterobacter spp and Stenotrophomonas. Blood cultures were positive for Klebsiella spp, MDR P. aeruginosa, E faecalis. Fungal infections include three patients with Aspergillus spp infections who received antifungals. No statistical difference was seen in mortality between patients with infections and not infections group. No statistical difference was seen between type of transplants for infection or mortality. Mortality at 90 days was 46%. Conclusion Transplant patients who received tocilizumab or baricitinib for severe or critical COVID-19 have poor outcome. This case series found high rates of mortality and opportunistic superinfections after tocilizumab and baricitinib use compared to the current literature. Future directions include a matched case-control study to compare the outcomes in this population. Disclosures Raymund R. Razonable, MD, Gilead: Grant/Research Support|Glaxo Smith Kline: Advisor/Consultant|Novartis: DSMB|Regeneron: Grant/Research Support|Roche: Grant/Research Support.

Abstract Background Cytomegalovirus (CMV) causes significant morbidity in solid organ transplant recipients (SOTR). As a lack of immunity predisposes to infection, a laboratory test that measures CMV-specific cell-mediated immunity (CMV CMI) may help guide antiviral prophylaxis, predict relapses and correlate with outcomes. We assessed CMV CMI in CMV D+/R- patients during valganciclovir primary prophylaxis and in CMV viremic SOTRs during antiviral treatment, and correlated the results with post-prophylaxis CMV infection and post-treatment relapse, respectively. Methods CMV CMI was assessed in two groups of SOTRs using the QuantiFERON© CMV interferon-gamma release assay (IGRA), with level &gt;0.2 IU/mL suggestive of immunity. The first group included CMV D+/R- SOTRs who underwent monthly CMV CMI testing during 6 months of valganciclovir prophylaxis. These patients were prospectively followed for CMV episodes for 1 year post transplant. The second group included SOTRs with CMV viremia or disease, who underwent CMV CMI testing at time of CMV diagnosis and at various time points during antiviral treatment. These patients were prospectively followed for CMV relapse for 1 year post-primary CMV episode. Standard definitions were used to define CMV infection and disease. Results In the primary prophylaxis cohort, 24 CMV mismatched (D+/R-) SOTRs were enrolled. Only 1 patient (4.2%) demonstrated a CMV CMI &gt;0.2 IU/mL by the end of prophylaxis; this patient did not develop CMV disease. Four (16.6%) patients developed post-prophylaxis CMV infection, none of which had CMV CMI &gt;0.2 IU/ml. In the post-treatment cohort, 20 CMV viremic SOTRs were enrolled, including 12 D+/R- (60%). Eighteen (90%) had CMV CMI levels &gt;0.2 IU/mL by end of treatment and none developed CMV relapse. In contrast, the single patient who relapsed after treatment had a CMV CMI response &lt; 0.2 IU/ml (p=0.05). Conclusion CMV D+/R- SOTRs are unlikely to develop CMV CMI during valganciclovir prophylaxis. Thus, the utility of CMV CMI for risk stratification of post-prophylaxis CMV infection in CMV D+/R- SOTRs is questionable. Conversely, CMV CMI testing may potentially be a useful marker of CMV relapse risk after treatment and guide the role of secondary antiviral prophylaxis. Disclosures Elitza Theel, PhD, D(ABMM), Euroimmun US: Advisor/Consultant|Oxford Immunotech: Advisor/Consultant|Roche Diagnostics: Advisor/Consultant|Serimmune Inc: Advisor/Consultant Raymund R. Razonable, MD, American Society of Transplantation: Board Member|gilead: Grant/Research Support|novartis: DSMB|regeneron: Grant/Research Support|Roche: Grant/Research Support.

Purpose of review Coronavirus disease-2019 (COVID-19) disproportionately causes severe outcomes in solid organ transplant recipients (SOTR). Antispike monoclonal antibodies have been authorized for therapy and prophylaxis for COVID-19. Here, we review the current state of antispike monoclonal antibodies and their role for SOTRs. Recent findings Bamlanivimab with or without etesevimab, casirivimab-imdevimab and sotrovimab have reduced the rates of hospitalization and severe disease in high-risk patients with mild-to-moderate COVID-19. Multiple retrospective studies have also demonstrated monoclonal antibodies are effective in SOTR populations. However, the evolution of resistant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concerns has resulted in revocation of the authorization of bamlanivimab with or without etesevimab, and casirivimab-imdevimab as treatment and postexposure prophylaxis (PEP). Sotrovimab and bebtelovimab are currently authorized for treatment of the predominant circulating SARS-CoV-2 B.1.1.529 (Omicron), but not as pre or PEP. Tixagevimab–cilgavimab, a long-acting antibody combination preparation, is authorized for preexposure prophylaxis in high-risk immunocompromised populations, including SOTRs, who are less likely to mount an effective immune response following vaccination series and booster. Summary Antispike monoclonal antibodies are useful for the prevention and treatment of mild-to-moderate COVID-19 in SOTRs. However, their clinical use should be determined by the evolving epidemiology of SARS-CoV-2 variants in the community.