Immunosuppressed Transplant Recipients Research Articles

#1245 Standard or personalized policy of peritoneal catheter removal at kidney transplantation?

Abstract Background and Aims The presence of peritoneal dialysis (PD) catheter in an immunosuppressed kidney transplant recipient can increment the risk of infectious complications after transplant. For this reason, it is thought that management of PD catheters at the time of transplant can have an impact on patient and graft outcomes. However, there is no agreement when to remove peritoneal dialysis catheter after transplantation. According to European Guidelines, the catheter can be left in situ for 3-4 months despite a functional graft. Our aim was to review the data from our center regarding infectious PD associated complications after kidney transplant. Method We retrospectively reviewed all 132 patients that were previously on PD and were admitted to our center for renal transplantation between January of 2013 and June of 2023, and had information regarding timing of removal of PD access. Simple descriptive and inferential statistics were used to generate results. Categorical data were described using frequency and percentage. Our main outcome was to assess the PD infectious catheter-associated complications. Our secondary outcomes were the timing of removal of PD catheter after renal transplantation, number of episodes of dialysis post transplantation, and kidney replacement therapy (KRT) used. Our follow up included the time from kidney transplantation (KT) until they removed PD catheter. Those who removed PD catheter at the timing of renal transplantation were excluded when evaluating the infectious complications. Results From the 132 kidney transplant recipients eight patients removed PD catheter at the time of the transplant due to ongoing PD associated infection. Sixty-nine patients were men (52.3%), with a median (IQR) age at transplantation of 48.4 years (41-57). Regarding donors’ characteristics, 88 (33.3%) were deceased, 21 of which were expanded criteria donors, and 44 (66.7%) were living donors. A total of 19 (14.4%) patients had history of PD infectious complications in the three months before transplantation. From the 124 patients that remained with the PD catheter after KT the adverse event infection occurred in 19 (15.3%) patients and two of these had previous access related infection in the 3 months interval before transplantation. The adverse events were: exit-site infection (ESI) 10.4% (n = 19), peritonitis 3% (n = 4) and tunnel infection 1.6% (n = 2). Half required hospitalization mainly due to center logistics for catheter removal. No deaths were registered. The identified microorganisms are present in Table 1. The median (IQR) time of removal of the PD catheter was 4 (3-5) months. Sixteen patients (12.9%) required KRT due to delayed graft function: ten patients used the Tenckhoff catheter and the rest performed haemodialysis (four using central venous catheter and two using arteriovenous fistula). Three patients remained dialysis dependent. When analysing the living donor group the rate of KRT was even lower, with three (6.8%) patients requiring dialysis, and only one used the PD catheter. Conclusion Despite the timing of PD catheter removal was according to the European Guidelines, the risk of PD catheter associated infections is not negligible (15.3%), not to mention the burden for the patient to keep an abdominal device demanding routinely care of the exit site. Peritonitis rate was low and comparable to previous studies. Considering the utility of remaining with the catheter, the risk of needing KRT, namely in living donor KT, was low. We postulate whether PD catheter removal at the time of KT should be considered, especially when the risk of late graft function is low, as in living donors, and/or the risk of PD catheter related infections is high. For this reason, we call for an individualized policy regarding catheter removal in the transition to KT.

Establishment of COS-BK cells persistently infected with archetype BK polyomavirus.

BK polyomavirus (BKPyV) was the first human polyomavirus to be isolated from an immunosuppressed kidney transplant recipient in 1971. BKPyV reactivation causes BKPyV-associated nephropathy and hemorrhagic cystitis. However, the mechanisms underlying BKPyV replication remain unclear. In the present study, we performed the long-term cultivation of COS-7 cells transfected with archetype KOM-5 DNA, which were designated as COS-BK cells. BKPyV derived from COS-BK cells was characterized by analyzing the amount of the virus based on hemagglutination, viral replication, and the production of viral protein 1 (VP1). Immunostaining showed that VP1-positive cells accounted for a small percentage of COS-BK cells. The nucleotide sequences encompassing the origin of the DNA replication of BKPyV derived from COS-BK cells were generated from KOM-5 by the deletion of an 8-bp sequence, which did not involve T antigen binding sites. BKPyV replicated most efficiently in COS-BK cells in DMEM containing 2% fetal bovine serum. These results indicate that COS-BK cells are a suitable culture system for studying the persistent infection of archetype BKPyV.

