Re-vaccination against SARS-COV2 in allogeneic HSCT patients: Repeated primary vaccines doses increases seroconversion rates

Patients undergoing treatment for haematological malignancies have been shown to have reduced antibody responses to vaccination against SARS-COV2. This is particularly important in patients who have undergone allogeneic haemopoietic stem cell transplantation (HSCT), in whom there is limited data about vaccine efficacy. In this retrospective single-centre analysis, we present data on serologic responses following one, two, three or four doses of either Pfizer-BioNTech (PB), AstraZeneca (AZ) or Moderna (MU) SARS-CoV- 2 vaccines from a series of 75 patients who have undergone allogeneic HSCT within 2 years from the time they were revaccinated. The seroconversion rates following post-HSCT vaccination were found to be 50.7%, 78%, 79% and 83% following the first, second, third and fourth primary post -HSCT vaccine doses, respectively. The median time from allograft to first revaccination was 145 days (range 79-700). Our findings suggest that failure to respond to the first SARS-CoV- 2 vaccine post-HSCT was associated with the presence of acute GVHD (p = 0.042) and treatment with rituximab within 12 months of vaccination (p = 0.019). A statistical trend was observed with the presence of chronic GVHD and failure to seroconvert following the second (p = 0.07) and third (p = 0.09) post-HSCT vaccine doses. Patients who had received one or more SARS-CoV- 2 vaccines prior to having an allogeneic stem cell transplant were more likely to demonstrate a positive antibody response following the first dose of revaccination against Sars-CoV- 2 (p = 0.019) and retained this seropositivity following subsequent doses. The incidence of confirmed COVID-19 diagnosis among this cohort at the time of analysis was 16%. 17% of these were hospitalised and there was one recorded death (8%) secondary to COVID-19 in a patient who was 15.7 months post allogeneic transplant. In summary, this study suggests that despite the initial low seroconversion rates observed postallogeneic transplant, increasing levels of antibody response are seen post the second primary vaccine dose. In addition, there seems to be lower risk of mortality secondary to COVID-19 in this vaccinated population, compared to what was reported in the earlier phases of the pandemic prior to use of SARS-COV2 vaccination. This adds support to the widely adopted policy of early full revaccination with repeat of primary vaccine doses and boosters post-HSCT to reduce mortality in this population. Finally, we have identified rituximab use and active GVHD as potential risk factors influencing serological responses to SARS-COV2 vaccination and further work should focus on further characterising this risk and optimum dosing schedule both pre-and post-transplant.

Association Between Severe SARS-CoV-2 Infection and De Novo HLA Donor Specific Antibody Production in Lung Transplant Recipients: Single-center study

Objectives: The COVID-19 pandemic has led to significant morbidity and mortality in lung transplant recipients (LTR). Respiratory viral infections may be associated with de-novo HLA donor-specific antibody (DSA) production and impact lung transplant outcome. Since one of the immunomodulation strategies post-SARS-CoV-2 infection in LTR include decreasing or holding anti-metabolites, concerns have been raised for higher incidence of de-novo DSA production in LTR. Method(s): We performed a retrospective chart review of 80 consecutive LTR diagnosed with COVID-19 to investigate this concern. COVID-19 disease severity was divided into 3 groups: mild, moderate, and severe. Mild disease was defined as patients with COVID-19 diagnosis who were stable enough to be treated as out-patients. Moderate disease was defined as patients who required admission to the hospital and were on less than 10 liters of oxygen at rest. Severe disease was identified as patients who required hospitalization and were on more than 10 liters of oxygen with or without mechanical ventilation or extra corporal membrane oxygenation (ECMO). Groups were compared using the Kruskal-Wallis test. Result(s): A total of 23, 47, and 10 LTR were diagnosed with mild, moderate, and severe COVID-19 respectively. De-novo HLA DSAwere detected in 0/23 (0%), 3/47 (6.3%), and 4/10 (40%) LTR with mild, moderate, and severe COVID-19 respectively (p = 0.0007) within 6 months post-COVID-19 diagnosis. Conclusion(s): Severe COVID-19 may be associated with increased risk of de novo HLA DSA production resulting in allograft dysfunction.Copyright © 2023 Elsevier Inc.

