Tx Recipients Research Articles

Donor-derived mold infections in lung transplant recipients: The importance of active surveillance.

Unexpected donor-derived fungal infections represent a rare but potentially fatal complication in lung transplant (Tx) recipients. Timely communication of the results of donor cultures and prompt treatment of recipients are crucial to mitigate the consequences of donor-derived transmissions. In this prospective cohort study, all consecutive patients who underwent lung transplantation from 2015 to 2022 were included. In December 2015, a Local Active Surveillance System has been implemented to provide biovigilance of donor culture results and optimize recipients' management. The aim of this study is to investigate the incidence of unexpected, mold-positive cultures among lung donors and the rate of transmission to recipients. Furthermore, management strategies and outcome of recipients with mold transmission are described. In case of isolation of the same mold in donor and recipient cultures, when possible, transmission was confirmed by dendrogram analysis. During the study period, 82 lung Tx were performed from 80 donors. The prevalence of donors with "unexpected" mold isolation from the respiratory tract was 3.75% (3/80). Isolated molds were Aspergillus niger, Rhizopus oryzae, and Aspergillus flavus. Transmissions occurred in all the three cases (100%) with a mean time of 5 days from lung Tx but none of the recipients developed invasive mold disease. Our Local Active Surveillance System allowed prompt recognition of lung donors unexpected mold colonization. Even though transmission occurred, introduction of early targeted antifungal therapy prevented potential catastrophic consequence of mold donor-derived infection in the immediate post-Tx period.

Personal Resources and Expectations and Health Behaviors Among Solid Organ Transplant Recipients—A Multicenter Study

BackgroundThe long-term success of organ transplantation (Tx) depends on the transplant recipient's ability to self-manage symptoms, treatment, lifestyle changes, and psychosocial consequences. Health behavior (HB) determinants include personality traits such as optimism, self-efficacy, and health locus of control. PurposeAssessing the relationship between personal resources and expectations and health behaviors of organ transplant recipients. Material and methodsThe study was conducted between 01/04/2018 and 30/10/2019 at 3 transplant centers in Poland. The study group consisted of 243 Tx recipients of kidney, heart, liver, and lung. The Health Behavior Inventory, Multidimensional Health Locus of Control Scale (MHLC), General Self-Efficacy Scale, Dispositional Optimism Scale, and Hospital Anxiety and Depression Scale were used to collect data. FindingsThe study group had medium levels of dispositional optimism (mean 15) and high levels of self-efficacy (mean 30.18). The MHLC scale was dominated by a belief in the influence of others and an internal locus of control over one's health. The respondents presented a high level of HB (mean 92.09). A positive relationship was found between personal resources (self-efficacy and optimism), MHLC and HB. The presence of depression and anxiety negatively affected personal resources and internal locus of health control and HB in terms of a positive mental attitude. Type of Tx differentiated internal locus of health control and HB. Predictors of HB were dispositional optimism, self-efficacy, influence of others with health locus of control, symptoms of depression, age and time since transplantation-explaining between 6.1% and 14.5% of health behavior categories. ConclusionsTo improve health practices among organ recipients, strengthening their personal resources is recommended. It is necessary to form an internal locus of control for adherence to positive HB.

Outcomes of Kidney Transplants From Toxoplasma-Positive Donors: An Organ Procurement and Transplant Network Database Analysis.

There is a need to reconsider the acceptance of organs from donors considered suboptimal, in the absence of data. Toxoplasma antibody-positive donors (TPD) constitute one such group. The objective of our study was to compare graft survival in deceased donor renal transplant (Tx) recipients, stratified by Toxoplasma IgG status, using the Organ Procurement and Transplantation Network (OPTN) database. A log-linear event history regression model for graft failure categorized by Toxoplasma IgG status, adjusting for confounders was applied to first kidney-only Tx recipients from 2018 to 2022. Of the 51,422 Tx, 4,317 (8.4%) were from TPD. Acute rejection and graft failure (5% each) were similar between groups. Crude graft failure was 7.3 failures per 100 person-years for TPD recipients compared to 6.5 failures per 100 person-years for the Toxoplasma-negative group (p 0.008). The crude failure rate ratio was 1.14 with an adjusted hazard rate ratio of 1.04 (95% CI: 0.94, 1.15, p 0.39). In renal Tx recipients, TPD graft recipients have comparable survival to Tx from Toxoplasma-negative recipients. While caution and close monitoring of recipients post-Tx for surveillance of disseminated toxoplasmosis are still warranted, our study suggests that patients can be successfully managed using TPD organs.

Quantitative PCR-based diagnosis and follow-up of Chagas disease primary infection after solid organ transplant: a multicentre study.

