Faculty Bibliography

Background. Coronavirus disease 2019 (COVID-19)"“associated pulmonary aspergillosis (CAPA) is likely underdiagnosed, and current diagnostic tools are either invasive or insensitive. Methods. A retrospective study of mechanically ventilated patients with COVID-19 admitted to 5 Johns Hopkins hospitals between March 2020 and June 2021 was performed. Multivariable logistic regression was used for the CAPA prediction model building. Performance of the model was assessed using the area under the receiver operating characteristic curve (AUC). Results. In the cohort of 832 patients, 98 (11.8%) met criteria for CAPA. Age, time since intubation, dexamethasone for COVID-19 treatment, underlying pulmonary circulatory diseases, human immunodeficiency virus, multiple myeloma, cancer, or hematologic malignancies were statistically significantly associated with CAPA and were included in the CAPA prediction model, which showed an AUC of 0.75 (95% confidence interval, .70"“.80). At a screening cutoff of ≥0.085, it had a sensitivity of 82%, a specificity of 51%, a positive predictive value of 18.6%, and a negative predictive value of 95.3%. (The CAPA screening score calculator is available at www.transplantmodels.com). Conclusions. We developed a CAPA risk score as a noninvasive tool to aid in CAPA screening for patients with severe COVID-19. Our score will also identify a group of patients who are unlikely to have CAPA and who therefore need not undergo additional diagnostics and/or empiric antifungal therapy.

OBJECTIVE:The feasibility and 6-month outcome safety of lung transplants (LTs) from hepatitis C virus (HCV)-viremic donors for HCV-seronegative recipients (R-) were established in 2019, but longer-term safety and uptake of this practice nationally remain unknown. METHODS:testing, rank-sum testing, and Cox regression to compare posttransplant outcomes between HCV D+/R- and D-/R- LT recipients. RESULTS:HCV D+/R- LT increased from 2 to 97/year; centers performing HCV D+/R- LT increased from 1 to 25. HCV D+/R- versus HCV D-/R- LT recipients had more obstructive disease (35.7% vs 23.3%, P < .001), lower lung allocation score (36.5 vs 41.1, P < .001), and longer waitlist time (P = .002). HCV D+/R- LT had similar risk of acute rejection (adjusted odds ratio [aOR], 0.87; P = .58), extracorporeal membranous oxygenation (aOR, 1.94; P = .10), and tracheostomy (aOR, 0.42; P = .16); similar median hospital stay (P = .07); and lower risk of ventilator > 48 hours (aOR, 0.68; P = .006). Adjusting for donor, recipient, and transplant characteristics, risk of all-cause graft failure and mortality were similar at 30 days, 1 year, and 3 years for HCV D+/R- versus HCV D-/R- LT (all P > .1), as well as for high- (≥20/year) versus low-volume LT centers and high- (≥5/year) versus low-volume HCV D+/R- LT centers (all P > .5). CONCLUSIONS:HCV D+/R- and HCV D-/R- LT have similar outcomes at 3 years posttransplant. These results underscore the safety of HCV D+/R- LT and the potential benefit of expanding this practice further.

BACKGROUND:Disparities in pediatric kidney transplantation (KT) result in reduced access and worse outcomes for minority children. We assessed the impact of recent systems changes on these disparities. METHODS:This is a retrospective cohort study of pediatric patients utilizing data from the US Renal Data System (n = 7547) and Scientific Registry of Transplant Recipients (n = 6567 waitlisted and n = 6848 transplanted patients). We compared access to transplantation, time to deceased donor kidney transplant (DDKT), and allograft failure (ACGF) in the 5 years preceding implementation of the Kidney Allocation System (KAS) to the 5 years post-KAS implementation 2010-2014 vs. 2015-2019, respectively. RESULTS:p = 0.05) while there was no difference in 3- or 5-year ACGF among LDKT recipients. CONCLUSIONS:After KAS implementation, there is equity in time to DDKT. Pre-KAS increased hazard of ACGF among Black children has decreased in the post-KAS era; however, persistent disparities exist in time to transplant listing among Black and Hispanic children when compared to white children. A higher resolution version of the Graphical abstract is available as Supplementary information.

