Need For Immunosuppressive Therapy Research Articles

E025 From risk to reward: a case of systemic antineutrophilic cytoplasmic antibody associated vasculitis

Abstract Background/Aims The background and aims of this case involve a 70-year-old female patient with a history of complex medical conditions, including bronchiectasis and dementia, who initially presented with respiratory symptoms and fever. The primary aim was to understand the underlying cause of her deteriorating condition, which did not respond to initial antibiotic treatment for suspected pneumonia. Subsequent diagnostic efforts, including extensive vasculitis workup, were undertaken to identify the source of her symptoms, which led to the discovery of positive PR3 results and elevated inflammatory markers. The key goal was to determine the most effective treatment strategy, considering the patient’s unique medical history, balancing the need for immunosuppressive therapy against the potential risks of exacerbating underlying infections. The case ultimately aimed to demonstrate the successful management of the patient’s complex clinical presentation through a multidisciplinary approach, including immunosuppressive therapy and supportive care, resulting in significant improvements in her neurological and functional status. Methods We conducted a comprehensive assessment of a 70-year-old patient with ANCA-associated vasculitis (AAV) involving the central nervous system (CNS) and cutaneous manifestations. Lab tests targeted PR3-positive ANCA, and imaging assessed disease extent. A multidisciplinary team designed a tailored treatment plan with cyclophosphamide, closely monitoring progress. Ethical considerations were adhered to, and a literature review provided context. Data analysis evaluated treatment efficacy, leading to a discussion of lessons learned in managing complex AAV cases. Results We documented the remarkable trajectory of a 70-year-old patient with ANCA-associated vasculitis (AAV) presenting with central nervous system (CNS) involvement and cutaneous manifestations. With a meticulous and tailored treatment plan involving the judicious use of cyclophosphamide, we witnessed a profound recovery marked by significant improvements in both motor and cognitive function. This case underscores the importance of balancing potent immunosuppression with the imperative to curb disease progression and mitigate treatment-associated repercussions in complex AAV presentations. The patient’s restoration to baseline functioning serves as a compelling testament to the potential of precision medicine in managing intricate clinical scenarios of AAV. Our findings emphasize the need for continued awareness and consideration of individualized treatment approaches in similar cases, offering hope and insights for improved outcomes in challenging AAV presentations. Conclusion This case offers valuable lessons on the complexities and challenges involved in diagnosing and managing a multi-faceted condition like AAV. It emphasizes the urgent need for a timely and accurate diagnosis, especially when presented with atypical cases involving the central nervous system and cutaneous manifestations. Moreover, the case enriches our understanding of AAV and contributes insights into its nuanced management. It calls for a sophisticated, patient-centered approach, informed by cutting-edge research, to optimize patient outcomes in this challenging clinical scenario. Disclosure A.J. AlZeera: None. D. Gurdeep: None.

Hemophagocytic Lymphohistiocytosis (HLH) in Patients with Tick-Borne Illness: A Scoping Review of 98 Cases.

Hemophagocytic lymphohistiocytosis (HLH) secondary to tick-borne infections is a rare but potentially life-threatening syndrome. We performed a scoping review according to PRISMA guidelines to systematically analyze the existing literature on the topic. A total of 98 patients were included, with a mean age of 43.7 years, of which 64% were men. Most cases, 31%, were reported from the USA. Immunosuppression was present in 21.4%, with the most common cause being previous solid organ transplantation. Constitutional symptoms were the most common, observed in 83.7% of the patients, while fever was reported in 70.4% of cases. Sepsis was present in 27.6%. The most common laboratory abnormalities in this cohort were thrombocytopenia in 81.6% of patients, while anemia, leukopenia, and leukocytosis were observed in 75.5%, 55.1%, and 10.2%, respectively. Liver enzyme elevation was noted in 63.3% of cases. The H-score was analyzed in 64 patients, with the mean value being 209, and bone marrow analysis was performed in 61.2% of patients. Ehrlichia spp. was the main isolated agent associated with HLH in 45.9%, followed by Rickettsia spp. in 14.3% and Anaplasma phagocytophilum in 12.2%. Notably, no patient with Powassan virus infection or Lyme borreliosis developed HLH. The most common complications were acute kidney injury (AKI) in 35.7% of patients, shock with multiple organ dysfunction in 22.5%, encephalopathy/seizure in 20.4%, respiratory failure in 16.3%, and cardiac complications in 7.1% of patients. Treatment included antibiotic therapy alone in 43.9%, while 5.1% of patients were treated with immunosuppressants alone. Treatment with both antibiotics and immunosuppressants was used in 51% of patients. Appropriate empiric antibiotics were used in 62.2%. In 43.9% of cases of HLH due to tick-borne disease, patients received only antimicrobial therapy, and 88.4% of those recovered completely without the need for immunosuppressive therapy. The mortality rate in our review was 16.3%, and patients who received inappropriate or delayed empiric therapy had a worse outcome. Hence, we suggest empiric antibiotic treatment in patients who are suspected of having HLH due to tick-borne disease or in whom diagnostic uncertainty persists due to diagnostic delay in order to minimize mortality.

Rejection Requiring Treatment within the First Year following Heart Transplantation: The UNOS Insight.