Burden of respiratory coinfections in haematology patients with COVID-19

Introduction: Following the lifting of generalised restrictions and universal masking, severe acute respiratory syndrome coronavirus 2 (SARS-CoV- 2)- infected patients, especially the clinically extremely vulnerable (CEV) haematology patients, are at an increased risk for other respiratory viral coinfections;therefore, physicians need to be cognizant about excluding other treatable respiratory pathogens. Here, we report coinfection with SARS-CoV- 2 and other respiratory pathogens in patients with haematological cancers presenting to a large tertiary care hospital. Method(s): From July 2022-December 2022, patients with haematological disorders were screened for SARS-CoV- 2 and other 10 common respiratory pathogens by PCR. We performed a retrospective analysis of patients with concurrent respiratory viruses and will prospectively evaluate the same from Jan 2023 to March 2023. Result(s): During this period a total of 322 inpatients had routine screening and additional 6213 swabs were done in the outpatient/ambulatory setting, of which 294 were positive in 221 patients. We excluded all patients who had a single positive PCR swab result and specifically analysed only patients with coinfections. We identified 30 patients (14%) who had respiratory coinfections with 73 viral infections/reactivations over 6 months period, which represented 25% of all positive swabs: 25 inpatients (19 symptomatic/6 asymptomatic) and 48 in outpatients (32 symptomatic/16 asymptomatic). The median age of the cohort was 47.3 years (21-77). Patients were post allograft (n = 15), autograft (n = 7), post CART (n = 5) and postchemotherapy (n = 4). Of the 30 cases, 13 patients had concurrent infections: 5 SARS-CoV2, 10 Respiratory syncytial virus (RSV), 7 Rhino and 4 Influenza A, with all patients having dual viral infection. The remaining 17 patients had multiple viral infections but separated by a median of 54 days (range 27-137 days): 16 SARS-CoV2, 5 RSV, 6 Rhino, 2 Parainfluenza, 2 Adeno and one each of Influenza A, Influenza B, and metapneumovirus. Of the treatable infections (n = 46), 22% were detected on routine asymptomatic swabbing, with 50% of SARS-CoV2 detected on routine swabs. All 8 patients with Influenza were treated with oseltamivir, of 16 RSV cases one was treated with oral ribavirin and of the 22 SARS-CoV2 patients, 5 were treated (4 Paxlovid and 1 Remdesivir). No patients needed intensive care support and no deaths were reported. Conclusion(s): The burden of respiratory coinfections in CEV cohort has a significant impact on respiratory isolation and management, including appropriate & timely initiation of therapy for treatable viral infections. Although mortality was not increased secondary to respiratory coinfections and none needed intensive care, larger prospective cohorts are needed to assess the exact impact.

7-year outcomes of the first successful pediatric bilateral hand transplantation

Introduction: The purpose of this case report is to describe the 7-year functional outcomes and health-related quality of life (HRQOL) of the first successful pediatric bilateral hand transplantation. The report focuses on activity and participation. The authors suggest assessment methods that can be applied to future cases. Method(s): The child underwent quadrimembral amputation at age two years and received bilateral hand allografts at age eight. Rehabilitation included biomechanical, neurorehabilitation, and occupational approaches in acute and outpatient settings. Therapist observed outcomes assessments, patientreported and parent-reported outcome questionnaires were repeated over a 7-year period. Result(s): At 7-years post transplantation, the adolescent and his mother reported a high level of satisfaction with the outcomes. Therapist observed assessments showed the adolescent achieved functional gross motor dexterity with each upper extremity. Although left gross and fine dexterity was superior to the right at all timepoints observed, the adolescent used his right upper extremity as dominant and incorporated both extremities as appropriate for bimanual tasks. The adolescent achieved modified independence to full independence with self-care activities. The adolescent participated in diverse activities with a high level of enjoyment. Participation was more diverse, social, and communitybased prior to and after the initial COVID-19 pandemic restrictions. At 7-years post transplantation when the adolescent was 15-years of age, the parent rated more instrumental activities of daily living as somewhat difficult. Discussion and Conclusion(s): Therapist observed outcomes assessments, patient-reported and parent-reported outcome questionnaires, showed the child had incorporated his hands into various activities, was completing daily activities independently, and HRQOL outcomes in social, emotional, cognitive, and physical domains were favorable. Most results were stable over time. The decrease in right hand dexterity scores might reflect small kinesiological changes in the right hand. Difficulty with some instrumental activities of daily living were likely due to new activities typical of child development for this now 15-year-old patient.

A single centre experience of using venetoclax and azacitidine in the treatment of AML

Background: The combination of venetoclax and azacitidine was licensed as a treatment regime for AML during the COVID-19 pandemic and has only been available for a short period of time. It has been widely adopted, including by our centre, for use in older adults and those with multiple co-morbidities, for whom intensive treatment might not be appropriate, but where low-intensity treatment or palliative care is also considered inappropriate. We feel that our patient cohort has been experiencing a lot of cytopaenias with the regime and thus treatment has been de-escalated more commonly than seen in the VIALE-A trial1 and so decided to carry out an audit of our practice. Method(s): Patients were identified by our pharmacy colleagues as having had Blueteq forms completed for venetoclax-azacitidine treatment. We then looked at their electronic medical records to ascertain their age, co-morbidities, treatment received, any treatment modifications made (and reasons for these adjustments), disease course and time until death. Result(s): We identified 22 patients who have received treatment with venetoclax and azacitidine, since October 2020. Eleven of these patients are now deceased (50%), with causes of death attributable to progressive disease or infection. The median age of our patient population was 72 years old (range of 51-84). The maximal number of cycles of venetoclax-azacitidine that have been delivered to a single patient is 12 (with cessation following disease progression). 9/22 patients had no dose modifications made to treatment, but of these, six patients only received one cycle of treatment (prior to progressive disease or death from sepsis). The rest of the patients (13) have had dose reductions to shorter courses of venetoclax (to between 21 days and 7 days) or have been changed to azacitidine alone (5/13 patients). One of our 22 patients has now received an allograft. Conclusion(s): Our patients routinely receive posaconazole prophylaxis, and thus a dose of 100 mg venetoclax (due to the known interaction), rather than the 400 mg dose used in the VIALE-A trial1-it may be that this, (and that it is equivalent to an actual dose of greater than 400 mg), is the reason behind the increased incidence of cytopaenias and increased need to de-escalate treatment. In the future it would be helpful and informative to compare our practice to that of other centres.