Humoral and cellular immune responses to COVID-19 mRNA vaccines in immunosuppressed liver transplant recipients

BackgroundLiver transplant recipients (LTRs) are at a high risk of severe COVID-19 owing to immunosuppression and comorbidities. LTRs are less responsive to mRNA vaccines than healthy donors (HDs) or other immunosuppressed patients. However, the disruption mechanism in humoral and cellular immune memory responses is unclear.MethodsWe longitudinally collected peripheral blood mononuclear cells and plasma samples from HDs (n = 44) and LTRs (n = 54) who received BNT162b2 or mRNA-1273 vaccines. We measured the levels of anti-receptor-binding domain (RBD) antibodies and spike-specific CD4+ and CD8+ T-cell responses.ResultsHere, we show that the induction of anti-RBD IgG was weaker in LTRs than in HDs. The use of multiple immunosuppressive drugs is associated with lower antibody titers than only calcineurin inhibitor, and limits the induction of CD4+ T-cell responses. However, spike-specific CD4+ T-cell and antibody responses improved with a third vaccination. Furthermore, mRNA vaccine-induced spike-specific CD8+ T cells are quantitatively, but not qualitatively, limited to LTRs. Both CD4+ and CD8+ T cells react to omicron sublineages, regardless of the presence in HDs or LTRs. However, there is no boosting effect of spike-specific memory CD8+ T-cell responses after a third vaccination in HDs or LTRs.ConclusionsThe third mRNA vaccination improves both humoral responses and spike-specific CD4+ T-cell responses in LTRs but provides no booster effect for spike-specific memory CD8+ T-cell responses. A third mRNA vaccination could be helpful in LTRs to prevent severe COVID-19, although further investigation is required to elicit CD8+ T-cell responses in LTRs and HDs.

Preexisting renal graft dysfunction as a major risk factor for SARS-CoV-2 Omicron variant pneumonia: A postinfection cross-sectional study of 312 immunosuppressed renal transplant recipients

ObjectivesSARS-CoV-2 pneumonia poses significant challenges to health systems worldwide, particularly, in severe and critical cases. Immunosuppressed renal transplant recipients appear to be at a particularly high risk for severe or critical COVID-19 illness. However, few studies elucidated the risk factors of SARS-CoV-2 pneumonia in renal transplant recipients with COVID-19. MethodsA postinfection cross-sectional survey was conducted in 312 renal transplant recipients and 503 age- and sex-matched controls to explore risk factors for SARS-CoV-2 pneumonia in immunosuppressed renal transplant recipients. ResultsThe results showed that renal transplant recipients had a much higher incidence of SARS-CoV-2 pneumonia (48.1%) after infection with the SARS-CoV-2 Omicron variant than controls (5.6%). The multivariate binary logistic regression analysis identified older age, lower creatinine clearance before infection, and higher dose of prednisone before infection as risk factors for SARS-CoV-2 pneumonia in renal transplant recipients. Preexisting renal dysfunction was a major risk factor for SARS-CoV-2 pneumonia, with an odds ratio of 3.27 (1.01-10.61). ConclusionsPreexisting renal graft dysfunction was a major risk factor for SARS-CoV-2 Omicron variant pneumonia. It is suggested that high-risk renal transplant recipients should undergo computed tomography scanning within 14 days after infection with SARS-CoV-2.