(1) Background: Heart failure is an extremely impactful health issue from both a social and quality-of-life point of view and the rate of patients with this condition is destined to rise in the next few years. Transplantation remains the mainstay of treatment for end-stage heart failure, but a shortage of organs represents a significant problem that prolongs time spent on the waiting list. In view of this, the selection of donor and recipient must be extremely meticulous, considering all factors that could predispose to organ failure. One of the main considerations regarding heart transplants is the risk of graft rejection and the need for immunosuppression therapy to mitigate that risk. In this study, we aimed to assess the characteristics of patients who need immunosuppression treatment for rejection within one year of heart transplantation and its impact on mid-term and long-term mortality. (2) Methods: The United Network for Organ Sharing (UNOS) Registry was queried to identify patients who solely underwent a heart transplant in the US between 2000 and 2021. Patients were divided into two groups according to the need for anti-rejection treatment within one year of heart transplantation. Patients' characteristics in the two groups were assessed, and 1 year and 10 year mortality rates were compared. (3) Results: A total of 43,763 patients underwent isolated heart transplantation in the study period, and 9946 (22.7%) needed anti-rejection treatment in the first year. Patients who required treatment for rejection within one year after transplant were more frequently younger (49 ± 14 vs. 52 ± 14 years, p < 0.001), women (31% vs. 23%, p < 0.001), and had a higher CPRA value (14 ± 26 vs. 11 ± 23, p < 0.001). Also, the rate of prior cardiac surgery was more than double in this group (27% vs. 12%, p < 0.001), while prior LVAD (12% vs. 11%, p < 0.001) and IABP (10% vs. 9%, p < 0.01) were more frequent in patients who did not receive anti-rejection treatment in the first year. Finally, pre-transplantation creatinine was significantly higher in patients who did not need treatment for rejection in the first year (1.4 vs. 1.3, p < 0.01). Most patients who did not require anti-rejection treatment underwent heart transplantation during the new allocation era, while less than half of the patients who required treatment underwent transplantation after the new allocation policy implementation (65% vs. 49%, p < 0.001). Patients who needed rejection treatment in the first year had a higher risk of unadjusted 1 year (HR: 2.25; 95% CI: 1.88-2.70; p < 0.001), 5 year (HR: 1.69; 95% CI: 1.60-1.79; p < 0.001), and 10 year (HR: 1.47; 95% CI: 1.41-1.54, p < 0.001) mortality, and this was confirmed at the adjusted analysis at all three time-points. (4) Conclusions: Medical treatment of acute rejection was associated with significantly increased 1 year mortality compared to patients who did not require anti-rejection therapy. The higher risk of mortality was confirmed at a 10 year follow-up. Further studies and newer follow-up data are required to investigate the role of anti-rejection therapy in the heart transplant population.

Predictors and outcomes of rejection requiring treatment within the first year following heart transplantation

Abstract Background Heart transplant remains the mainstay of treatment for end stage heart failure not controllable with maximum pharmacotherapy or surgical interventions. One of the main considerations regarding heart transplant is the risk for graft rejection and the need for immunosuppression therapy to mitigate that risk. Purpose To assess the impact of the need for immunosuppression for rejection treatment within one year for heart transplantation on mortality. Secondary objectives include risk factors for the need for anti-rejection treatment. Methods The United Network for Organ Sharing (UNOS) Registry was queried to identify patients who solely underwent heart transplant in the US between 2000 and 2021. Patients were divided into two groups according to the need for antirejection treatment within one year from heart transplantation. Results Patient demographics are summarized in Figure 1. Patients who required treatment for rejection within one year after transplant were younger (49±14 vs 52±14 years, p&amp;lt;0.001) and had higher CPRA value (14±26 vs 11±23, p&amp;lt;0.001) than patients who did not require treatment. Moreover, the majority of the patients who did not require antirejection treatment underwent heart transplantation during the new allocation era, while less than half of the patients who required treatment underwent transplant after the new allocation policy implementation (65% vs 49%, p&amp;lt;0.001). The latter group had higher risk for 10-year mortality (HR: 1.34; 95% CI: 1.29, 1.39, p&amp;lt;0.001; Figure 2), although no difference was noted at the 1-year timepoint. Conclusions Although medical treatment of acute rejection was associated with similar 1-year mortality with patients who did not require antirejection therapy, 10-year mortality was higher in this patient population. Further studies and newer follow up data are required to investigate the role of antirejection therapy in the heart transplant population.Figure 1Figure 2

Immune-Mediated Non-Infectious Periaortitis After Aortic Graft Replacement Surgery: A Case Report Highlighting the Need for Immunosuppressive Therapy.

BACKGROUND A non-infectious inflammatory reaction against replaced aortic graft for aortic dissection often manifests as fever, malaise, and peri-graft effusion. It usually lasts less than 1 month and subsides spontaneously without immunosuppressive treatment. CASE REPORT A 49-year-old man underwent ascending aorta and total arch replacement for acute thoracic aortic dissection. He had fever, malaise, nausea, and elevated serum C-reactive protein for 1 month postoperatively. Pathological examination of the aorta revealed no aortitis, and repeated blood cultures were negative. We also noted periaortic graft fluid collection, and a small amount of pleural and pericardial effusions. We suspected post-pericardiotomy syndrome. Colchicine and prednisolone were administered, with an excellent clinical response. Three weeks after discontinuation of a 7-week prednisolone treatment, the same symptoms recurred and gradually worsened. Prednisolone was restarted 6 months after the first surgery, with good clinical response. Thereafter, he developed left-sided weakness and dysarthria, being diagnosed as ischemic stroke. Contrast-enhanced computed tomography revealed fluid collection with contrast leak around the aortic grafts, suggesting peel dehiscence, and thrombus formation in anastomotic pseudoaneurysm. He underwent surgical repair. He was diagnosed with non-infectious periaortitis, likely due to an immune reaction to the grafts, based on an excellent clinical response to immunosuppressive therapy. CONCLUSIONS We report a case of non-infectious periaortitis around a thoracic aortic graft, probably with an immune-mediated mechanism, requiring immunosuppressive treatment. When fever persists after aortic graft replacement surgery, non-infectious periaortitis should be considered and immunosuppressive treatment should be considered to prevent critical complications of anastomotic pseudoaneurysm and graft dehiscence.