Chagas disease in solid organ transplant (Tx) recipients may present as a primary infection (PI). Early detection is crucial for timely treatment. This is the largest observational multicentre study evaluating qPCR for early diagnosis and treatment monitoring of PI in seronegative recipients of organs from seropositive donors. Out of 34 patients, admitted at five health centers, PI was detected by qPCR in 8 (23.5%) within a post-Tx period of 40 days (IQR:31-50). No PI was detected by Strout or clinical symptoms/signs. All patients had favourable treatment outcome with negative qPCR 31 days (IQR:18-35) after treatment, with no post-treatment relapse episodes.

Effect of circulating tumor cells distribution in treatment naive and treated patients with advance stage breast cancer on disease burden.

e12517 Background: Breast malignancies is a leading cause of cancer-related mortalities and show ascending incidence rate. Despite advancements in our understanding of the disease, its clinical outcome is often dismal. This largely remains owing to the characteristic wide window of relapse, spanning months to decades after primary treatment. Therefore, continuous monitoring of the disease is an offered choice to detect metastatic progression and recurrence. Circulating tumor cells (CTCs) have emerged as a powerful prognostic tool to predict the disease outcome in many epithelial cancers. CTCs are a real-time surrogate biomarker accounting for minimal residual disease (MRD) which is often missed in CT PET scanning. This leads to a progression of metastasis when the patient is often considered as ‘clinically disease free’. Here, we analyzed the presence of CTCs in treatment-naïve and chemo-recipient breast cancer patients. Methods: In this retrospective study on 417 breast cancer patients, CTCs were isolated from 1.5 ml of blood using the Drug Controller General of India (DCGI) approved OncoDiscover CTC test. This platform contains affinity-based magnetic nanoparticles to mediate EpCAM-based CTC isolation. CTCs were detected as CK18+, DAPI+ and CD45- cells based on automated digital imaging platform. Results: 42.6 % (n=178) of patients were clinically at progressive stage (stage II and III) and treatment naïve. On the other hand, 47.4 % of patients received treatment including surgery and chemotherapy. CTCs were not observed in 5.6 % (n=10) of the treatment naïve population while 32% (n=75) of patients who received therapy did not show CTCs. The mean CTC number in treatment naïve patients was 15, while the mean CTC count in patients receiving therapy was drastically reduced to 2. This implied that therapy effectively countered the tumor progression and reduced the shedding of tumor cells in circulation. The distribution of CTC in treatment naïve patients exhibited a bimodal trend centered at values of 10 and 50, suggesting two distinct populations of patients with respect to CTC count. CTC count did not show any correlation with the age in both population groups. Surprisingly CTC count in younger patients (20-50 years) was 50% higher compared to the older population (50-75 years). Conclusions: The presence of CTCs in treatment naïve, progressive breast cancer patients indicated the biologically aggravated disease. Although therapeutic intervention drastically reduced the CTC burden, their presence in a large population was suggestive of an MRD and the likelihood of recurrence after discontinuation of therapy. A distinct pattern of CTC occurrences in Tx naïve and Tx recipient patient suggested that CTCs can be an important clinical indicator to monitor the therapy response, progression and residual disease.

Distinct association between chronic Epstein-Barr virus infection and T cell compartments from pediatric heart, kidney, and liver transplant recipients

Chronic Epstein-Barr virus (EBV) infection after pediatric organ transplantation (Tx) accounts for significant morbidity and mortality. The risk of complications, such as posttransplant lymphoproliferative disorders, in high viral load (HVL) carriers is the highest in heart Tx recipients. However, the immunologic signatures of such a risk have been insufficiently defined. Here, we assessed the phenotypic, functional, and transcriptomic profiles of peripheral blood CD8+/CD4+ T cells, including EBV-specific T cells, in 77 pediatric heart, kidney, and liver Tx recipients and established the relationship between memory differentiation and progression toward exhaustion. Unlike kidney and liver HVL carriers, heart HVL carriers displayed distinct CD8+ T cells with (1) up-regulation of interleukin-21R, (2) decreased naive phenotype and altered memory differentiation, (3) accumulation of terminally exhausted (TEX PD-1+T-bet−Eomes+) and decrease of functional precursors of exhausted (TPEX PD-1intT-bet+) effector subsets, and (4) transcriptomic signatures supporting the phenotypic changes. In addition, CD4+ T cells from heart HVL carriers displayed similar changes in naive and memory subsets, elevated Th1 follicular helper cells, and plasma interleukin-21, suggesting an alternative inflammatory mechanism that governs T cell responses in heart Tx recipients. These results may explain the different incidences of EBV complications and may help improve the risk stratification and clinical management of different types of Tx recipients.

Multi-drug resistant strains as etiological agents of urinary tract infections in patients after solid organ transplantation.