Incidence, Management and Outcome of Post-Transplant Lymphoproliferative Disease after 5797 Solid-Organ Transplants over a 30-Year Period in a Single Hospital

Introduction: Post-transplant lymphoproliferative disorders (PTLD) are heterogenous lymphoproliferative disorders that develop because of immunosuppression in transplant recipients. Epstein-Barr Virus (EBV) infection is a major risk factor for the development of PTLD. Its management generally involves a reduction in immunosuppression and initial treatment with rituximab monotherapy (RM). Aim: To present the epidemiology, management, and outcomes of PTLD in a large unicentric Spanish cohort of solid organ transplant (SOT) recipient who were transplanted over a 30-year period. Methods: This is a retrospective study of 5797 SOT recipients who had their first transplant between 1992 and 2021 at Hospital Universitario 12 de Octubre. For each type of transplant, we calculated the incidence rate of PTLD. OS (Overall survival) was analyzed using the Kaplan-Meier model and the log-rank test Prognostic impact of the main clinical, analytical variables and prognostic indexes were analyzed. Results: With a median follow-up of 16.4 years, 105 of 5797 SOT developed a monomorphic or Hodking-like PTLD (1.8%). The incidence was: 10% multivisceral transplantation (MVT), 2.8% heart, 2.3% liver, 2.2% lung, 1.4% kidney and 1.3% simultaneous kidney-pancreas (SPK). Median age at transplant was 48.3 (1-89) years. 12 were pediatric recipients' (1 lung, 1 kidney, 10 liver). 72% were men. Histochemical stains for Epstein-Barr virus (EBV) were performed in 75 of 105 diagnoses. EBER-positive histology was observed in the majority of patients (n = 44/77, 57%). Median time from transplantation to PTLD was 6.7 (0-16.4) years (21% in the 1st year post-transplant). In EBER-positive the onset was earlier (3.2 vs 9.2 years; p: .004) with 36% arising the 1st year post-transplant. 5-years cumulative incidence was 10% in MTV compared to 0.18%-1.6% in the rest. With a median follow-up of 6.9 years; median OS was 79.5 months, with no difference between type of organ transplanted, era of transplant, EBER histology or time from transplant to PTLD. Using logistic regression, age, beta-2-microglobulin (B2M), as well as the IPI, modified R-IPI, NCCN-IPI and GELTAMO-IPI prognostic indices were found to be significant prognostic factors for OS ( Table 1). Interestingly, the highest OS stratification was observed with the modified R-IPI, showing a median OS not reached in the low-risk group, versus 38 months at high risk and 3.2 months at very high risk (p<0.001). Immunosuppression (IS) was switched as the 1st therapeutic aptitude in 57% of the patients. Median OS was not reached in patients with IS switch (n=41) (plateau at 10 years; estimated OS 56%) vs. 15.3m for patients without IS switch (n=39) (P: .004) ( Figure 1). IS was reduced in 80%. It also reached OS impact (P: .05). There were 89 monomorphic patients who were treated as follows: RM (n=22), R-Chemotherapy (n=37), chemotherapy (n=6), no treatment (n=7), unknown (n=16). Of the 22 RM patients, 9 (41%) achieved complete remission (CR) with RM and required no further treatment. In the R-Chemotherapy (n=37) group (70% R-CHOP), 26 (70%) reached CR. There was no significant difference in OS between the two groups. 8/22 (36%) died in the RM group (2/22 (9%) due progressive disease (PD), 2/22 (9%) died pre-remission of non-PTLD causes and 4/37 (18%) died in remission of unrelated causes). In the R-Chemo group 8/37 (48%) patients dead (4/37 (10%) patients died of PD, 6/37 (16%) died pre-remission of non-PTLD causes and 8/37 (22%) died in remission of unrelated causes). Conclusion: With this SOT cohort from a center with long experience we demonstrated an incidence of PTLD of 1.8%. EBV positive PTLD emerged sooner but OS was similar to those EBV negative. Stablished prognostic indices in DLBCL such as IPI, NCCN-IPI, and modified R-IPI were also applicable in PTLD. The modified R-IPI showed the best separation between the groups. Switch or reduction of the IS is an essential point to improve its prognosis. Our data suggest that first-line RM is an interesting option to consider. Strategies to tailor treatment with the least possible toxicity are necessary in these vulnerable patients. Additionally, our results suggest the utility of modified R-IPI in the clinical practice of PTLD and may serve as a basis for the development of specific prognostic models for this entity.