The Effect of Genetic HLA Matching on Liver Transplantation Outcome: A Systematic Review and Meta-Analysis.

We aim to investigate the effects of genetically based HLA matching on patient and graft survival, and acute and chronic rejection after liver transplantation. Liver transplantation is a common treatment for patients with end-stage liver disease. In contrast to most other solid organ transplantations, there is no conclusive evidence supporting human leukocyte antigen (HLA) matching for liver transplantations. With emerging alternatives such as transplantation of bankable (stem) cells, HLA matching becomes feasible, which may decrease the need for immunosuppressive therapy and improve transplantation outcomes. We systematically searched the PubMed, Embase, and Cochrane databases and performed a meta-analysis investigating the effect of genetic HLA matching on liver transplantation outcomes (acute/chronic rejection, graft failure, and mortality). We included 14 studies with 2682 patients. HLA-C mismatching significantly increased the risk of acute rejection (full mismatching: risk ratio = 1.90, 95% confidence interval = 1.08 to 3.33, P = 0.03; partial mismatching: risk ratio = 1.33, 95% confidence interval = 1.07 to 1.66, P = 0.01). We did not discern any significant effect of HLA mismatching per locus on acute rejection for HLA-A, -B, -DR, and -DQ, nor on chronic rejection, graft failure, or mortality for HLA-DR, and -DQ. We found evidence that genetic HLA-C matching reduces the risk of acute rejection after liver transplantation while matching for other loci does not reduce the risk of acute rejection, chronic rejection, graft failure, or mortality.

Comparative Evaluation of the Clinical Severity of COVID-19 Produced by the Omicron Variant Versus the Wuhan Strain

Abstract Purpose: Starting from the observations of the in vitro studies that describe a lower pathogenicity of the Omicron variant, we proposed to comparatively analyze two groups of patients admitted to our clinic, one at the beginning of the COVID-19 pandemic, and the other one at the beginning of the Omicron wave of the pandemic, and to compare the severity of disease episodes. Patients and methods: 2 groups of patients with COVID-19, one group of 480 patients hospitalized in our clinic in March-August 2020 and one group of 320 patients admitted in January-June 2022, were selected. Demographic data, paraclinical profile at admission, comorbidities, the type and duration of treatment and the evolution of the patients in the two groups, were analyzed comparatively. Results: Our study showed statistically significant differences between group A compared to the group B, which support the aggressiveness of the Wuhan strain and the severity of its disease forms, such as: the predominance of pulmonary opacity on radiographies, a higher need for immunosuppressive therapies, a lower oxygen saturation, and a higher average values of inflammatory markers at admission, in the first group. Also, some factors with predictive potential for a severe clinical form, with predominance in group 2 (older age, a higher score of cumulative comorbidities, a higher value of D-dimers and aspartateaminotransferase, a lower value of concentration of prothrombin, and the higher average CURB-65 score, at admission) were observed. Conclusion: Our study identified predictive parameters of severity (D-dimers, aspartate-aminotransferase, prothrombin concentration, CURB-65 Score), statistically significant modified in the Omicron wave group compared to the Wuhan wave group, which draw attention to the possibility of severe and unfavorable evolution of the infection with Omicron in elderly population with multiple comorbidities.

Single-cell RNA sequencing reveals peripheral blood mononuclear immune cell landscape associated with operational tolerance in a kidney transplant recipient

Operational tolerance (OT) after kidney transplantation is defined as stable graft acceptance without the need for immunosuppression therapy. However, it is not clear which cellular and molecular pathways are driving tolerance in these patients. In this first-of-its-kind pilot study, we assessed the immune landscape associated with OT using single-cell analyses. Peripheral mononuclear cells from a kidney transplant recipient with OT (Tol), 2 healthy individuals (HC), and a kidney transplant recipient with normal kidney function on standard-of-care immunosuppression (SOC) were evaluated. The immune landscape of the Tol was drastically different from that of SOC and emerged closer to the profile of HC. TCL1A+ naive B cells and LSGAL1+ regulatory T cells (Tregs) were in higher proportions in Tol. We were unable to identify the Treg subcluster in SOC. The ligand-receptor analysis in HC and Tol identified interactions between B cells, and Tregs that enhance the proliferation and suppressive function of Tregs. SOC reported the highest proportion of activated B cells with more cells in the G2M phase. Our single-cell RNA sequencing study identified the mediators of tolerance; however, it emphasizes the requirement of similar investigations on a larger cohort to reaffirm the role of immune cells in tolerance.