Kidney transplant recipients (KTRs) show poorer response to SARS-CoV-2 mRNA vaccination, yet response patterns and mechanistic drivers following third doses are ill-defined. We administered third monovalent mRNA vaccines to n = 81 KTRs with negative or low-titer anti-receptor binding domain (RBD) antibody (n = 39 anti-RBD^NEG; n = 42 anti-RBD^LO), compared with healthy controls (HCs, n = 19), measuring anti-RBD, Omicron neutralization, spike-specific CD8⁺%, and SARS-CoV-2-reactive T cell receptor (TCR) repertoires. By day 30, 44% anti-RBD^NEG remained seronegative; 5% KTRs developed BA.5 neutralization (vs 68% HCs, P < .001). Day 30 spike-specific CD8⁺% was negative in 91% KTRs (vs 20% HCs; P = .07), without correlation to anti-RBD (r_s = 0.17). Day 30 SARS-CoV-2-reactive TCR repertoires were detected in 52% KTRs vs 74% HCs (P = .11). Spike-specific CD4⁺ TCR expansion was similar between KTRs and HCs, yet KTR CD8⁺ TCR depth was 7.6-fold lower (P = .001). Global negative response was seen in 7% KTRs, associated with high-dose MMF (P = .037); 44% showed global positive response. Of the KTRs, 16% experienced breakthrough infections, with 2 hospitalizations; prebreakthrough variant neutralization was poor. Absent neutralizing and CD8⁺ responses in KTRs indicate vulnerability to COVID-19 despite 3-dose mRNA vaccination. Lack of neutralization despite CD4⁺ expansion suggests B cell dysfunction and/or ineffective T cell help. Development of more effective KTR vaccine strategies is critical. (NCT04969263).

Background: Pediatric transplant candidates have historically been disadvantaged on the transplant waitlist, with nearly half of pediatric deceased donor organs allocated to adult recipients (Hsu, Gastroenterology, 2017), and allocation pediatric end-stage liver disease (PELD) scores that underestimate children's expected 3-month mortality compared to that of adult patients (Chang, JAMA Pediatrics, 2018). Disparities in organ distribution prompted revision of the liver allocation policy in 2020 from donation services areas (DSA) to a series of distance-based concentric circles called acuity circles (AC) before being offered nationally (US GAO, 2022), which was designed to minimize geographic inequity in liver transplant. Prior to implementation of the new liver allocation policy, analysis using the Liver Simulated Allocation Model projected that AC allocation would decrease disparities for pediatric liver transplant candidates and recipients by increasing transplants and decreasing waitlist mortality (Mogul, Transplantation, 2020). In this study, we evaluate differences in pediatric whole liver transplants performed before and after the implementation of acuity circle liver allocation policy.
Study Design: We evaluated patient characteristics, adjusted MELD/PELD at time of transplant, calculated donor age at time of transplant among pediatric whole liver transplant recipients in low versus high-volume pediatric liver transplant centers performed before and after implementation of AC-based liver allocation policy using the Scientific Registry of Transplant Recipients.
Result(s): Before and after the implementation of ACs, differences in pediatric liver transplants by age group (<2 years, 2-5 years old, 5-12 years old, and 12-18 years old) remained significantly different between low and high-volume pediatric transplant centers. Under DSA allocation policy, the median MELD/PELD at transplant was 37.0 (IQR 30.0-41.0) in low-volume centers and 40.0 (IQR 30.0-41.0) in high-volume centers. After the implementation of acuity circles, median MELD/PELD at transplant decreased to 35.0 (IQR 21.0-41.0) in low-volume centers and 35.0 (IQR 25.0-41.0) in high-volume centers. Finally, donor age at time of transplant increased from 8.0 (IQR 2.00-18.0) to 13.5 (IQR 4.5-21.0) at low-volume centers, and from 3.0 (IQR 1.0-14.0) to 4.0 (IQR 1.0-14.0) at high-volume centers before and after the implementation of ACs.
Conclusion(s): The change from DSAs to ACs in allocation policy and the shift from regional to national review boards have affected the characteristics of organ recipients, adjusted MELD/PELD at time of transplant, and donor age at time of transplant differentially between whole liver transplant recipients at low-and high-volume pediatric liver transplant centers