INVASIVE TRICHOSPORON INFECTION IN A SARS-COV-2 AND INFLUENZA COINFECTED PATIENT: A CASE REPORT

Trichosporon species can cause systemic or mucosal-associated or superficial infections, including white piedra, as well as invasive fungal infections. They can be an opportunistic cause of invasive infection, especially in patients with hematological malignancies and solid organ tumors or immunosuppressed transplant recipients. There has been an increase in invasive infections due to Trichosporon species in recent years. Treatment of patients with trichosporonosis poses a problem due to limited data regarding the antifungal agents used. In this article, we present a case that resulted in death as a result of invasive trichosporonosis infection that developed after a long stay in intensive care due to co-infection of COVID-19 and influenza.

SAT239 Deceased Donor Parathyroid Allotransplant For Sever Refractory Iatrogenic Hypoparathyroidism

Abstract Disclosure: K.M. Devon: None. A. Zahedi: None. A. Madani: None. J.D. Pasternak: None. B. Saravana-Bawan: None. A. Humar: None. T. Kathryn: None. While Halstead experimented with dog parathyroid transplantation, the first reported human parathyroid allotransplant appeared in the Annals of Surgery in 1911. Efforts of varying success in restoring calcium homeostasis in patients with refractory hypoparathyroidism after thyroidectomy have included parathyroid transplantation(tx), mainly in immunosuppressed kidney transplant recipients, using cryopreserved, cultured, or hypercellular tissues. Recently, cases of living-donor parathyroid allotransplants have been reported. We present a 46 year-old woman who developed hypoparathyroidism following total thyroidectomy 9 years prior. Treatment included two years of continuous teriparatide via CAD pump. Complications of portacath sepsis and pulmonary emboli, required intensive care. At the time of transplantation, our patient was taking elemental calcium 16 grams daily, magnesium 12 grams daily, calcitriol 8 ug daily, hydroochlorothiazide 25 mg twice daily, and nonetheless requiring biweekly intravenous calcium for symptoms and Calcium levels of 1.6 mmol/l (2.2-2.6 mmol/L). PTH ranged between 0.6- 1.2 pmol/l with poor quality of life. A medically suitable neurologically deceased donor was identified through the provincial organ donation organization. Her cumulative cPRA was 98% (Class I-95%/II-81%). Virtual crossmatch only positive for DQ2 specificity with weak positive B-cell flow crossmatch. Four healthy parathyroids were retrieved. The tissue was minced and placed into pockets in the recipient’s right brachioradialis muscle, under local anaesthesia with sedation. Ischemic time was 2.5 hours. She was induced with basiliximab and received tacrolimus, mycophenolate, and prednisone as immunotherapy. Evidence of biochemical parathyroid function was present post-tx day 9, and she was weaned off all calcium homeostatic medications by day 35, remaining asymptomatic at 7 months at the time of writing, with no calcium infusions. Self-reported quality of life is significantly improved. PTH 0.8-2.8 pmol/L and Calcium 2.06-2.37 mmol/l. To our knowledge this is the first successful fresh normal tissue deceased donor parathyroid transplant in a non-transplant recipient in North America. One study suggests that despite immunosuppression risks, 14 percent of patients would entertain parathyroid allotransplantation. We are currently recruiting additional patients with the aim of demonstrating that deceased donor parathyroid allotransplant using fresh tissue and immunosuppression is a novel viable and curative approach to treat permanent severe hypoparathyroidism. Presentation: Saturday, June 17, 2023

Local blockade of tacrolimus promotes T-cell-mediated tumor regression in systemically immunosuppressed hosts

BackgroundImmunosuppressive drugs such as tacrolimus have revolutionized our ability to transplant organs between individuals. Tacrolimus acts systemically to suppress the activity of T-cells within and around transplanted organs. However, tacrolimus...