Abstract 797: COVID-19 vaccines in patients with solid tumor cancers receiving immune checkpoint inhibitors

Abstract Background: The interaction between checkpoint inhibitors (CPI) and Sars-COV-2 vaccines has been understudied. One potential complication in pts receiving CPI is immune-mediated adverse events (irAEs) resulting from overactivation of the immune system. It is unknown whether concurrent CPI and Sars-COV-2 vaccine administration increases the risk of irAEs. This retrospective study examined the incidence of severe irAEs in cancer patients receiving CPI therapy at the time of vaccination against Sars CoV-2. Methods: Following IRB approval, pts with solid tumors who received any approved CPI since FDA authorization of the COVID-19 vaccine in December 2020 were identified via institutional electronic health record. Pts who received one or more doses of an authorized vaccine within 60 days of CPI treatment were included. The primary endpoint was to evaluate the incidence of severe irAE (one or more of the following: grade 3 AE or above, multi-system involvement, need for hospitalization). Secondary endpoints included time between CPI and vaccination, need for immunosuppressive therapy, and rate of discontinuation of CPI due to irAE. Data was analyzed using descriptive statistics. Results: 290 pts with bladder, head/neck, liver, skin (melanoma, SCC), renal, and gynecologic cancer were included in analysis. The median age was 67 years (IQR: 59.0-74.0) and 66% pts were male. At the time of vaccination, 201 pts (69.3%) received CPI monotherapy, 53 pts (18.3%) received combination (combo) CPI therapy, and 36 pts (12.4%) received other therapies (chemo, TKIs, etc.) with CPI. The vaccine manufacturer was Pfizer Bio-N-Tech in 162 pts (55.9%), Moderna in 122 pts (42.1%), and Johnson and Johnson in 6 pts (2.1%). The number of vaccinations received was &amp;gt;/= 3 in 214 pts, 2 in 64 pts, and 1 in 11 pts. 30 pts (11.5%) experienced severe irAEs following vaccination. The rate of severe irAEs was 10.3% (30/290) in the total population [6% (12/201) with CPI monotherapy, 19% (10/53) with combo CPI, and 22% (8/36) in the combo CPI-other group]. Severe irAEs occurred after the first vaccine dose in 5 pts (16.7%), second dose in 16 pts (53.3%), and third dose in 9 pts (30%) pts. The median time between CPI treatment and vaccination in pts who experienced irAE was15.5 days (IQR: 10.2-23.0). Hospitalization was required for 19 patients (63.3%). 24 pts (80.0%) required immunosuppressive therapy with a median therapy duration of 98.5 days (IQR 40.2-173.0). 16 pts (53.5%) discontinued CPI therapy following severe irAEs Conclusions: In this retrospective study, we observed a 10.3% rate of severe irAE in cancer pts receiving CPI concurrently with COVID-19 vaccines. Further investigation in pts with additional cancer types is warranted to help determine best practice guidelines for COVID-19 vaccination in cancer patients receiving CPI Support: NCI University of Colorado Cancer Center Support Grant 5P30CA046934-30, Health Compass Data Warehouse project Citation Format: Danielle Gilbert, Junxiao Hu, Elaine T. Lam. COVID-19 vaccines in patients with solid tumor cancers receiving immune checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 797.

COVID-19 vaccines in patients with urothelial cancers receiving immune checkpoint inhibitors.

491 Background: COVID-19 vaccination recommendations for cancer patients (pts) are similar to the general population. The interaction between checkpoint inhibitors (CPI) and Sars-COV-2 vaccines has been understudied. One potential complication in pts receiving CPI is the occurrence of immune-mediated adverse events (irAEs) resulting from overactivation of the immune system. This retrospective study examined the incidence of severe irAEs in pts with bladder urothelial cancer (UC) treated with CPI therapy who received concurrent vaccinations against Sars-CoV-2. Methods: Following IRB approval, UC pts who received any approved CPI treatment since FDA authorization of the first COVID-19 vaccine in December 2020 were identified via institutional electronic health record. Pts who received 1 or more doses of an authorized vaccine within 60 days of CPI treatment were included. The primary endpoint was to evaluate the incidence of severe irAE (defined as one or more of the following: grade 3 AE or above, multi-system involvement, need for hospitalization). Secondary endpoints included time between CPI and vaccination, need for immunosuppressive therapy, and rate of discontinuation. Data was analyzed using descriptive statistics. Results: Forty pts were included in our analysis with a median age of 72.5 years (IQR: 66.0-79.2); 82% pts were male. At the time of vaccination, 37 pts (92.5%) received CPI monotherapy, 2 pts (5.0%) received combination (combo) CPI therapy, and 1 pt (2.5%) received combo platinum-based chemotherapy and CPI. The vaccine manufacturer was Pfizer Bio-N-Tech in 22 pts (55.0%), Moderna in 17 pts (42.5%), and Johnson and Johnson in 1 pt (2.5%). Number of vaccinations received was &gt;/= 3 in 27 pts, 2 in 11 pts, and 1 in 2 pts. Six pts (15.0%) experienced severe irAEs following vaccination, including nephritis, colitis, pneumonitis, DKA, and infusion-related reaction. Rates of severe irAEs were 16.2% (6/37) with CPI monotherapy, no severe irAEs occurred in the combo CPI and combo CPI-chemo groups. Severe irAEs occurred after the first vaccine dose in 1 pt (16.7%), second dose in 3 pts (50.0%), and third dose in 2 pts (33.3%) pts. The median time between CPI treatment and vaccination in this group was 22.0 days (IQR: 15.8-36.5. Hospitalization was required for all 6 patients (100%). Three pts (50.0%) required immunosuppressive therapy with a median therapy duration of 64.0 days (IQR 47.0-83.5). Five pts (83.3%) discontinued CPI therapy following severe irAEs. Conclusions: In this retrospective study, we observed a 15% rate severe irAE in UC pts receiving CPI concurrently with COVID-19 vaccines. Further investigation in pts with additional cancer types is warranted to help determine best practice guidelines for COVID-19 vaccination in cancer patients receiving CPI. NCI University of Colorado Cancer Center Support Grant 5P30CA046934-30, Health Data Compass Data Warehouse project (healthdatacompass.org).

