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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 multistate 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.
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Purpose: Sirolimus (SIR), a mammalian target of rapamycin inhibitor (mTORi), may be used with or without a calcineurin inhibitor after heart transplant (HT). The antiproliferative properties & 72-hour half-life (T1/2) that make SIR desirable to provide uniform drug exposure & attenuate cardiac allograft vasculopathy add complications when surgical needs or toxicities arise.1,2 SIR-related wound healing impairment necessitates cessation before invasive procedures, yet managing long-acting SIR in these settings is complex due a large volume of distribution & vulnerability to interactions with CYP3A4 inhibitors, prolonging T1/2.2 Phenytoin (PHY), a potent inducer of CYP3A4, has been used to speed tacrolimus (FK) clearance.3 Interaction between PHY & SIR is reported.4 Strategic use of PHY to clear SIR is not described. Method(s): Case review leveraging PHY-inducing effects to expedite SIR & FK elimination while awaiting urgent thoracotomy for mucormycosis. Result(s): The patient developed invasive pulmonary mucormycosis 3 years post-HT. Supratherapeutic levels on admission were SIR 20 ng/mL & FK 15 ng/mL with mycophenolate 500 mg twice daily & prednisone 5 mg twice daily. Treatment was initiated with CYP3A4-inhibiting isavuconazonium sulfate (ISU) & amphotericin B irrigation. Infected lung segment resection was delayed for wound healing risks of SIR. To hasten SIR elimination via CYP3A4 induction, fosPHY load then PHY 100 mg orally thrice daily was initiated on day 5. To maintain infection treatment while inducing metabolism, ISU was converted to systemic amphotericin B. Figure 1 describes SIR, FK, ISU & PHY courses. The calculated T1/2 was shorted from 440 hours on ISU days 3-5 to 32 hours days 7-10 (allowing time for induction). On day 14 thoracotomy & left upper lobectomy were successfully performed with FK & SIR unquantifiable. Conclusion(s): This case illustrates effective induction SIR & FK metabolism using PHY. In the era of CYP 3A4-inhibiting nirmatrelvir-ritonavir availability for COVID-19, strategies to address inadvertent calcineurin inhibitor or mTORi toxicity are paramount. Employing this approach when needing to clear drugs quickly may be beneficial.
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Purpose: The OPTN DTAC, a multidisciplinary group, evaluates potential donor derived transmission events (PDDTE) to assess the likelihood of disease transmission. Method(s): Retrospective study of PDDTE cases reported to the OPTN between 01/20 and 12/20. DTAC reviewed cases using a standardized classification algorithm. Result(s): During 2020, there were 18,318 donors and 37,583 unique recipients. DTAC reviewed 261/427 PDDTE from donor (111) or recipient (150) findings. 64/261 (25%) donors had proven/probable transmission (P/P Tr) of infection, malignancies or other to 84/206 (41%) exposed recipients [figure]. 12 involved living donors. Infection occurred with 44/64 P/P cases affecting 63 recipients. Viruses were most frequent P/P infections with 29 recipients having P/P Tr from 19 donors. COVID-19 PDDTE represented 11% (29/261) of all cases reviewed involving 29 donors and 15 lung and 76 non-lung recipients. One lung recipient had P/P Tr and died;none of the non-lung recipients developed P/P Tr. For bacteria, 20 recipients had P/P Tr from 14 donors. Deaths from infection (N=10) occurred at a median of 20 days (5-89 days). Attributable death was highest for fungal (4/12, 33%) and bacterial infections (6/20, 30%). 7 donors with malignancies were classified as P/P impacting 15 recipients with 1 attributable death. 53 non-infection, non-malignancy PDDTE were reported;13 resulted in P/P Tr to 14 recipients. Conclusion(s): Although P/P events remain rare, 1/4 reviewed cases resulted in unanticipated P/P Tr. This is a conservative estimate due to passive reporting and empiric interventions. In 29 COVID-19 PDDTE only 1 lung recipient had P/P Tr. The DTAC continues to evaluate PDDTE to maximize organ use and minimize the risk of transmission. (Table Presented).
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Purpose: Decision to transplant organs from SARS-CoV-2 NAT+ donors(N+D) balances risk of donor-derived infection with the scarcity of available organs to meet the needs of waitlisted candidates. Method(s): OPTN Ad Hoc Disease Transmission Advisory Committee (DTAC) reports on the use of organs from N+D from the onset of required SARS-CoV-2 lower respiratory tract(LRT) testing for lung donors (May 27, 2021) through August 31, 2021. OPTN data were analyzed for donors with a positive LRT or upper respiratory tract (URT) test reported in DonorNet discrete data fields (N+D), compared with donors who did not have positive LRT or URT in the discrete data fields (N-D). Result(s): Organs were recovered from 120 N+D (all OPTN Regions and 40/57 OPOs (70%)). Median donor age was 42 (IQR: 32-52) for N+D and 43 (30-56) for N-D. There was a greater proportion of DCD N+D than N-D (37.5% vs 28.3%, p=0.04). Underlying COD of anoxia and other were different (N+D 31.7%, 16.7% vs N-D 48%, 2.7%, respectively). Transplanted N+D and N-D did not differ by KDPI, LDRI or LVEF for kidney(KT), liver(LT) or heart(HT), respectively (Table 1). Median time from donor admission to first reported test (any result) was 0 and 4 days for URT and LRT, respectively. N+D recovery occurred a median of 2 (IQR: 1-6) days from last positive test. 246 organs (152KT, 50LT, 22HT, 22other) were transplanted from 107 N+D compared to 8969 organs from 3348 N-D. Recipients from N+D and N-D were similar in age, MELD/PELD (LT) and medical urgency status (HT). Median time from listing to transplant similar for N+D for all organs. The match run sequence number for final acceptor was higher for N+D for all organ types (Table 2). Median length of stay was similar for N+D and N-D for KT and LT (5d and 12-13d, respectively). For HT, median stay was shorter for N+D (30 vs 34d). For N+D, 3 of 50 LT died within 30d of transplant. During this timeframe, no PDDTEs were reported for any N+D at the time of transplant. Conclusion(s): N+D and N-D were similar in terms organ quality characteristics. Recipients receiving organs from N+D had higher match run sequence numbers, suggesting use of organs from N+D is not widespread across centers;however, with small numbers, this data will need to be verified. We cannot assess the relatedness of the three early mortality events in N+D recipients to donor or recipient characteristics. However, these data highlight the importance of ongoing outcome review of N+D recipients. (Figure Presented).