Research highlights on kidney transplantation in 2021: Voices from China

Over the past 70 years, kidney transplantation has become not only the most mature but also the highest-success-rate surgery among all organ transplantation surgeries. However, the long-term survival of kidney transplant recipients is still challenged by such key factors as ischemia-reperfusion injury related to kidney transplantation, rejection, chronic renal allograft dysfunction, renal allograft fibrosis, immunosuppressive therapy, infections and others. Relevant fundamental and clinical studies have emerged endlessly. At the same time, the research related to kidney transplantation also becomes a new hot spot accordingly in the context of the normalization of novel coronavirus pneumonia. This article reviewed the cutting-edge hot spots in relation to the fundamental and clinical aspects of kidney transplantation together with relevant new techniques and new visions. The studies included in this article focused on the reports published by Chinese teams that are more applicable to the current situation of kidney transplantation in China, for the purpose of providing new thoughts and strategies for the diagnosis and treatment of kidney transplantation related issues in China.Copyright © 2022 Organ Transplantation. All rights reserved.

Renal Allograft Cortical Necrosis in a COVID-19 Positive Patient.

The incidence of acute kidney injury (AKI) has been reported to be higher in kidney transplant recipients infected with SARS-CoV-2 compared with the general population. Here, we report a case of cortical necrosis in the graft kidney due to COVID infection in a patient with stable graft function over the years. The patient was started on hemodialysis and treated with steroids, and anticoagulants for COVID infection. Later, he had gradual improvement in his graft function and became dialysis independent on follow up.

Hospitalisation and death in lung transplant recipients following COVID-19 infection

Introduction/Aim: Rates of hospitalisation and death from COVID-19 in lung transplant (LTx) recipients vary internationally. We aimed to assess risk factors for this in an Australian cohort. Method(s): We performed a retrospective cohort study of all LTx recipients between January 2020 and September 2022. LTx recipients with COVID-19 were included. Baseline characteristics and treatments were recorded. Multivariate logistic regression was performed to identify risk factors associated with hospitalisation and death. Result(s): 128/387 (33%) recipients tested positive to SARS-CoV-2 during the study period, 97.6% during the Omicron waves with 40(31.3%) requiring hospitalisation and 10 (7.8%) died. The median (IQR) recipient age was 50.6 (22-77). The cohort was of Caucasian ethnicity 105 (82%), 48% were female with high vaccination rates (98.4%). Chronic lung allograft dysfunction (CLAD) was present in 48 (37.5%). 103 (80.5%) of patients received early SARS-CoV-2 treatment with either Sotrovimab 84(65%), Molnupirivir 50(39%) or combination 31(24%). 25 patients (19.5%) received no early treatment. All hospitalised patients received Remdesivir and Dexamethasone as per local treatment protocols. Regarding risk of hospitalisation, multivariate analysis showed that recipient age (1-unit change OR 1.04 95% CI 1.01-1.07 p = 0.019) was associated with an increased risk, whereas Molnupiravir was protective (OR 0.32 95% CI 0.13-0.80 p = 0.02). In univariable analysis, increasing age (1-unit change, OR 1.07 95% CI 1.02-1.129 p = 0.01) and severe disease (OR 9.95 95% CI 2.58-38.32 p =< 0.001) were associated with an increased risk of death. Male gender, non-Caucasian ethnicity, CLAD, CKD stage 3-5 were correlated with death with weak association. Conclusion(s): Recipient age is a significant risk factor for both hospitalisation and death, and older patients with COVID-19 should be monitored closely during COVID-19 illness. Molnupirivir is protective against hospitalisation, with Sotrovimab having a weak association. Further analysis of the protective effect of pre-exposure prophylaxis with emerging therapies such as Evusheld would be helpful to fully evaluate the currently available early disease therapies in Australia.

COVID pneumonitis, a risk factor for persistent lung allograft dysfunction

Introduction/Aim: There is a paucity of data regarding the impact of COVID-19 on allograft function in lung transplant (LTx) recipients. Method(s): We performed a retrospective cohort study of all living LTx recipients in our service between January 2020 and September 2022. Patients with COVID-19 were identified and baseline characteristics recorded. Pre- and post-COVID-19 spirometry was used to identify persistent decline in allograft function (>=10% of FEV 1 decline at 90 days after infection and failure to return to baseline during the study period). Multivariable logistic regression was performed to identify risk factors associated with persistent allograft decline. Result(s): 128/387 (33%) LTx recipients tested positive to SARS-CoV-2 during the study period. The majority, 125 (97%) during the Omicron waves. In those with COVID-19, the median (IQR) recipient age was 50.6 (22-77) with median time post-transplant of 1522 (17-9842) days. The cohort was of Caucasian ethnicity, 105 (82%), with vaccination rates (98.4%) and 48% female. Chronic lung allograft dysfunction (CLAD) was present at time of infection in 48 (37.5%). Severe disease (oxygen requirement) was present in 40 (31%) patients and 10 (7.8%) died. Recipients were followed for median of 172 days (range 90-339) post infection. Persistent FEV 1 decline occurred in 37 (31.4%). Multivariate analysis showed severe disease was independently associated with an increased risk of persistent FEV 1 decline (OR 5.55 [95% CI 2.28-13.48] p =< 0.001). Non-Caucasian ethnicity (OR 2.83, [95% CI 0.92-8.65], p = 0.07) and the presence of CLAD (OR 2.39, [95% CI 0.94-6.08], p = 0.06), were positively correlated, with weak association. No significant association between recipient age, gender, time post-transplant, early COVID therapy, SARS-CoV-2 variant with persistent FEV 1 decline was seen. Conclusion(s): Persistent decline in lung allograft function is common post COVID-19 infection. Severe disease is strongly associated with this outcome and these patients should be monitored for poor long-term allograft recovery. Further investigation into pathological mechanisms responsible for persistent allograft decline is required.