P205 Impact of histologic disease activity on long-term outcomes in patients with ileal pouch-anal anastomosis for ulcerative colitis

Abstract Background Total proctocolectomy with ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC) can incur in several complications like pouchitis leading to the need of immunosuppressive therapy, hospitalization and pouch failure. Unlike non-operated UC patients, therapeutic goals are an unmet need in UC-IPAA patients and the impact of the histologic activity on the development of complications is unknown. The aim of the study was to assess the association between histology and the risk of long-term negative outcomes in UC subjects with IPAA. Methods This is a single-center, retrospective study which included UC adult patients with IPAA undergoing at least one pouchscopy with biopsies in the pouch body after ileostomy closure. Pouch biopsies were blindly reviewed by a gastrointestinal pathologist with expertise in IBD. Histologic disease remission was defined as a Pouchitis Disease Activity Index (PDAI) histology subscore £ 1. Negative outcomes were: IPAA related complications (acute or chronic pouchitis, hospitalization, pouch failure) and escalation of medical therapy (start of immunosuppressive or biologics). Both descriptive and inferential statistical analyses carried out Results A total of 66 patients were included (male n=37; 56,1%) of whom 40,9% (n=27) had histological activity at the baseline pouchscopy. The characteristics of the study population are represented in table 1. The median time of follow up was 38,5 months (range 12-151). During the study period, 27 patients (40,9%) developed acute pouchitis and 10 patients (15,2%) chronic pouchitis. Thirty-nine subjects (59,1%) required antibiotic therapy while 8 subjects required systemic steroids (12,1%). Furthermore, 15 patients (22,7%) started immunomodulatory therapy with either azathioprine or biologic agents. Six patients (9,1%) needed pouch-related hospitalization and 1 patients (1,5%) experienced pouch failure. Chronic pouchitis and the need of immunosuppressive/biology therapy was observed more frequently in patients with pouch histologic activity (29,6% vs. 5,1%, and 40,7% vs. 10,3%, respectively) (P&amp;lt;0.05). After adjusting for risk factors for pouchitis, the presence of histologic activity remained an independent risk factor for developing acute pouchitis (OR 4.10, 95% CI 1.39-12.04; P= 0.010), chronic pouchitis (OR 8.51, 95% CI 1.51-47.80, P=0.015) and the need for immunosuppressive or biologic therapy (OR 6.98, 95% CI 1.69-28.80; P=0.007). Conclusion Histologic activity was associated with an increased risk of developing both acute and chronic pouchitis and with the need for immunosuppressive/biologic therapy. Future research will clarify whether histologic remission might be considered as a therapeutic target for UC-IPAA patients developing pouchitis.

COVID-19 Vaccines for Adults and Children with Autoimmune Gut or Liver Disease.

The SARS-CoV-2 pandemic raised many challenges for all patients with chronic conditions and those with autoimmune diseases, both adults and children. Special attention is paid to their immunological status, concomitant diseases, and the need for immunosuppressive therapy. All of these factors may impact their COVID-19 course and outcome. COVID-19 vaccination is accepted as one of the most successful strategies for pandemic control. However, individuals with immune-mediated chronic diseases, including autoimmune liver and gut diseases, have been excluded from the vaccine clinical trials. Therefore, we rely on real-world data from vaccination after vaccine approval for these patients to fill the evidence gap for the long-term safety and efficacy of COVID-19 vaccines in patients with autoimmune gut and liver diseases. Current recommendations from inflammatory bowel disease (IBD) societies suggest COVID-19 vaccination in children older than 5 years old, adults and even pregnant females with IBD. The same recommendations are applied to patients with autoimmune liver diseases. Nevertheless, autoimmune disease patients still experience high levels of COVID-19 vaccine hesitancy, and more studies have to be conducted to clarify this issue.

Upregulated circulating mir-424 and its' diagnostic value for gram-negative bacteremia after thoracic transplantation.