An analysis of iris pattern as a risk factor for skin cancer development in immunosuppressed renal transplant recipients.

Renal transplant recipients are at increased risk of keratinocyte skin cancers with a tendency to have multiple, aggressive and difficult to treat tumours. The eye and the skin share the same embryological ectoderm. Iris pattern has recently been reported as a predictive risk factor for skin cancer in non-immunosuppressed Southern European (Grigore et al., J Eur Acad Dermatol Venereol, 2018, 1662) and Irish populations (Ridge et al., J Eur Acad Dermatol Venereol, 2022, e542). To analyse if an individual's iris pattern is an independent risk factor for the development of keratinocyte skin cancers in renal transplant recipients. Iris patterns of 110 renal transplant recipients were evaluated using the Simionescu visual three-step technique (iris periphery, colarette and iris freckling [Simionescu et al., Ann Res Rev Biol, 2014, 2525]). Established risk factors for skin cancer in transplant patients were recorded as confounding factors. Observational cross-sectional study including 110 renal transplant population. Thirty-one participants had skin cancer. In the skin cancer group, iris periphery was blue/grey in 74.3% (p = 0.053, OR 2.5), the colarette was light brown in 57.1% (p < 0.0043) and iris freckles were present in 55%(p = 0.044). Dark brown and blue colarettes were observed in controls. Binary Logistic Regression analysis showed light brown colarette is a significant independent risk factor for skin cancer (OR 4.54, p < 0.02, CI 1.56-10.57). Within this renal transplant population a blue iris periphery, light brown colarette and presence of freckling confers an independent risk for keratinocyte skin cancer. Iris pattern is a useful tool for identification of transplant patients at risk of keratinocyte skin cancer and an easy-to-use technique for risk evaluation in this cohort. This is the first study looking at iris pattern and keratinocyte skin cancer risk in renal transplant population.

Delayed and Attenuated Antibody Responses to Coronavirus Disease 2019 Vaccination With Poor Cross-Variant Neutralization in Solid-Organ Transplant Recipients-A Prospective Longitudinal Study.

Therapeutically immunosuppressed transplant recipients exhibit attenuated responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines. To elucidate the kinetics and variant cross-protection of vaccine-induced antibodies in this population, we conducted a prospective longitudinal study in heart and lung transplant recipients receiving the SARS-CoV-2 messenger RNA (mRNA) 3-dose vaccination series. We measured longitudinal serum antibody and neutralization responses against the ancestral and major variants of SARS-CoV-2 in SARS-CoV-2-uninfected lung (n = 18) and heart (n = 17) transplant recipients, non-lung-transplanted patients with cystic fibrosis (n = 7), and healthy controls (n = 12) before, during, and after the primary mRNA vaccination series. Among healthy controls, strong anti-spike responses arose immediately following vaccination and displayed cross-neutralization against all variants. In contrast, among transplant recipients, after the first 2 vaccine doses, increases in antibody concentrations occurred gradually, and cross-neutralization was completely absent against the Omicron B.1.1.529 variant. However, most (73%) of the transplant recipients had a significant response to the third vaccine dose, reaching levels comparable to those of healthy controls, with improved but attenuated neutralization of immune evasive variants, particularly Beta, Gamma, and Omicron. Responses in non-lung-transplanted patients with cystic fibrosis paralleled those in healthy controls. In this prospective, longitudinal analysis of variant-specific antibody responses, lung and heart transplant recipients display delayed and defective responses to the first 2 SARS-CoV-2 vaccine doses but significantly augmented responses to a third dose. Gaps in antibody-mediated immunity among transplant recipients are compounded by decreased neutralization against Omicron variants, leaving many patients with substantially weakened immunity against currently circulating variants.

Establishment and characterization of a novel reverse genetic system of BK polyomavirus.