Fresh Versus Cryopreserved Allograft Outcomes in Peripheral Blood Stem Cell Transplantations

Background: The emergence of the COVID-19 pandemic saw an increased use of cryopreserved (cryo) peripheral blood (PB) grafts for allogeneic hematopoietic stem cell transplantation (HSCT). Outcomes of patients receiving either fresh or cryo grafts have yielded heterogeneous results. Herein, we retrospectively compared the outcomes of patients receiving fresh and cryo grafts at a single center.(Table Presented)Methods: Between 2019 and 2021, we reviewed data from 380 patients;167 (44%) received a fresh, and 213 (56%) received a cryo graft. Patients underwent myeloablative or nonmyeloablative HSCT from either matched or mismatched, related or unrelated donors. Cell doses were determined by number of donor cells collected and recipient weight at infusion. Engraftment, disease risk (DR) and acute GVHD were classified based on established criteria. Donor chimerism was collected at approximately day 28 and day 80 after HSCT. Unadjusted and adjusted estimates of overall survival (OS), relapse, and non-relapse mortality (NRM) as a function of time were obtained. The adjusted odds (grades III-IV acute GVHD) and the adjusted cause-specific hazard of failure (all other outcomes) were compared between the 2 groups. with the use of logistic (Figure Presented) or Cox regression, respectively. These models were adjusted for various factors known to be associated with each outcome. Result(s): The characteristics of patients between the 2 groups are shown in Table 1. There was a higher proportion of patients with high/very high DR in the fresh graft group (Table 1). Median time to neutrophil engraftment was 17 and 18 days in fresh vs. cryo, respectively. The adjusted hazard ratio (HR) of neutrophil engraftment (fresh vs. cryo) was 1.07 (95% CI, 0.86-1.34, p=0.54). Median time to platelet engraftment was 13 and 15 days, respectively, and the adjusted HR of platelet engraftment was 1.32 (1.06-1.65, p=0.01). Day 28 chimerism data were available for 272 patients (113 fresh and 159 cryo). At day 28, donor CD3 chimerism was below 50% in 5 out of 113 (4.4%) and 17 out of 159 (10.7%) patients receiving fresh and cryo grafts, respectively (p= 0.06). At day 80, 3 out of 121 (2.5%) patients in the fresh group and 4 out of 165 (2.4%) in the cryo group had CD3 chimerism below 50%. The adjusted HRs (fresh vs. cryo) for death and NRM were 0.83 (0.54-1.28, p=0.40) and 0.71 (0.38-1.33, p=0.29), respectively (Figures 1 and 2). The adjusted HR for relapse was 0.65 (0.42-0.99, p=0.05) (Figure 3). The adjusted odds ratio (fresh vs. cryo) for grades III-IV GVHD was 1.65 (0.94-2.9, p=0.07). Conclusion(s): In this single-center retrospective study we observed numerically better outcomes with fresh grafts relative to cryo grafts for all examined endpoints with the exception of grades III-IV aGVHD, although none of the differences were definitive with the possible exception of relapse and platelet engraftment. Further studies are needed to confirm our observations.Copyright © 2023 American Society for Transplantation and Cellular Therapy

Sarcoidosis-Associated Immune Thrombocytopenic Purpura and Focal Segmental Glomerulosclerosis

Purpose of study A 32-years old male with known multi-system sarcoidosis in remission for 5 years off treatment presented to the emergency room with complaints of generalized weakness, hematemesis, epistaxis, and bruises. Physical examination was notable for petechiae, ecchymosis along with papules and plaques suggestive of active sarcoid skin lesions on his extremities. Laboratory workup was significant for thrombocytopenia 3000/uL, acute kidney injury with sub-nephrotic proteinuria. Peripheral blood smear did not show evidence of hemolysis and direct Coombs test was negative. Infectious workup including COVID-19, HIV, and hepatitis serologies were negative. Computed Tomography (CT) of chest, abdomen, and pelvis showed mild splenomegaly and an increased number of sub-centimeter hilar and mediastinal lymph nodes. The patient was treated with dexamethasone 40 mg daily for 4 days and intravenousimmunoglobulins (IVIG-2 gm/kg) for possible Immune Thrombocytopenic Purpura (ITP) with improvement in platelet count to 42000/uL by day 3. His workup for AKI and sub-nephrotic proteinuria was negative apart from a positive ANA (1: 160) with low complements. The anti-phospholipid antibody panel was negative. The ACE level was markedly elevated (>80U/L). The patient could not get a renal biopsy due to severe thrombocytopenia. He was discharged but was re-admitted in 15 days for severe thrombocytopenia of 1000/uL, epistaxis, and bruising. We continued high dose steroids along with IVIG 1 gm/kg for refractory ITP with minimal response and started anti-CD20 agent (Rituximab) 375 mg/m2 weekly with thrombopoietin-receptor agonist (Eltrombopag). His platelets count improved in response to treatment and subsequent renal biopsy showed focal and segmental glomerulosclerosis along with mild interstitial fibrosis, tubular atrophy thought to be from long standing sarcoidosis. There was also evidence of focal arteriosclerosis with no evidence of granulomas, immune complex, complement, or IgG4 deposition. Given skin lesions, thrombocytopenia, extensive lymphadenopathy, and renal involvement with markedly elevated ACE levels the overall picture was consistent with active multi-system sarcoidosis. His platelet count increased to 177,000/uL at the time of discharge. Currently, the patient is on slow steroid taper along with Eltrombopag 25 mg every other day without any recurrence of his symptoms so far. Methods used We described one case of sarcoidosis with hematologic and renal involvement. Summary of results Our patient developed hematologic and renal complications approximately 6 years after being diagnosed with sarcoidosis. Initially, he did not demonstrate sufficient clinical response to IVIG and high dose steroids. However, after a course of anti-CD20 agent (Rituximab) and with the addition of thrombopoietin-receptor agonist (Eltrombopag) he showed improvement of platelet count and stabilization of the renal function. Currently, the patient is receiving maintenance therapy with Prednisone 7.5 mg daily along with Eltrombopag 25 mg twice weekly with no recurrence of ITP and stable renal function. A further decision on whether the patient needs another cycle of Rituximab will be determined by the patient's clinical course. Conclusions Highly variable manifestations of Sarcoidosis can pose a significant diagnostic and therapeutic challenge as can be seen from our case. ITP is a rare hematological manifestation of sarcoidosis and addition of anti-CD20 agents should be considered in refractory cases.