Urinary tract infections (UTIs) caused by multi-drug resistant strains are a serious and growing problem in organ transplant (TX) recipients. The aim of the study was to assess the prevalence and risk factors of UTIs caused by multi-drug resistant strains in hospitalized patients after kidney or liver transplantation in a large transplant center. 392 cases of UTIs in patients after kidney or liver TX hospitalized in 2014, 2015 and 2016 were analyzed. Among the assessed cases of UTIs, 66.07% occurred in women, 33.93% - in men, 80.1% - in kidney TX recipients and 19.9% - in liver TX recipients. The median age of the patients was 57.51 years and the median time since TX was 41.44 months. Most episodes of UTIs were observed during the first year after TX - 121 (30.78%) of cases. A total of 506 pathogens were cultured: 345 Gram-negative bacteria (68.182%), 146 Gram-positive bacteria (28.854%) and 15 fungi (2.964%). More than one pathogen was found in 25.51% of urine cultures. Among bacteria (n=491), a resistance mechanism was detected in 166 (33.81%) pathogens (133 Gram-negative and 33 Gram-positive). The most common etiological agents were: E. coli ESBL- (23.72%), K. pneumoniae ESBL+ (17.19%), E. faecalis (11.27%) and E. faecium (7.71%). Diabetes was present in 129 (35.46%) of patients, and the number of UTI cases was similar in the group with and without diabetes. Compared to the general population, in hospitalized patients after kidney or liver transplantation UTIs occur more often in men and are more often caused by Gram-positive bacteria. In 33.81% of cases UTIs are caused by multi-drug resistant strains, predominantly Gram-negative bacteria.

Should the First Rejected Kidney Implant be Removed?

Renal transplantation (TX) is widely used as a definitive therapy for chronic, end-stage organ failure. T cells are pivotal in rejection (RX), and RX is a process whereby donor tissue is recognized and destroyed by the host immune system. Within a rejecting graft it is likely that high concentrations of IL-2 are present. The binding of interleukin 2(IL-2) to its receptor (IL-2R) on human T cells constitutes the key regulatory event in the initiation and maintenance of the immune response. The receptor, IL-2R, is found in two forms: cellular and soluble. The surgical removal of a transplanted kidney following RX or failure can be hazardous. Two surgical techniques were applied: extracapsular and intracapsular removal. The technique of kidney transplant removal by either the intra- or extra-capsular route of the exact timing of the operation are important features for safe treatment of patients with end-stage graft failure. The results of the report are a prospective study on 21 renal TX recipients, and show that nephrectomy of previous TX kidney will reduce the levels of four markers in serum and urine.

Racial and Socioeconomic Disparities in Pediatric Heart Transplant Outcomes in the Era of Anti-Thymocyte Globulin Induction

<h3>Purpose</h3> A recent multicenter pediatric study using antithymocyte globulin (ATG) induction found a reduced risk of first yr rejection in Black heart transplant (tx) recipients. We investigated this finding in the broader field and studied the effects of race and socioeconomic disparity on outcomes in ATG-induced children. <h3>Methods</h3> Using the Pediatric Heart Transplant Society registry, we compared outcomes in Black and White children 1-17 yrs old who underwent heart tx with ATG induction between 2000-2020. The primary outcomes of treated rejection, rejection with hemodynamic compromise (HC), and graft loss (death or re-transplant) were studied over 1- and 10-yr time intervals as well as late outcomes conditional on 1-yr survival<i>.</i> We explored the association of these outcomes with race and socioeconomic disparity, assessed using neighborhood deprivation index [NDI] score at 1-yr post-tx (high NDI score implies more socioeconomic disadvantage). <h3>Results</h3> The study cohort included 1719 ATG-induced pediatric heart tx recipients (23% Black, 77% White). There was no racial difference in incidence of first yr treated rejection (Black 24.5%, White 28.1%, p = 0.2). During the 10 yr follow up, the risk of treated rejection was similar between Black and White recipients; however, Black recipients were at higher risk of HC rejection (p = 0.009) and graft loss (p = 0.02, log rank test). Black recipients had a higher mean NDI score (0.43 vs 0.36, p < 0.001). A higher risk of graft loss was associated with high NDI score in both White and Black recipients (p < 0.001, Fig). In a multivariable Cox model, both high NDI score (HR 2.03, 95% CI 1.38-2.98) and Black race (HR 1.99, 95% CI 1.36-2.93) were associated with graft loss. <h3>Conclusion</h3> Black race and socioeconomic disadvantage remain associated with HC rejection and graft loss after the first post-transplant year in pediatric heart tx patients with ATG induction. These disparities represent important opportunities to improve long term tx outcomes in children.