AimsEarly post-transplant complications such as acute graft rejection and infections are associated with high morbidity and mortality of heart and lung transplant recipients who are in vital need of immunosuppressive therapy. MiR-424 is a member of the miR-16 family, which plays an important physiological role in the development of cardiovascular and respiratory pathology, is involved in the regulation of monocyte and macrophage differentiation, and has an immunosuppressive potential. The aim of the study was to determine the diagnostic value of circulating miR-424 as a potential biomarker of post-transplant complications in heart and lung transplant recipients.MethodsThe study enrolled 83 heart transplant recipients, aged 18 to 70 (48 ± 13) years; 26 lung transplant recipients, aged 10 to 74 (36 ± 16) years. The miR-424 plasma expression was detected by real-time PCR (Qiagen, USA). Significance of miR-424 level was assessed through the ΔCt method. Acute graft rejection was verified by the results of endomyocardial or transbronchial biopsy. Post-transplant infectious complications were verified through microbiological identification of bacteremia from blood cultures.ResultsOur study shows miR-424 upregulation in plasma of patients with chronic heart or respiratory failure in comparison with healthy individuals (p = 0.003 and p = 0.04 resp.). There was a direct correlation of miR-424 expression with red blood cells and hemoglobin levels in patients before heart transplantation (p = 0.01 and p = 0.03 resp.). After transplantation the expression of plasma miR-424 correlated with the level of C-reactive protein (CRP) both in heart (r = 0.75; p = 0.02) and lung (r = 0.50; p = 0.04) transplant recipients. The expression of plasma miR-424 correlated with tacrolimus blood concentration after heart transplantation (r = 0.38; p = 0.04). The miR-424 level didn't differ in heart or lung transplant recipients with and without acute graft rejection (p = 0.47 and p = 0.78 resp.), but was significantly higher in heart and lung transplant recipients with gram-negative bacteremia (p = 0.002). When the miR-424 level is above a threshold value (−5.72 fold change), the relative risk of bacteremia is RR = 3.84 [95% CI 1.94–7.61]; Se = 60.0%; Sp = 89.2%. CRP concentration above 7 mg/L in duplex test with miR-424 improves the diagnostic characteristics of miR-424 for post-transplant gram-negative bacteremia in heart and lung transplant recipients up to RR = 9.17 [95% CI 1.37–61.46]; Se = 83.3% and Sp = 90.1%.ConclusionMiR-424 plasma expression was upregulated in patients with chronic heart and respiratory failure and in heart and lung transplant recipients in the early post-transplant period. The duplex test, including miR-424 and CRP, has a diagnostic value for detecting the high risk of post-transplant gram-negative bacteremia in heart and lung transplant recipients.

Mathematical and Computational Modeling of Poroelastic Cell Scaffolds Used in the Design of an Implantable Bioartificial Pancreas

We present a multi-scale mathematical model and a novel numerical solver to study blood plasma flow and oxygen concentration in a prototype model of an implantable Bioartificial Pancreas (iBAP) that operates under arteriovenous pressure differential without the need for immunosuppressive therapy. The iBAP design consists of a poroelastic cell scaffold containing the healthy transplanted cells, encapsulated between two semi-permeable nano-pore size membranes to prevent the patient’s own immune cells from attacking the transplant. The device is connected to the patient’s vascular system via an anastomosis graft bringing oxygen and nutrients to the transplanted cells of which oxygen is the limiting factor for long-term viability. Mathematically, we propose a (nolinear) fluid–poroelastic structure interaction model to describe the flow of blood plasma through the scaffold containing the cells, and a set of (nonlinear) advection–reaction–diffusion equations defined on moving domains to study oxygen supply to the cells. These macro-scale models are solved using finite element method based solvers. One of the novelties of this work is the design of a novel second-order accurate fluid–poroelastic structure interaction solver, for which we prove that it is unconditionally stable. At the micro/nano-scale, Smoothed Particle Hydrodynamics (SPH) simulations are used to capture the micro/nano-structure (architecture) of cell scaffolds and obtain macro-scale parameters, such as hydraulic conductivity/permeability, from the micro-scale scaffold-specific architecture. To avoid expensive micro-scale simulations based on SPH simulations for every new scaffold architecture, we use Encoder–Decoder Convolution Neural Networks. Based on our numerical simulations, we propose improvements in the current prototype design. For example, we show that highly elastic scaffolds have a higher capacity for oxygen transfer, which is an important finding considering that scaffold elasticity can be controlled during their fabrication, and that elastic scaffolds improve cell viability. The mathematical and computational approaches developed in this work provide a benchmark tool for computational analysis of not only iBAP, but also, more generally, of cell encapsulation strategies used in the design of devices for cell therapy and bio-artificial organs.

An open-label, multicenter, phase 1 study of RP3 as a single agent and in combination with nivolumab in patients (pts) with solid tumors.