Neutralizing antibody (nAb) responses are attenuated in solid organ transplant recipients (SOTRs) despite severe acute respiratory syndrome-coronavirus-2 vaccination. Preexposure prophylaxis (PrEP) with the antibody combination tixagevimab and cilgavimab (T+C) might augment immunoprotection, yet in vitro activity and durability against Omicron sublineages BA.4/5 in fully vaccinated SOTRs have not been delineated. Vaccinated SOTRs, who received 300 + 300 mg T+C (ie, full dose), within a prospective observational cohort submitted pre and postinjection samples between January 31, 2022, and July 6, 2022. The peak live virus nAb was measured against Omicron sublineages (BA.1, BA.2, BA.2.12.1, and BA.4), and surrogate neutralization (percent inhibition of angiotensin-converting enzyme 2 receptor binding to full length spike, validated vs live virus) was measured out to 3 months against sublineages, including BA.4/5. With live virus testing, the proportion of SOTRs with any nAb increased against BA.2 (47%-100%; P < .01), BA.2.12.1 (27%-80%; P < .01), and BA.4 (27%-93%; P < .01), but not against BA.1 (40%-33%; P = .6). The proportion of SOTRs with surrogate neutralizing inhibition against BA.5, however, fell to 15% by 3 months. Two participants developed mild severe acute respiratory syndrome-coronavirus-2 infection during follow-up. The majority of fully vaccinated SOTRs receiving T+C PrEP achieved BA.4/5 neutralization, yet nAb activity commonly waned by 3 months postinjection. It is critical to assess the optimal dose and interval of T+C PrEP to maximize protection in a changing variant climate.

BACKGROUND:Tixagevimab and Cilgavimab (T + C) is authorized for pre-exposure prophylaxis (PrEP) against Coronavirus Disease 2019 (COVID-19) in solid organ transplant recipients (SOTRs), yet patient-reported outcomes after injection are not well described. Furthermore, changes in risk tolerance after T + C PrEP have not been reported, of interest given uncertain activity against emerging Omicron sublineages. METHODS:Within a national prospective observational study, SOTRs who reported receiving T + C were surveyed for 3 months to ascertain: (1) local and systemic reactogenicity, (2) severe adverse events with focus on cardiovascular and alloimmune complications, and (3) breakthrough COVID-19, contextualized through (4) changes in attitudes regarding COVID-19 risk and behaviors. RESULTS:At 7 days postinjection, the most common reactions were mild fatigue (29%), headache (20%), and pain at injection sites (18%). Severe adverse events were uncommon; over 3 months of follow-up, 4/392 (1%) reported acute rejection and one (.3%) reported a myocardial infarction. Breakthrough COVID-19 occurred in 9%, 16-129 days after receiving full dose (300/300 mg) T + C, including two non-ICU hospitalizations. Most surveyed SOTRs (65%) felt T + C PrEP was likely to reduce their COVID-19 risk, and 70% reported increased willingness to engage in social activities such as visiting friends. However, few felt safe to return to in-person work (20%) or cease public mask-wearing (15%). CONCLUSIONS:In this prospective study of patient-reported outcomes, T + C was well tolerated with few serious events. Several COVID-19 breakthroughs were reported, notable as most SOTRs reported changes in risk tolerance after T + C. These results aid counseling of SOTRs regarding real-world safety and effectiveness of T + C.