Variances in Humoral Responses to Different Spike Protein Domains After SARS-CoV-2 Vaccination in Lung and Heart Transplant Recipients

PurposeSolid organ transplant recipients are lacking an adequate immune response to SARS-CoV-2 vaccination. Therefore, these patients are still at risk and potentially in need of booster vaccinations. Furthermore, it is important to differentiate between the recipients of distinct organs. The efficacy of SARS-CoV-2 vaccination is usually examined via antibodies specific for the spike protein with assays containing the S1 and receptor-binding-domains (RBD) and rather rarely the S2 domain. To gain information about the humoral response in Tx recipients, it is feasible to compare the immunogenicity of these three domains. To address this, we compared the IgG antibody levels specific for the three spike protein domains in heart (HTx) vs lung (LTx) transplant recipients.MethodsBlood plasma 4-6 weeks after the second dose of SARS-CoV-2 vaccination (85% mRNA) of n=100 LTx and n=40 HTx patients was analysed for S1, S2 and RBD-specific IgG antibodies by Luminex-based multiplex assays. The threshold for positive antibody responses was set separately for each spike domain based on the median MFI + 2σ in an unexposed pre-pandemic control group.ResultsFor all three spike protein domains, HTx patients showed a significantly higher rate of positive IgG responses than the LTx patients (73% vs 43%). The comparison of MFI values for S1-, S2- and RBD-specific IgG further underlines the superior antibody response by HTx patients with higher MFI values for S1 (p = 0.0001, S2 p = 0.008, RBD p < 0.0001). In the LTx cohort, MFI values for S2- (p < 0.0001) as well as for RBD-specific IgG (p < 0.0001) were higher than for S1. The same applies for S2 vs S1 (p < 0.0001) and RBD vs S1 (p = 0.0018) in the HTx cohort. Comparing the MFI of S2 vs RBD, the levels of domain-specific IgG were higher for S2 than RBD in both LTx (p < 0.0001) and HTx patients (p = 0.0914).ConclusionHTx patients exhibit a moderately good IgG response to vaccination while LTx recipients show lower antibody responses. Based on the more efficient antibody production against S2 as opposed to the RBD and especially S1-domain, the S2-specific IgG response should be taken into consideration when evaluating the general immune response and the resulting protection after SARS-CoV-2 vaccination in transplant recipients. Both groups of patients might benefit from booster vaccinations.

Uncovering a Long-term Graft Survival Advantage Afforded by Infant Renal Transplants-An Organ Procurement and Transplantation Network Database Analysis.

Background.Renal transplants (Tx) are performed infrequently in infants, due to concerns related to poor outcomes. The aim of our study was to compare graft failure rates in infant (<1 y) renal Tx recipients compared with older children.Methods.Retrospective cohort study of pediatric renal Tx recipients from 2000 to 2015, using the Organ Procurement and Transplant Network database. A log-linear event history regression model for time to graft failure, adjusting for age group and important confounders, was used to estimate post-Tx graft failure probabilities.Results.In 2696 Tx followed for a median of 6.1 y, 704 failures were observed. Significant predictors of graft failure were year of Tx (for each year after 2000, rates were 8.6% lower), Black race-ethnicity (63% higher compared with Whites), and number of HLA matches. For infants (n = 27), estimated graft failure percentage (95% confidence interval) within the first 1-, 2-, and 5-y post-Tx were 10.4 (0.1–21.1), 11.9 (1.2–22.6), and 16.4 (4.9–27.9). For the 1- to 11-y-olds (n = 1429), these were 3.8 (3.0–4.6), 6.3 (5.4–7.3), and 13.6 (12.2–15.0), respectively, and for the 12+ y olds (n = 1240), they were 3.8 (3.1–4.5), 8.1 (7.2–9.0), and 19.9 (18.1–21.7), respectively (P < 0.001 for 5-y graft failure rate across age groups).Conclusions.Infant renal Tx recipients experience a higher graft failure rate in the first year, compared with older cohorts, but over longer intervals, cumulative failure rates are comparable or even lower. To minimize early graft losses such Tx should be performed in experienced centers.