BK polyomavirus (BKV) is a small non-enveloped DNA virus. BKV infection or reactivation may cause BKV-associated nephropathy and hemorrhagic cystitis in immunosuppressed transplant recipients. No effective antivirals or prevention strategies are available against BKV infections. The current BKV reverse system employs the transfection of purified full-length linear viral genomes released by enzyme digestion from BKV genomic plasmids. The method is laborious and often results in variable DNA yield and quality, which can affect the efficiency of transfection and subsequent formation of circular viral genomes in cells. In this study, we report the generation of circular viral genomes by Cre-mediated DNA recombination in cells directly transfected with BKV precursor genomic plasmids. The novel system supported efficient viral expression and replication, and produced a higher level of infectious virions compared with the transfection with linear BKV genomes. Furthermore, we successfully constructed recombinant BKV capable of reporter gene expression. In conclusion, the novel BKV reverse genetic system allows for simpler manipulation of BKV genome with better virus yield, providing a tool for the study of BKV life cycle and antiviral screening.

Identification of Genetic Risk Factors for Keratinocyte Cancer in Immunosuppressed Solid Organ Transplant Recipients: A Case-Control Study

Because of long-term immunosuppression, solid organ transplant recipients are at increased risk for keratinocyte cancer. We matched solid organ transplant patients (n = 150), cases with keratinocyte cancers and tumor-free controls, considering the most important risk factors for keratinocyte cancer in solid organ transplant recipients. Using whole exome data of germline DNA from this patient cohort, we identified several genetic loci associated with the occurrence of multiple keratinocyte cancers. We found one genome-wide significant association of a common single nucleotide polymorphism located in EXOC3 (rs72698504). In addition, we found several variants with a p-value of less than 10−5 associated with the number of keratinocyte cancers. These variants were located in the genes CYB561, WASHC1, PITRM1-AS1, MUC8, ABI3BP, and THBS2-AS1. Using whole exome sequencing data, we performed groupwise tests for rare missense variants in our dataset and found robust associations (p &lt; 10−6, Burden Zeggini test) between MC1R, EPHA8, EPO, MYCT1, ADGRG3, and MGME1 and keratinocyte cancer. Thus, overall, we detected genes involved in pigmentation/UV protection, tumor suppression, immunomodulation, intracellular traffic, and response to UV as genetic risk factors for multiple keratinocyte cancers in solid organ transplant recipients. We also grouped selected genes to pathways and found a selection of genes involved in the “cellular response to UV” to be significantly associated with multiple keratinocyte cancers.

BI02 Disseminated toxoplasmosis presenting as panniculitis in an immunocompromised patient

Abstract Inflammatory dermatoses and inflammatory reaction patterns to underlying systemic disease are relatively uncommon in immunosuppressed organ transplant recipients (OTRs) and infection should always be suspected as a possible cause. We present an OTR with biopsy-proven panniculitis resulting from disseminated toxoplasmosis, only identified after extensive histological analysis. A 45-year-old Nigerian woman who was profoundly immunocompromised through a combination of a kidney transplant 12 months earlier, hyposplenism due to sickle cell anaemia and a CD4+ count 74 × 106 cells L–1 (&amp;gt; 455 × 106 L–1) presented with a 3-month history of &amp;gt; 20 painful, red–purple and hyperpigmented subcutaneous nodules and plaques up to 2 cm in diameter limited to her legs, associated with fatigue and weight loss. She only had childhood contact with cats. There was no lymphoedema or lymphadenopathy, and she was HIV negative. Urgent skin biopsy excluded Kaposi sarcoma and demonstrated a lobular, necrotizing panniculitis, a mixed inflammatory cell infiltrate and evidence of vasculitis. The cause was unclear; cultures for mycobacterial, fungal and bacterial infections were negative. However, on rereview of histology, within areas of inflammation and necrosis in the subcutaneous fat, there were a few scattered structures (10–30 μm in diameter) consisting of small basophilic periodic acid–Schiff-positive ‘dots’ within bright eosinophilic cytoplasm, raising the possibility of toxoplasmosis. Toxoplasma immuno­staining was positive. Further tertiary review of histology and immunostaining by the Hospital for Tropical Diseases agreed that there was no other causative organism and the panniculitis and vasculitis were consistent with active toxoplasmosis. The diagnosis of toxoplasma reactivation was supported by positive toxoplasma IgG on pretransplant bloods. Magnetic resonance imaging of the head was consistent with cerebral toxoplasmosis. She received treatment with clindamycin, pyrimethamine and folinic acid and, thereafter, long-term cotrimoxazole prophylaxis. Cutaneous toxoplasmosis is rare, with only three reported cases over the last 10 years. Historically, a wide spectrum of clinical morphologies has been described, including maculopapular rashes, nodules, ulcers, dermatomyositis and even mimicry of varicella and graft-versus-host disease. Most cases affect immunocompromised patients. In our patient, this was the result of reactivation of latent infection, which is more common in West Africa, coinciding with profound immunosuppression. In our case, a diagnosis was only made after extensive histological review. Given the varied morphologies of clinical presentations, it is possible that this condition may be easily missed, with potentially serious consequences. In summary, we highlight the importance of maintaining a high index of suspicion for infection and the need for careful clinicopathological correlation in OTRs presenting with apparently atypical inflammatory skin lesions.