BACKGROUND:Postacute sequelae of SARS-CoV-2 infection (PASC) is an increasingly recognized phenomenon and manifested by long-lasting cognitive, mental, and physical symptoms beyond the acute infection period. We aimed to estimate the frequency of PASC symptoms in solid organ transplant (SOT) recipients and compared their frequency between those with SARS-CoV-2 infection requiring hospitalization and those who did not require hospitalization. METHODS:A survey consisting of 7 standardized questionnaires was administered to 111 SOT recipients with history of SARS-CoV-2 infection diagnosed >4 wk before survey administration. RESULTS:Median (interquartile range) time from SARS-CoV-2 diagnosis was 167 d (138-221). Hospitalization for SARS-CoV-2 infection was reported in 33 (30%) participants. Symptoms after the COVID episode were perceived as following: significant trauma (53%), cognitive decline (50%), fatigue (41%), depression (36%), breathing problems (35%), anxiety (23%), dysgeusia (22%), dysosmia (21%), and pain (19%). Hospitalized patients had poorer median scores in cognition (Quick Dementia Rating System survey score: 2.0 versus 0.5, P = 0.02), quality of life (Health-related Quality of Life survey: 2.0 versus 1.0, P = 0.015), physical health (Global physical health scale: 10.0 versus 11.0, P = 0.005), respiratory status (Breathlessness, Cough and Sputum Scale: 1.0 versus 0.0, P = 0.035), and pain (Pain score: 3 versus 0 out of 10, P = 0.003). Among patients with infection >6 mo prior, some symptoms were still present as following: abnormal breathing (42%), cough (40%), dysosmia (29%), and dysgeusia (34%). CONCLUSIONS:SOT recipients reported a high frequency of PASC symptoms. Multidisciplinary approach is needed to care for these patients beyond the acute phase.

UNLABELLED:Following the outbreak of coronavirus disease 2019 (COVID-19) in the United States, the number of kidney waitlist additions and living-donor and deceased-donor kidney transplants (LDKT/DDKT) decreased substantially but began recovering within a few months. Since then, there have been several additional waves of infection, most notably, the Delta and Omicron surges beginning in August and December 2021, respectively. METHODS/UNASSIGNED:Using SRTR data, we compared observed waitlist registrations, waitlist mortality, waitlist removal due to deteriorating condition, LDKT, and DDKT over 5 distinct pandemic periods to expected events based on calculations from preepidemic data while accounting for seasonality and secular trends. RESULTS/UNASSIGNED:). CONCLUSIONS/UNASSIGNED:Despite exceptionally high COVID-19 incidence during the Omicron wave, the transplant system responded similarly to prior waves that imposed a lesser disease burden, demonstrating the transplant system's growing adaptations and resilience to this now endemic disease.

Decreased postdonation eGFR is associated with a higher risk of ESRD after living kidney donation, even when accounting for predonation characteristics. The Toulouse-Rangueil model (TRM) estimates 12 month postdonation eGFR (eGFR12) to inform counseling of candidates for living donation. The TRM was validated in several single-center European cohorts but has not been validated in US donors. We assessed the TRM in living kidney donors in the US using SRTR data 1/2000-6/2021. We compared the 2021 CKD-EPI equation eGFR12 observed estimates to the TRM eGFR12 predictions. Median (IQR) bias was -3.4 (-9.3, 3.4) mL/min/1.73 m². Bias was higher for males vs. females (bias [IQR] -4.4 [-9.9, 1.8] vs. -2.9 [-8.8, 4.1]) and younger (31-40) vs. older donors (>50) (bias -4.9 [-10.6, 3.0] vs. -2.1 [-7.5, 4.0]). Bias was also larger for Black vs. White donors (bias (-6.7 [-12.1, -0.3], p < 0.001) vs. (-3.4 [-9.1, 3.1], p < 0.001)). Overall correlation was 0.71. In a sensitivity analysis using the 2009 CKD-EPI equation, results were generally consistent with exception to a higher overall bias (bias -4.2 [-9.8, 2.4]). The TRM overestimates postdonation renal function among US donors. Overestimation was greatest for those at higher risk for postdonation ESRD including male, Black, and younger donors. A new equation is needed to estimate postdonation renal function.