105.4: Impact of the COVID-19 Lockdown on Behavior, Stress, Anxiety and Glycemic Control in Patients With Beta Cell Transplantation

Introduction: Patients with severely complicated type 1 diabetes (T1D) who receive β-cell transplantation (Tx) have multiple risk factors for a severe course of coronavirus disease, including the use of immunosuppression (IS). Lockdown strategies implemented due to the COVID-19 pandemic are known to impact both mental and physical health, but this impact is expected to be even greater in patients at high risk for a severe course of COVID-19. We therefore aimed to investigate the behavioral, mental and physical implications of the nationwide lockdown in islet and pancreas transplant recipients (referred to in this abstract as β-cell Tx). Methods: In order to study the effect of the lockdown on glycemic control, all patients with T1D and an islet transplantation or pancreas transplantation with non-optimal graft function according to the Igls criteria using IS were eligible. As a control group, patients with T1D without IS were included. Lockdown behavior and self-reported changes in anxiety, stress, physical activity, weight, and glycemic control were assessed using questionnaires. HbA1c and continuous glucose monitoring (CGM) metrics during lockdown were compared to measurements before lockdown. Results: Islet and pancreas (β-cell) Tx recipients (n = 51, age 55 (48 – 59) years, BMI 23.3 (20.9 – 27.4) kg/m2, diabetes duration 42 (34 – 48) years) adhered more stringently to lockdown measures compared to patients with T1D alone (n = 272, age 53 (37 – 62) years, BMI 25.2 (23.0 – 28.0) kg/m2, diabetes duration 27 (15 – 39) years). In β-cell Tx recipients as compared to T1D, 52.1% vs 18.3% (p <0.001) reported not going out for groceries and 45.8% vs 14.0% (p <0.001) reported not leaving the house at all. Fear of coronavirus infection was higher in β-cell Tx recipients (VAS 5.0 (3.0 – 7.0) vs 3.0 (2.0 – 5.0), p=0.004) and glycemic control worsened during lockdown as assessed by HbA1c (ΔHbA1c +1.67 ± 8.74 vs -1.72 ± 6.15 mmol/mol, p=0.006) as well as CGM (Δ time in range β-cell Tx -4.5% (-6.0% – 1.5%) vs T1D 3.0% (-2.0% – 6.0%), p=0.038; Δ time above range β-cell Tx 5.5% (-0.5% – 7.5%) vs T1D -3.0% (-7.5% – 3.0%), p=0.025). Among β-cell Tx recipients, 29.2% self-reported more difficulty with glycemic control, 26.8% increased insulin use, 40.0% less physical activity, 41.7% weight gain, 29.2% increased anxiety and 33.3% increased stress since the start of lockdown. Having had a β-cell Tx was the most important predictor of not leaving the house during the COVID-19 lockdown. Conclusions: The COVID-19 pandemic and subsequent lockdown add additional fear of infection, deterioration of glycemic control and more stringent social isolation behavior when patients with T1D also have an islet or pancreas transplant. These patients undertake less physical activity and experience more weight gain, stress and anxiety. Health care professionals should be aware of these behavioral, mental and physical implications to be able to provide extra support.

Prevalence, progression and implications of breast artery calcification in patients with chronic kidney disease.

ABSTRACTBreast arterial calcification (BAC) is increasingly recognized as a specific marker of medial calcification. The present retrospective observational cohort study aimed to define the prevalence, progression rate, risk factors and clinical implications of BAC in chronic kidney disease (CKD) patients across stages of disease. The presence and extent of BAC were determined on mammograms in 310 females (58.7 ± 10.8 years, Caucasian) with CKD across various stages of disease [CKD G2–5D n = 132; transplant (Tx) recipients n = 178]. In a subset of 88 patients, repeat mammography was performed, allowing us to calculate the annualized BAC rate. Overall, BAC was observed in 34.7% of the patients. BAC prevalence (P = 0.02) and BAC score (P = 0.05) increased along the progression of CKD. In the overall cohort, patients with BAC were characterized by older age, more cardiovascular disease, more inflammation, higher pulse pressure and borderline higher prevalence of diabetes and were more often treated with a vitamin K antagonist (VKA). The BAC progression rate was significantly lower in Tx patients as compared with CKD G5D. Progressors were characterized by more inflammation, worse kidney function, higher BAC score and higher serum phosphate level (Tx only) at baseline and were more often treated with a VKA. Major adverse cardiovascular event-free survival was significantly worse in Tx patients with BAC. In conclusion, BAC is common among CKD patients, progresses at a slower pace in Tx patients as compared with CKD 5D and associates with dismal cardiovascular outcomes. BAC score, kidney function, serum phosphate at baseline and VKA usage seem to be important determinants of progression.

CD4+CD25+CD127-Foxp3+ and CD8+CD28- Tregs in Renal Transplant Recipients: Phenotypic Patterns, Association With Immunosuppressive Drugs, and Interaction With Effector CD8+ T Cells and CD19+IL-10+ Bregs.