TPS2705 Background: RP3 is a genetically modified herpes simplex virus 1 (HSV-1) that contains insertions for the gibbon ape leukemia virus surface glycoprotein (GALV-GP) with the R- sequence deleted (R-), an anti–cytotoxic T lymphocyte antigen 4 (CTLA-4) antibody-like molecule, CD40 ligand, and 4-1BB ligand. Together, these insertions are expected to increase oncolytic potency, cell-to-cell spread, immunogenic cell death, and systemic immune activation. RP3 has demonstrated antitumor activity in preclinical models using viruses similar to RP3 expressing murine versions of anti-CTLA-4, CD40L, and 4-1BBL both alone and in combination with PD1-1 blockade. Methods: This is an open-label, multicenter, Phase 1 study evaluating RP3 as monotherapy or in combination with nivolumab (nivo) in patients (pts) with solid tumors (NCT04735978). Part 1 evaluated escalating doses of RP3. Pts in Part 1 received IT injections of up to 10 mL RP3 into superficial, nodal, or visceral lesions Q2W x 5 across two dose levels (DL1: 105 plaque-forming units (PFU)/mL once, then 106 PFU/mL x 4; DL2: 106 PFU/mL once, then 107 PFU/mL x4). The RP2D is 106 PFU/mL once, followed by 107 PFU/mL IT Q2W. In Part 2, pts are being enrolled into expansion cohorts of 45 patients with GI (including HCC), lung, breast, and squamous cell carcinoma of the head and neck treated with RP1 combined with nivo. Additional cohorts will enroll patients treated with RP3 followed by nivo, RP3 monotherapy to further explore biomarkers in injected and uninjected tumors, and with the potential to also open a cohort in melanoma. Pts in both Part 1 and Part 2 may receive up to 8 additional doses of RP3 if protocol-specified criteria are met. Key inclusion criteria: confirmed advanced or metastatic non-neurological solid tumors, at least one measurable tumor ≥ 1 cm and injectable tumors ≥ 1 cm in aggregate, ECOG ≤1, and adequate hematologic, hepatic, and renal function. In Cohorts 1, 2, and 4, approximately 50% of the pts with lung, breast, and GI cancer must have liver lesions intended for injection. Exclusion criteria include prior oncolytic virus treatment, need for immunosuppressive therapy, an autoimmune disease requiring systemic therapy, active significant herpetic infections or prior complications of HSV-1 infection, active or chronic HBV or HCV infection, known HIV infection, or prior active malignancy within 3 years. Clinical trial information: NCT04735978.

COVID-19 vaccine and incidence of severe immune-mediated adverse events in patients with renal cell carcinoma (RCC) on checkpoint inhibitor immunotherapy (CPI).

e16509 Background: Immune-mediated adverse events (irAEs) can be seen in patients (pts) receiving checkpoint inhibitors (CPI). It is unknown whether the immune response to vaccines against Sars-CoV-2 interacts with the immune activation from CPI therapy. In this retrospective study, we examined the incidence of severe irAEs in pts with renal cell carcinoma (RCC) who received vaccines against Sars-CoV-2 during the course of their CPI therapy. Methods: Following IRB approval, RCC pts who received any CPI treatment since FDA authorization of the first COVID-19 vaccine in March 2021 were identified via institutional electronic health record. Pts who received one or more doses of an authorized vaccine within 60 days of CPI treatment were included. The primary endpoint was to evaluate the incidence of severe irAE (defined as one or more of the following: grade 3 AE or above, multi-system involvement, need for hospitalization). Secondary endpoints included time between CPI and vaccination, need for immunosuppressive therapy, and rate of discontinuation. Data was analyzed using descriptive statistics. Results: Sixty-five pts were included in our analysis with a median age of 66 years (IQR: 58.0, 73.0); 80% pts were male. At the time of vaccination, 26 pts (40.0%) received CPI monotherapy, 12 pts (18.4%) received combination (combo) CPI therapy, and 27 pts (41.6%) received combo therapy with a tyrosine kinase inhibitor (TKI) and CPI. The type of vaccine received was Pfizer Bio-N-Tech in 30 pts (46.2%), Moderna in 33 pts (50.7%), and Johnson and Johnson in 2 pts (3.1%). Six pts received only one vaccination (9.2%), 18 pts received two vaccinations (27.7%), and 40 pts received 3 or more vaccinations (61.5%). Eleven pts (16.9%) experienced severe irAEs following vaccination. Rates of severe irAEs was 3.8% (1/26) with CPI monotherapy, 25% (3/12) with combo CPI, and 25.9% (7/27) with combo CPI and TKI. Severe irAEs occurred after the first vaccine dose in 4 pts (36.4%), second dose in 3 pts (27.3%), and third dose in 4 pts (36.4%) pts. The median time between CPI treatment and vaccination in this group was 11.0 days (IQR: 7.5-15.5). Hospitalization was required for 6 patients (54.5%). Ten pts (90.9%) required immunosuppressive therapy with a median steroid duration of 85.5 days (IQR 36.8, 176.0). Six pts (54.5%) discontinued CPI therapy following severe irAEs. Conclusions: In this retrospective study, the observed rate of severe irAEs in RCC patients who received CPI and COVID-19 vaccine concomitantly was similar to historical controls, suggesting that there is no definite increase in the incidence of severe irAEs in pts undergoing CPI therapy and receiving COVID-19 vaccination. Future confirmatory studies are warranted. Supported by the Health Data Compass Data Warehouse project (healthdatacompass.org)

086 Thymectomy in myasthenia gravis – a review of 36 patients

Guidelines set by the Association of British Neurologists recommend thymectomy for patients under the age of 45 with positive AChR antibodies or thymoma. Previous literature supports this, as thymectomy had been shown to improve clinical outcomes and reduce the need for immunosuppressive therapy. However, given the advancement of more successful immunosuppressive medicine the need for thymec- tomy can be questioned.Aim- to identify whether thymectomy aids Myasthenia Gravis (MG) management by reducing the need for immunosuppressive medication.Method- A retrospective evaluation identified 173 patients who had thymectomy in the UHB trust in the past 10 years, from which patients who had a primary indication of MG were extracted. Patient records were reviewed to collate data. Relevant trusts departments were contacted to fill the missing data.Results- 36 patients filled the criteria for inclusion. The average dose of prednisolone had an insignificant reduction by 22mg (STD- 10mg). 16 patients (44%) had a lower dose of prednisolone than prior to surgery. The average dose of Azathioprine had an insignificant increase since surgery by 18mg. There was also a reduction in the use of IVIG and plasma exchange.Conclusion- Thymectomy is unlikely to cause a significant reduction in the need for immunosuppressive therapy. Further research may be required to secure a larger sample size over a longer time period.saiju.jacob@uhb.nhs.uk