Severe delayed graft function in a living-related kidney transplant recipient due to combination of alloimmunity, autoimmunity, and heterologous immunity: A case report.

BACKGROUND: Delayed graft function is a manifestation of acute kidney injury unique to transplantation usually related to donor ischemia or recipient immunological causes. Ischemia also considered the most important trigger for innate immunity activation and production of non-HLA antibodies. While ischemia is inevitable after deceased donor transplantation, this complication is rare after living transplantation. Heterologous Immunity commonly used to describe the activation of T cells recognizing specific pathogen-related antigens as well unrelated antigens is common post-viral infection. In transplant-setting induction of heterologous immunity that cross-react with HLA-antigens and subsequent reactivation of memory T cells can lead to allograft rejection. METHODS: Here we describe a non-sensitized child with ESRD secondary to lupus nephritis and recent history of COVID-19 infection who experienced 17 days of anuria after first kidney living transplantation from her young HLA-haploidentical uncle donor. Graft histology showed acute cellular rejection, evidence of mild antibody-mediated rejection and vascular wall necrosis in some arterioles suggesting possibility of intraoperative graft ischemia. Both pre- and post-transplant sera showed very high level of several non-HLA antibodies. RESULTS: The patient was treated for cellular and antibody-mediated rejection while maintained on hemodialysis before her graft function started to improve on day seventeen post transplantation. CONCLUSION: The cellular rejection likely trigged by ischemia that activated T-cells-mediated immunity. The high level of non- HLA-antibodies further aggravated the damage and the rapid onset of rejection may be partly related to memory T-cell activation induced by heterologous immunity.

Two-Hit Kidney Allograft Injury by SARS-CoV-2.

Coronavirus disease 2019 (COVID-19) has been associated with acute kidney injury in kidney transplant recipients by several mechanisms. The authors report a case of acute kidney allograft dysfunction in a 48-year-old patient who presented in the emergency room with anasarca and nephrotic syndrome close after mild COVID-19 and no other clinical condition. Histopathology of the allograft biopsy revealed two distinct and simultaneous kidney lesions, collapsing glomerulopathy and thrombotic microangiopathy. Renal function persistently deteriorated, and definitive dialysis was initiated. After excluding other plausible causes for the findings, this case strengthens the hypothesis that the kidney allograft is also a target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Multivessel Epicardial Coronary Artery Thrombosis after Heart Transplantation

Introduction: Although cardiac allograft vasculopathy (CAV) remains one of the leading causes of graft failure after heart transplantation (HTx), simultaneous thrombosis of multiple epicardial coronary arteries (CA) is an uncommon finding. Case Report: A 43-year-old male patient with non-ischemic dilated cardiomyopathy underwent successful HTx in 2019. The first two years after HTx were uneventful, surveillance endomyocardial biopsies (EMB) did not reveal any rejection episodes, coronary CTA revealed only minimal non-calcified CA plaques. The patient was admitted to hospital due to fever and chest pain in 2021. Immunosuppressive therapy consisted of tacrolimus, mycophenolate-mofetil and methylprednisolone. ECG verified sinus rhythm. Laboratory test revealed elevated hsTroponin T, NT-proBNP and CRP levels. Cytomegalovirus, SARS-CoV-2-virus and hemoculture testing was negative. Several high-titre donor-specific HLA class I and II antibodies (DSAs;including complement-binding DQ7) could have been detected since 2020. Echocardiography confirmed mildly decreased left ventricular systolic function and apical hypokinesis. EMB verified mild cellular and antibody-mediated rejection (ABMR) according to ISHLT grading criteria. Cardiac MRI revealed inferobasal and apical myocardial infarction (MI);thus, an urgent coronary angiography was performed. This confirmed thrombotic occlusions in all three main epicardial CAs and in first diagonal CA. As revascularization was not feasible, antithrombotic therapy with acetylsalicylic acid, clopidogrel and enoxaparin was started for secondary prevention. Tests for immune system disorders, thrombophilia and cancer were negative. Patient suddenly died ten days after admission. Necropsy revealed intimal proliferation in all three main epicardial CAs, endothelitis, thrombosis, chronic pericoronary fat inflammation, fat necrosis, and subacute MI. CA vasculitis owing to persistent high-titre DSAs, chronic ABMR and acute cellular and antibody-mediated rejection led to multivessel CA thrombosis and acute multiple MI. ABMR after HTx may be underdiagnosed with traditional pathological methods. Pathologies affecting coronary vasculature of HTx patients with DSAs, unique manifestations of CAV lesions and occlusive thrombosis of non-stenotic, non-atherosclerotic lesions should be emphasized.Copyright © 2023