IntroductionGaps still exist regarding knowledge on regulatory cells in transplant recipients. We studied the phenotypic patterns of CD4+, CD8+CD28- Tregs, and CD19+IL-10+ Bregs in the blood of healthy controls (HC), end-stage kidney disease patients (ESKD), early and late stable renal transplant recipients (Tx), and transplant recipients with steroid-treated acute cellular rejection 1 week–3 months after successful treatment. We also investigated the relationship between immunosuppressive drugs and the aforementioned regulatory cells in transplant recipients.MethodsWe recruited 32 HC, 83 ESKD, 51 early Tx, 95 late Tx, and 9 transplant patients with a recent steroid-treated acute cellular rejection. Besides CD19+IL-10+ Bregs, we analyzed absolute and relative frequencies of CD4+CD25+CD127-Foxp3+ Tregs and CD8+CD28- Tregs and their expression of IL-10, TGF-ß, IFN-g, and Helios.ResultsWe found a negative correlation between absolute CD4+CD25+CD127-Foxp3+ Treg and relative CD19+IL-10+ Breg frequencies in early Tx recipients (r=-0.433, p=0.015, n=31). In that group, absolute CD4+CD25+CD127-Foxp3+ Tregs were negatively associated with steroid dose and tacrolimus trough levels (r=-0.377, p = 0.021, n=37; r=-0.43, p=0.033, n=25, respectively), opposite to IL-10+ Bregs, whose frequency apparently was not negatively affected by potent immunosuppression early posttransplant. We found also lower CD4+CD25+CD127-Foxp3+ Tregs in patients treated with basiliximab or rATG as compared with ESKD patients (p=0.001 and p <0.001, respectively). No difference in absolute IL-10+ Bregs could be detected among these 3 patient groups. Early Tx recipients showed lower CD4+CD25+CD127-Foxp3+ Tregs within 3 months of antibody induction than after 3 months (p = 0.034), whereas IL-10+ Bregs showed higher relative counts during the first 3 months post antibody induction than after 3 months (p = 0.022). Our findings suggest that IL-10+ Bregs decrease with time posttransplantation independent of the effect of antibody induction and dose of other immunosuppressive drugs.ConclusionThese findings suggest that CD19+IL-10+ Bregs and CD4+CD25+CD127-Foxp3+ Tregs behave in opposite ways during the early posttransplant period, possibly due to a predominant negative impact of high doses of immunosuppressants on Tregs. CD19+IL-10+Bregs do not seem to be suppressed by antibody induction and early potent immunosuppression with chemical drugs.

Scedosporium and Lomentospora infections in lung transplant recipients

Infections caused by uncommon or rare mould pathogens often complicate the management of lung transplant (Tx) recipients contributing to high mortality. This review explores the epidemiology, diagnosis, and management of Scedosporium and Lomentospora (S/L) infections in lung Tx recipients as well as highlighting constraints in the current management and areas for future research. The number of reported S/L infections remains low among lung Tx recipients whilst the diagnosis and treatment of S/L infections remains challenging. The very few studies which evaluated clinical characteristics, prognostic factors and treatment outcomes of lung Tx patients with lomentosporiosis and/or scedosporiosis were limited by single-centre and observational study design. The requirement to standardise surveillance and culture procedure for S/L infections in lung Tx remains. Better diagnostic tools and antifungal agents are needed to manage S/L infection in this patient cohort. Prospective clinical registries or online databases for lung Tx recipients with these rare mould infections are essential to refine disease management and to improve clinical outcomes in the future.

NETosis in Broncho-Alveolar Lavage-Fluid (BAL-f) from Bronchiolitis Obliterans Syndrome (BOS) Patients

Purpose Bronchiolitis obliterans Syndrome (BOS) is a major long term complication after lung transplant. The role of Neutrophil (Neu) activation in BOS pathogenesis has been repeatedly suggested but needs to be fully clarified. Human Neutrophil Elastase (HNE) as well as complexes of alpha-1-antitrypsin (AAT)/HNE are more frequently detected in BAL-f from BOS patients thus suggesting chronic Neu activation BOS. NETosis is a mechanism of Neu response to pathogens which can drive severe epithelial injury. Here, we aim to analyze possible role of NETosis in BOS by assessing number of Neu and related markers in BAL-f. Methods A total of 16 BAL samples from BOS (n° 8, 3 BOS1, 2 BOS2 and 2 BOS3) and from stable lung recipients (n°8) were included. Patients with sarcoidosis (Sarco) were used as control (n°3). The following measures were performed: BAL Neu counts; HNE, IL1beta and IL8 (ELISA); NETs (measuring HNE-DNA complexes by ELISA); AAT/HNE complexes (WB). Results NETs were measurable in all BAL samples from Tx recipients, with a not-significant trend towards higher values among BOS patients (p=0.275). Interestingly NETs levels did not correlate with Neu counts (r=0.575; p=0.143) but, limited to BOS patients, significantly correlated with IL-8 (r=0.786; p=0.028), HNE (r=0.736; p=0.028), and AAT/HNE complexes (r=0.73; p=0.05).No correlation with IL1beta levels was found. Conclusion This is the first preliminary evidence of the possibility to detect NETs in BAL-f of lung transplant recipients and, interestingly points out that NETs levels do not seem to correlate simply with Neu counts but rather with inflammation and specific Neu activation. Thus, they could potentially represent a marker of higher inflammatory state. In addition, given the evidence that NETs drive epithelial cell injury and cause EMT their significant pathogenic role in BOS can be suggested and future therapeutic strategies can be hypothesized.