P146 A CASE OF TYROSINE–KINASE INHIBITOR INDUCED CARDIOTOXICITY

Abstract This case is about a 69 years–old woman with no prior cardiovascular disease and a history of rheumatoid arthritis;in 2017 underwent right nephrectomy for renal cancer. A few weeks before admission, due to evidence of secondary bone lesions at a follow–up CT–scan, a single dose of the tyrosine kinase inhibitor (TKI) Nivolumab was administered. On the same evening she suffered from a severe reacutization of arthritic symptoms, that led her Oncologist to suspend treatment with nivolumab, and oral corticosteroid therapy was initiated. The following weeks remained though characterized by intense persistent asthenia, severe arthralgias, profuse diarrhea and a syncopal episode; no chest pain was reported. Given the persistence of symptoms, she went to the Emergency Room. Initial work–up revealed a complete heart block, with a previously unknown right bundle branch block (see Figure 1). At blood tests there was a significant increase of troponin I to 7616 ng/L (Normal&amp;lt;12ng/L), BNP 1113 pg/mL (NR &amp;lt; 100 pg/mL), creatinine 2.34 mg/dL (NR 0.55–1.02mg/dL), CPK 1681 U/L (NR 10–145 U/L) and D–dimer 17780 mcg/L (NR &amp;lt; 600). She was immediately transferred to our Cardiologic Intensive Care Unit, where an echocardiogram showed normally functioning ventricular chambers and no valvulopathies. Due to the ongoing acute kidney injury and the history of right nephrectomy, a coronary angiography was not immediately performed, considering the low probability of ACS (no typical symptoms, no regional wall motion abnormalities).Suspecting nivolumab–induced myocarditis, high–dose glucocorticoids were initiated. After a few days we observed persistence of bradycardia and complete AV block despite isoprenaline infusion, and due to signs of peripheral malperfusion (acute kidney injury, hypotension) a definitive leadless pace–maker Micra was implanted (this choice given the need of immunosuppressive therapy that could predispose her to device infections). After normalization of renal function, we performed a coronary angiography that showed normal coronary arteries. Despite the initial improvement of the clinical conditions, the patient suffered a fatal cardiac arrest due to electromechanical dissociation 3 weeks after admission. This case report is an important example showing the significant mortality of cardiotoxicity induced by tyrosine–kinase inhibitors, a side effect that every Cardiologist must be aware of in order to recognize it and immediately intervene with the appropriate therapy.

Corynebacterium amycolatum infective endocarditis in a patient with severe COVID-19: a case report

Objective. To present a case of successful treatment of a secondary bacterial infection caused by nondiphtheritic corynebacterium in a patient with severe COVID-19 and known beta-lactam intolerance. Materials and Methods. A clinical case of infective endocarditis (IE) caused by Corynebacterium amycolatum in a 74-year-old patient hospitalized with severe COVID-19 is presented. Comorbidity (secondary immune deficiency due to active malignancy, chemotherapy courses; previous heart disease) and the need for immunosuppressive therapy were triggers for infection caused by a rare Gram-positive bacterium which is usually considered as clinically non-significant. The choice of empiric antimicrobial treatment was limited by the patient’s history of beta-lactam intolerance. Results. A multidisciplinary approach to medical care of the patient and alertness to secondary infections helped to diagnose IE in a timely manner and to choose effective antimicrobial therapy. Combination therapy with vancomycin and amikacin helped to make blood flow free from infection. The further switch to oral doxycycline in outpatient settings resulted in the patient recovery from the infection. Conclusions. Under conditions of limited choice of drug therapy, it is critical to have access to modern microbiological diagnostics which make it possible to diagnose rare pathogens. A dialogue between treating physician and clinical pharmacologist helps to choose an empirical and targeted antimicrobial therapy with the best efficacy-safety ratio. There is a need to be alert to secondary infections, including those of atypical locations and courses and caused by rare or opportunistic pathogens.

КЛИНИЧЕСКИЙ СЛУЧАЙ ТЯЖЕЛОГО ТЕЧЕНИЯ ИНФЕКЦИИ COVID-19 С ПОЛИОРГАННОЙ ДИСФУНКЦИЕЙ У ПАЦИЕНТА С ХРОНИЧЕСКОЙ БОЛЕЗНЬЮ ПОЧЕК 5 СТАДИИ НА ФОНЕ ФУНКЦИОНИРУЮЩЕГО ПОЧЕЧНОГО ТРАНСПЛАНТАТА

Abstract. In most cases, COVID-19 is asymptomatic or mild and not life-threatening, but there is a category of patients for whom the infection poses a serious threat – organ transplant recipients. The severity of the disease in such patients is due to the need for immunosuppressive therapy, due to the high risk of developing infectious complications due to prolonged immunosuppression and a pronounced comorbid background. In the given clinical case, the experience of diagnosis and successful treatment of a patient with COVID-19 infection is presented complicated by multiple organ dysfunction and, as a consequence, renal transplant dysfunction in a 36-year-old patient with stage 5 chronic kidney disease who was hospitalized at the Grodno University Hospital.