The Impact Of Years Since Transplant On The Clinical Course After SARS-CoV-2 Infection In Heart Transplant Recipients

Introduction: The risk of Severe Acute Respiratory Syndrome - Coronavirus-2 (SARS-CoV-2) infection and mortality is higher in heart transplant (HT) recipients compared to immunocompetent individuals. The impact of years since transplant on clinical course risk is unknown. We evaluated the differences in clinical phenotypes and outcomes according to years since transplant in HT recipients with active SARS-CoV-2 infection. Method(s): Consecutive HT recipients from our National Transplant Centre with confirmed SARS-CoV-2 between April 2020 and March 2022 were enrolled in this retrospective observational study. Patients were stratified into 2 groups: <5 years after HT (Group A) and >/= 5 years after HT (Group B). Result(s): A total of 63 HT recipients were enrolled [median age 56 (41,66) years, 32% female] with 33% of patients (n=21) assigned to Group A, and 67% (n=42) to Group B. In Group B patients, the prevalence of diabetes mellitus and cardiac allograft vasculopathy was significantly higher compared to those in Group A. Meanwhile, Group A patients were more likely to have a history of neutropenia prior to SARS-CoV-2 infection and were more frequently taking maintenance steroids and antimetabolite immunosuppressants (Table 1). Those recipients less than 5 years since HT were also significantly more likely than those >5 years out to develop the infection despite a 3rd dose of COVID vaccine (60% vs 31%, p 0.03).During the active infection, Group A recipients more frequently developed neutropenia (73% vs 27%, p 0.01), and trended towards higher rates of hospitalizations (57% vs 32%, p 0.06). Notably, none of the patients in Group A required mechanical ventilation compared to just under 10 % (n=4) of those in Group B. Further, no Group A patients died during the active infection hospitalization compared to 14% (n=6) of those in Group B. Conclusion(s): In HT recipients, years since transplant is a simple, clinically useful parameter stratifying outcomes after SARS-CoV-2 infection. While patients with less than 5 years since transplant are more likely to develop infection despite booster vaccination and require hospitalization, greater number of years since transplant was associated with more severe consequences during hospitalization.Copyright © 2022

Association of urinary mitochondrial DNA with COVID-19 related acute kidney injury, mitochondrial stress, and inflammation in renal transplant recipients

Introduction: ACE-receptors are profusely expressed in the renal cell, making it highly susceptible for severe acute respiratory syndrome corona virus-2 (SARS-CoV-2) infection. After entering the cells, the virus induces high levels of cytokines, chemokines, and inflammatory responses, resulting neutrophilic infiltration, activation, and profuse reactive oxygen species (ROS) formation, leading to cellular necrosis and acute tubular injury. Proximal convoluted tube cell are rich in mitochondria and susceptible for developing acute kidney injury (AKI) due to mitochondrial stress. Early detection of AKI may helpful in its management, limiting the severity, avoiding nephrotoxic medicines and modifying the drug dose depending on renal function. Therefore, in the current study, we have determined the utility of urinary mitochondrial DNA (umt-DNA) and neutrophil gelatinase-associated lipocalin (NGAL) in predicting COVID-19-associated acute kidney injury (AKI) and mitochondrial stress and demonstrated the inflammatory response of urinary mt-DNA. Method(s): Live-related RTRs(n=66), who acquired SARS-CoV-2 infection and were admitted to a COVID hospital were included and subclassified into AKI (N=19) with > 25% spike in serum creatinine level from the pre-COVID-19 serum creatinine level, and non-AKI (N=47) whose serum creatinine value remained stable similar to the baseline value, or a rise of < 25% of the baseline values of pre-COVID-19. A 50ml urine sample was collected and umt-DNA and N-GAL was determined by the RT-PCR and ELISA methods respectively. A 10ml blood sample from 10 healthy volunteers was also collected for PBMC isolation and inflammatory response demonstration. A 1x106 PBMC was stimulated for 24hrs. with 1microg/ml of urinary DNA or TLR9 agonist CpG oligodeoxynucleotide (5'-tcgtcgttttcggcgc:gcgccg-3') in duplicate. Unstimulated PBMCs served as control. The gene expression of IL-10, IL-6, MYD88 was analyzed by the RT-PCR and IL-6, IL-10 level in supernatants by the ELISA. Result(s): Both the urinary mitochondrial gene ND-1 and NGAL level was significantly higher in AKI group compared to non-AKI. The mean ND-1 gene Ct in AKI group was (19.44+/-2.58 a.u) compared to non-AKI (21.77+/-3.60;p=0.013). The normalized ND-1 gene Ct in AKI was (0.79+/-0.11 a.u) compared to non-AKI (0.89+0.14;P=0.007). The median urinary NGAL level in AKI group was (453.53;range, 320.22-725.02, 95% CI) ng/ml compared to non-AKI (212.78;range, 219.80-383.06, 95%CI;p=0.015). The median urine creatinine normalized uNGAL was 4.78 (0.58-70.39) ng/mg in AKI group compared to 11.26 ng/mg (0.41-329.71) in non-AKI group. The area under curve of ND-1 gene Ct was 0.725, normalized ND-1 Ct was 0.713 and uNGAL was 0.663 and normalized uNGAL was 0.667 for detecting the AKI and mitochondrial stress. The IL-10 gene expression was downregulated in umt-DNA treated PBMCs compared to control (-3.5+/-0.40vs1.02+/-0.02, p<0.001). IL-6 and Myd88 gene expression was upregulated. The culture supernatant IL-10 and IL-6 level in umt-DNA treatment PBMCs vs control was 10.65+/-2.02 vs 30.3+/-5.47, p=0.001;and 200.2+/-33.67 vs 47.6+/-12.83, p=0.001 pg/ml respectively. Conclusion(s): Urinary mt-DNA quantification can detect the Covid19 associated AKI and mitochondrial distress with higher sensitivity than uNGAL in RTRs. Urinary mt-DNA also induces a robust inflammatory response in PBMCs, which may exacerbate the Covid19 associated allograft injury. No conflict of interestCopyright © 2023

Covid-19 in lung allograft recipients - better outcomes after vaccination?