Lung Transplant Outcomes Based on Immunosuppressive Regimen at Discharge: Data from the US Scientific Registry of Transplant Recipients (SRTR)

<h3>Purpose</h3> There is currently no FDA approved immunosuppressive regimen for lung transplant (Tx) recipients; however, patients routinely receive a CNI-based regimen. The SRTR database was analyzed to provide real-world evidence of the efficacy and safety of tacrolimus-based immunosuppressive regimens post lung Tx. <h3>Methods</h3> Adult and pediatric recipients of a primary deceased donor lung Tx between January 1, 1999 and December 31, 2017 were followed for 3 years post-transplant based on immunosuppressive regimen at discharge: immediate-release tacrolimus (TAC IR)+mycophenolate mofetil (MMF), TAC IR+azathioprine (AZA), cyclosporine (CYA)+MMF, or CYA+AZA. The primary outcome was the composite endpoint of graft failure or death (all cause) at 1 year post-transplant. Cox proportional hazard models were used to test for baseline characteristics associated with a greater risk of graft failure or death in adults. <h3>Results</h3> Data were available for 26,080 lung Tx recipients (25,355 adults and 725 pediatric patients). The most common discharge immunosuppressive regimen was TAC IR+MMF in both groups. Post-transplant outcomes are shown in Tables 1 (adults) and 2 (pediatrics). Factors associated with a greater risk of graft failure or death in adults on TAC IR+MMF included: recipient age ≥65 years, single lung transplant, hospital stay >24 days, BMI <18.5 kg/m², serum creatinine ≥1.0 mg/dL, donor age ≥55 years, and donor race (Black). The risk of graft failure or death was significantly greater in adults receiving CYA+MMF or CYA+AZA compared to TAC IR+MMF. <h3>Conclusion</h3> Discharge immunosuppressive regimens in lung Tx recipients changed over the period from 1999-2017, with a substantial increase in the use of TAC IR+MMF. Adult and pediatric lung Tx recipients receiving TAC IR+MMF had a cumulative incidence of graft failure or death at 1 year post transplant less than 9% (graft survival >91%) and had the lowest rejection rates without increased risks of infection or malignancy.

Immunosuppressive Treatment Does Not Prevent Humoral and Cellular Virus-Specific Immunity in Heart or Lung Recipients with SARS-CoV-2 Pneumonia

PurposeClinical characteristics of SARS-CoV-2 infection and virus-specific humoral and cellular response were analyzed in 4 heart (HR) and 3 lung (LR) Tx recipients in standard triple immunosuppressive regimen.MethodsSARS-CoV-2 infection was diagnosed by real-time PCR on naso-pharingeal swabs (NPS). T-cell response to structural antigens Spike (S), Envelope (E), Membrane (M) and Nucleocapsid (N) was evaluated by PBMC stimulation with overlapping peptides spanning the entire viral proteins and subsequent detection of cell activation markers CD137 and CD25. Serum IgG antibody to S and N, and IgA antibody to S were determined by ELISA.ResultsThree patients developed SARS-CoV-2 infection early (<3 months) and four patients late (>3 years) after Tx. One HR was asymptomatic, one LR presented only gastrointestinal symptoms, and five patients developed dyspnea with radiologic signs of interstitial pneumonia (in one HR ICU admittance was necessary. All patients recovered from SARS-CoV-2 infection, with viral clearance from NPS within 3 weeks. However, two HR (one early and one late HR) died at 6 and 4 months after infection because of multi-organ failure and sudden death. Both deaths were considered as unrelated to SARS-CoV2 infection. Patients who had no lung involvement did not develop specific antibody response, while all the other five patients developed IgG and IgA antibodies to S, and IgG antibody to N, within 2 months after infection. All the symptomatic patients developed a detectable CD4+ T-cell response to two or more antigens. Four patients were subsequently examined >3 months after infection, showing the persistence of IgG and IgA antibodies to S and a decline of IgG antibody to N, while CD4+ T-cell response to N was maintained. Timing of Tx did not affect the occurrence of virus specific immunity.ConclusionAlthough this series is small, the data indicate that immunosuppression does not prevent the development of a specific humoral and cellular anti-SARS-CoV-2 response, more likely in patients who have experienced clinically relevant pneumonia. These preliminary data encourage the maintenance of regular follow-up to monitor the persistence of immune response and the potential occurrence of SARS-CoV-2-related sequelae in heart and lung recipients.