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Background: Prognosis of COVID-19 is poor in the setting of immunosuppression. Casirivimab/imdevimab (REGEN-COV), bamlanivimab, and sotrovimab are investigational monoclonal antibodies (MoAbs) authorized for treatment of mild/moderate COVID-19 for patients (pts) 12 years or older and who are at high-risk for progression to severe COVID-19. These neutralizing antibodies, against SARS-CoV-2 spike proteins, have been shown to decrease risk of progression to severe disease. Recipients of allogeneic stem cell transplants (allo-SCT) or chimeric antigen T cell therapy (CAR T cell) represent a high risk population. However, treatment outcomes with these MoAbs in these pts are not well described. Methods: This retrospective study included 33 consecutive adult pts who developed mild/moderate COVID-19 and received anti-spike SARS-CoV-2 MoAbs between December 2020 and November 2021. Allo-SCT (N=27) or CAR T cell (N=6) recipients were included, and outcomes were analyzed separately. Pts received REGEN-COV (N=19), bamlanivimab (N=11), or sotrovimab (N=1), missing (N=2). Results: In the allo-SCT cohort (N=27), median age at time of COVID-19 was 55 (23-76) years. Median time from allo-SCT to COVID-19 was 31 (22-64) months. Two pts received CAR T-cell therapy prior to allo-SCT. Diagnoses included leukemia or myeloid diseases (82%), lymphoma (11%), or myeloma (7%). Transplant characteristics are summarized (Table). Thirteen pts were vaccinated against SARS-CoV-2 prior to breakthrough COVID-19. Events considered included hospitalization due to COVID- 19, disease progression, or death from any cause. The 6-month event-free and overall survivals were 81% and 91%, respectively. In the CAR T cell recipients cohort (N=6), 4 pts received axicabtagene ciloleucel for diffuse large B-cell or follicular lymphoma and 2 received brexucabtagene autoleucel for mantle cell lymphoma. The median follow-up was 8 (1-11) months. Two pts received autologous SCT prior to COVID-19. Median time from CAR T cell therapy to COVID-19 was 10 (3-24) months. Three pts were vaccinated prior to COVID-19. Only 1 pt was hospitalized due to severe COVID- 19 requiring mechanical ventilation leading to death. Conclusions: These results show a potential benefit of MoAbs in high-risk pts, namely allo-SCT or CAR T cell recipients. Future studies should evaluate the role of prophylactic use MoAbs in these populations. A comparative analysis with a matched control cohort (who did not receive MoAbs) will be provided at the meeting.
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Purpose: US Solid organ transplantation rates significantly decreased during the initial wave of the COVID-19 pandemic. The concern for potential donor derived COVID-19 was one of many contributing factors. We describe the early experience of the Organ Procurement and Transplantation Network (OPTN) Disease Transmission Advisory Committee (DTAC) Coronavirus disease 2019 (COVID-19) investigations. Methods: COVID-19 cases reported to DTAC between January 2020 and October 2020 as potential donor-derived transmission events (PPDTE) were included. All of the events were investigated by the Centers for Disease Control and Prevention and adjudicated by the DTAC based on consensus definitions. Results: Eighteen PDTE COVID-19 events were reported during the study period. 12 PDTE reports have completed DTAC adjudication (Table 1). These included 12 donors with 44 recipients. Ten investigations were initiated by the transplant center due to recipient testing (36 total recipients). The median time to presentation in these index cases was 11 days (IQR 7-16). Nine donors in these events (35 recipients) had a prospective or retrospective pre-recovery negative SARS-CoV-2 PCR result. In all of these events, the index recipient had either a possible or confirmed community or hospital exposure. In one recipient index case (5 total recipients), the positive SARS-CoV-2 PCR result post-transplant was ultimately deemed a false positive and considered not a case by the committee. Two investigations were initiated by an OPO (8 recipients). In both events, the OPO performed SARS-CoV-2 PCR was negative, but a post-procurement nasopharyngeal SARS-CoV-2 PCR performed by the tissue collector was reported as positive and retrospectively deemed false positives. None of these recipients developed COVID-19;the events were adjudicated as not cases. Conclusions: The initial DTAC experience reflecting the early pandemic era emphasizes the need to implement hospital prevention measures to avoid nosocomial transmission, provide patient education to avoid community exposure and to recognize the possibility of post-procurement SARS-CoV-2 false positive testing. Vigilance for the possibility of a SARS-CoV-2 donor derived event remains important as the pandemic continues. (Table Presented) .