Vaccination remains a main weapon against Coronavirus Disease 2019 (Covid-19). Although its efficacy is reduced in the immunocompromised population, we felt empirically that outcomes of Covid-19 in lung transplant recipients (LTRs) were better after widespread vaccination than in earlier phases of the pandemic. We aimed to compare outcomes of unvaccinated and vaccinated LTRs infected with SARS-CoV-2. All LTRs followed in our hospital were reviewed and those with a positive polymerase chain reaction test were included. We analysed disease severity (using World Health Organization criteria) and mortality rates in unvaccinated and fully vaccinated patients (pts). Twenty-four pts were included, two-thirds of which were male, with a mean age of 51 years. Main diagnoses were hypersensitivity pneumonitis (25%), chronic obstructive pulmonary disease (16,7%), idiopathic pulmonary fibrosis (12,5%) and cystic fibrosis (12,5%). Lung transplant was bilateral in 79,2% of pts, unilateral in 16,7% and lobar in one pt (4,1%). The most common immunosuppression regimen was tacrolimus, mycophenolate-mofetil and prednisolone. Thirteen pts were unvaccinated and 11 were vaccinated at time of infection, with a mean time since transplant of 746 and 1641 days, respectively. In the unvaccinated group 69,2% had mild disease, 30,8% had severe disease and mortality was 25%. No deaths occurred among fully vaccinated pts;disease was mild in 72,7%, moderate in 18,2% and severe in 9,1%. Neither the difference in severity (p=0,156) or mortality (p=0,089) reached statistical significance, presumably due to the small sample size. Nevertheless, we confirmed that, in our centre, vaccinated LTRs had better overall outcomes than unvaccinated pts.

A Comprehensive Review of 275 Kidney Transplants Performed over 3 1/2 Years;a Single Center Experience

Introduction: Access to kidney transplantation has always been a problem in the African countries with many patients having to travel to other medically advanced countries in Asia, Europe and America. This involves unnecessary excessive expenditure and the travails of journey and stay in an unknown foreign land. To ease this situation and to provide affordable Renal transplant services in their home land, we have made an effort to start the transplant services at our medical facility and have successfully carried out about 275 transplants over a period starting from Nov 2018 till September 2022. Method(s): All the Kidney transplants done between the period Nov 2018- September 2022 (275 cases) were included in the analysis. All the transplants were performed at a single center and the data were collected progressively during their Pre transplant evaluation, perioperative course and post op follow up. All the laboratory and radiological tests were done locally at the center except the HLA cross matches and tissue typing, which were outsourced to Transplant immunology labs outside the country. All the patients with positive DSA titres [about 70%], underwent Plasmapheresis and received IVIg before the transplantation. immunological assessment was done by NGS high resolution, for A B C DP DQ DR loci and X match was done by SAB analysis for class 1 and Class II antigens. All the patients underwent laparoscopic donor nephrectomy. All Patients received vaccinations for Hepatitis B, Pneumonia, Infuenza & Covid. Result(s): A series of 275 kidney transplants were performed over a period of 42 months [ Nov 2018- September 2022] at a private hospital successfully. All the cases were live donor kidney transplants with majority of the donors being 1st or 2nd degree relatives or spousal donors. About 70% of the patients had some degree of sensitization in the form of weakly positive B cell X match, or positive for DSAs at CL I, CLII with MFIs > 1000. All high-risk patients received induction with rabbit Thymoglobulin, and IV methyl prednisolone. Around 50 patients received Basiliximab. Of all patients, 4were HBsAg positive, and 6 were HIV positive,& HCV 1 patient. 8 patients required pretransplant Parathyroidectomy for refractory hyperparathyroidism, 3 patients required simultaneous native kidney nephrectomy at the time of transplant. 25 patients had multiple renal vessels which were double barreled and anastamosed.4 patients had lower urinary tract abnormalities requiring simultaneous/subsequent repair. Overall, 4 patients underwent 2nd transplant. All the donors underwent laparoscopic nephrectomy. Most of the patients had good immediate graft function except in 40 patients, who had delayed graft function;most of them improving over 2 - 6 weeks. 6 Patients had hyperacute rejection and the graft was lost,.4patients had main renal artery thrombosis, Renal allograft biopsy was done in 20 patients. Overall, the Patient survival was 95 %.at 1 year and graft survival 90%. Conclusion(s): Our experience shows that kidney transplantation is a viable and practical option for End stage kidney disease and can be performed even in resource constrained centers in third world countries and the survival rates of patients and the grafts are comparable to other centers across the world. No conflict of interestCopyright © 2023

A Study of Long-Term Outcome of Mycophenolate Dose Modulation in Renal Allograft Recipients With SARS-CoV2 Infection During COVID-19 Pandemic