Daratumumab as Salvage Therapy in Pediatric Thoracic Organ Transplantation: An Addition to the Antibody Mediated Rejection Toolbox?

Purpose Antibody mediated rejection (AMR) is difficult to treat and often results in death or graft loss. Therapies targeted at antibodies or B cells are inadequate for decreasing donor specific antibodies (DSA), particularly to MHC class II. Bortezomib, a small molecule proteasome inhibitor targets plasma cells, but has many side effects and unsatisfactory results. Alternatively, we used Daratumumab (DAR), an anti-CD38 monoclonal antibody, in two pediatric transplant (Tx) recipients. Methods Chart review. Results An 18-year-old female with cystic fibrosis had a lung-liver Tx at 12-years-old. Twenty months post-Tx she developed severe AMR and Acute cellular rejection (ACR) treated with ATG, rituximab, TPE, photopheresis, and steroids. She ultimately required redo lung Tx. She did well for three years, but then developed AMR. She again received TPE, ATG, photopheresis, and rituximab. She was not considered a candidate for third lung Tx so all attempts were made to salvage her graft. She had no B cells, but continued to make DSA, so a plasma cell targeted therapy was desired. She received three doses of DAR 16 mg/kg on days 0, 7 and 21 with no infusion reactions. She developed neutropenia 2 months later which resolved with 3 weeks of GCSF. Both total PRA and DSA significantly decreased after DAR and have not returned 7 months later. PRA class I dropped from peak of 96% to 0, class II from peak 34% to 3%. She is maintained on subcutaneous IgG replacement for secondary hypogammaglobulinemia. Her graft function is poor, but has stabilized since DAR. She had one episode of presumed line associated sepsis and MSSA pneumonia without sequalae. A 3-year-old girl two years post heart Tx developed refractory AMR (by C4d and elevated DSA) despite ATG, TPE, IVIG, eculizumab, and ofatumumab. She then received two doses of DAR, 16 mg/kg each on days 0 and 14. She tolerated the infusions without any initial side effects. Not enough time has elapsed to follow up antibody levels or graft function. Conclusion Treatment for AMR remains challenging, especially when due to class II HLA antibodies. We safely administered DAR to two pediatric patients without infusion reactions or significant infectious complications to date. One patient had a decline in antibodies, while the other is too soon to determine. While more studies are needed, DAR may be a promising addition to the AMR toolbox.

Tacrolimus Level Variability in Setting of Gastric Sleeve

<h3>Introduction</h3> While weight loss surgery can allow obese transplant (tx) candidates to meet body mass index (BMI) criteria for listing, it may impact immunosuppression (IS) exposure. IS pharmacokinetics (PK) are affected by alterations in the gastrointestinal tract and have been described in tx recipients receiving roux-en-y gastric bypass, gastrectomy and laproscopic gastric sleeves (LGS). We report a unique case with a patient with notable variability in IS exposure after LSG. <h3>Case Report</h3> Our patient is a 42 year old Black male deferred on the waitlist due to BMI >40 kg/m2. He received a LSG resulting in 19 kg weight loss and underwent heart tx 8 months later. IS immediately post-tx consisted of triple drug IS with immediate release tacrolimus (goal 10-13 ng/mL), mycophenolate mofetil and prednisone with posaconazole anti-fungal prophylaxis. Throughout the first 4 months levels were stable and monitored at least weekly. Then the patient began to have variable levels despite adherence and no dose changes leading to 2R rejection at 5 months. Tacrolimus levels continued to fluctuate with weekly labs despite adding CYP3A4 inhibitors (diltiazem, itraconazole) to help achieve therapeutic levels. Conversion to extended release (XR) tacrolimus [Envarsus] was done to reduce headaches, tremors and attempt for stable levels. Levels remained erratic on the XR formulation despite consistency in timing of administration and food consumption. A peak and trough of XR tacrolimus was measured in conjunction with a mycophenolic acid (MPA) mini area under the curve (AUC). The MPA mini AUC was unchanged from directly post tx (56.6 vs 43.2 mcg/mL). Tacrolimus PK was abnormal with identical trough and 3 hour peak levels (10.7 ng/mL). <h3>Summary</h3> To achieve goal tacrolimus levels (8-12 ng/mL) our adherent patient required doses from 8 to 38 mg/day (0.07 - 0.33 mg/kg/day). This variation contributed to rejection and neurotoxicity and may have been related to alterations in tacrolimus exposure after LSG. Patients with LSG warrant increased IS monitoring post tx.