Introduction: A significant reduction of acute rejection rates was observed after using Mycophenolate mofetil (MMF) in renal transplant recipients (RTR). However, side-effects like hematological and gastrointestinal intolerance often occur when MMF is used in routine doses.MMF dose reduction is required during its side-effects or co-existing infection in RTR.The outcome of MMF dose modulation in RTR is not well established. COVID-19 pandemic has given an opportunity to study the effect of MMF dose modulation on graft function as large number of RTR who had Covid19 received MMF dose reduction or discontinuation. This study's objective was to determine whether MMF dose reduction or discontinuation was associated with the effect on allograft function after renal transplantation. We included all RTR who had an infection with SARS-CoV2 and received MMF dose reduction or discontinuation Methods: We prospectively collected data of Renal transplant recipients developing covid 19 infection during the first and second covid waves. Management including decision on admission, immunosuppression modulation, antibiotics were done based on clinician's discretion subject to logistics and the prevailing guidelines by the ISOT. All patients were followed up for minimum 15 months for graft dysfunction, biopsy rate, biopsy proven acute rejection ( BPAR). The effect of immunosuppression modulation - MMF cessation (Group A) Vs MMF reduction/no manipulation (Group B) and its bearing on the incidence of rejection and was compared. Additional factors such as follow - up sub therapeutic CNI levels, development of DSA ( when done ), steroid increment were studied regression model. Kaplan - meier survival curves for 24 months drawn. Result(s): Among 251 renal transplant patients with SARS-CoV2 infection, 38 patients died during Index admission. 45 patients has not completed for 15 months.168 patients completed 15 month follow - up. Among them, anti-metabolite were reduced in 115 ( 68.5%), stopped in 42 (25%), not manipulated in 5 ( 3%) and 6 patients were not on anti-metabolites and hence excluded from present analysis. Of the 162 patients, MMF had been stopped for 2 weeks or until presumed clinical recovery in 42 patients ( Group A) and the rest in 120 patients ( Group B). Mean age was 41.18 ( +/- 12.8) and 75.6 % had mild COVID. Median duration of follow-up was 18 months ( 14q1-22q3 months). Total Readmission rate was 66 ( 40.7%) (Group A 21( 50%) Vs Group B 45 ( 37.5 %). Graft Biopsy was done in 16% of patients. 9.3 % patients had acute rejection ( 11.9% Vs 8.3%, p 0.05). Among those who had rejection, ABMR was seen in 2, ACR in 3, CABMR in 5 and combined rejection in 1. Conclusion(s): MMF dose modulation to tackle an infectious episode may be associated with graft dysfunction and rejection on follow-up and close follow up is needed in any patient in whom MMF dose in manipulated No conflict of interestCopyright © 2023

Clinical Profile, Immunosuppressive Managment and Outcome in Adult Renal Allograft Recipients with Covid-19 Infection: A Case Series from Single Centre in Bangladesh

Introduction: The Novel Coronavirus disease 2019 (COVID-19), a respiratory infection has become a global concern. Given to the extent of the COVID-19 pandemic, it has been explored that Renal Allograft Recipients are considered high risk group for unfavourable outcome due to multiple comorbidities, long term immunosuppressive medications and residual CKD. This case series demonstrates clinical characteristics and outcome of COVID-19 infection in Renal Allograft Recipients. Method(s): Here we present 20 adult Renal Allograft Recipients admitted with moderate to severe symptom and RT PCR confirmed COVID-19 infection at united hospital limited from August 2020 to December 2021. We assessed demographic characteristics, comorbidities, clinical and laboratory parameters, radiological findings, immunosuppressive management and outcome. Result(s): Among all,15 patients were male with median age 55 years (range,34-75years). Mean time interval between renal transplantation were 90 months (24-132 months). Common comorbidities were hypertension (n=19), DM (n=18), lung diseases (n=13), IHD (n=9). Fever (100%) was most common symptom followed by cough(80%), sore throat(75%), and diarrhoea(60%). Nine (45%) patients who presented with dyspnoea during admission further progressed to poor outcome. During admission mean baseline creatinine was 1.51mg/dl(0.66-3.1 mg/dl), 15 patients had lymphopenia and 11 patients had higher inflammatory markers like high ferritin level, CRP, procalcitonin, LDH and D-dimer. Total 15 patients had abnormal HRCT findings and most common finding was unilateral or bilateral Ground glass opacity followed by consolidation, pleural effusion and interlobular septal thickening with mean TSS scoring being 8 (range 4-16). All patients were on triple immunosuppressive regimen (antimetabolites, CNI, low dose steroid).After admission antimetabolites were withdrawn in all patients, CNI were continued in 10 patients, 50% reduction in 2 patients, complete cessation of CNI in 8 patients and low dose steroids were switched to dexamethasone 6mg/ day. Other treatments included antiviral (Favipiravir, Remdisivir), antibiotics, LMWH followed by Rivaroxaban. Total 3 patients received Tocilizumab and Convalescent plasma was administered in 2 patients. Among all, 18 patients received different form of oxygen therapy, 9 patients were transferred to ICU, 7 patients required mechanical ventilation and 4 patients developed ARDS. 8 patients had other bacterial or fungal coinfection. six patients developed AKI and 2 of them needed Renal replacement therapy (RRT). Total 4 patients of AKI and 1 patient who required RRT finally expired. Total 6 patients died and after a median 18 days of admission. Conclusion(s): In this case series we describe 30% mortality rate. Older age, severe symptom specially dyspnoea during presentation, multiple comorbidities, high inflammatory markers, high baseline creatinine developing AKI, high TSS score at HRCT and requirement of mechanical ventilation were associated with high risk of death. No conflict of interestCopyright © 2023