Invasive fungal sinusitis risk factors among immunosuppressed hematopoietic stem cell transplant recipients.

Invasive fungal sinusitis (IFS) rate and risk factors in transplant recipients were explored IFS rate is higher in allogeneic recipients with prior transplants and worse comorbidity scores The at-risk timeframes for IFS development were identified.

αβ and γδ T-cell responses to Epstein-Barr Virus: insights in immunocompetence, immune failure and therapeutic augmentation in transplant patients.

Epstein-Barr Virus (EBV) is a human gamma herpes virus, which causes several diseases in immunocompetent (mononucleosis, chronic fatigue syndrome, gastric cancer, endemic Burkitt's lymphoma, head and neck cancer) and immunosuppressed (post-transplant lymphoproliferative disease, EBV-associated soft tissue tumors) patients. It elicits a complex humoral and cellular immune response with both innate and adaptive immune components. Substantial progress has been made in understanding the interplay of immune cells in EBV-associated diseases in recent years, and several therapeutic approaches have been developed to augment cellular immunity toward EBV for control of EBV-associated malignancy. This review will focus on recent developments in immunosuppressed transplant recipients.

Successful Kidney Transplantation of Two Patients with Donors Positive for Severe Acute Respiratory Syndrome Coronavirus Infection

Despite preventative measures, including vaccination, severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection may result in severe illness, particularly in immunosuppressed transplant recipients. This has had a negative impact on organ donation and transplantation rates. However, the risk of transmission from SARS-CoV-2 positive donors to kidney transplant recipients is unknown. We describe 2 cases of successful kidney transplantation from SARS-CoV-2 positive donors. Case 1: 38-year old unvaccinated female, established on haemodialysis for 1 year, with underlying reflux nephropathy. Donor tested SARS-CoV-2 positive on polymerase chain reaction testing with a cycle threshold (CT) value of 29 initially. Sequential testing demonstrated a rise in CT value (37.8), aiding the decision to proceed. The recipient was high immunological risk and received a controlled category 3 donation after circulatory death (DCD) kidney transplant. She had immediate graft function and did not develop SARS-CoV-2 infection. Case 2: 63-year old female, with diabetes mellitus and hypertension. She was low immunological risk and for pre-emptive transplantation. The donor was SARS-CoV-2 positive with a CT value of 41.5 and was subsequently negative. Decision was made to proceed with a donation after brainstem death (DBD) transplant. The recipient had immediate graft function and did not develop SARS-CoV-2 infection. We report 2 cases of successful transplantation from SARS-CoV-2 positive donors, without severe infection, with no transmission seen in the recipients post-operatively. Decisions to proceed were primarily made on clinical grounds with assistance from RT-PCR CT values, making this a useful additional tool in determining suitability of organ donation in people who are SARS-CoV-2 positive.

Importance of Physiotherapy in Post Pneumonectomy Renal Transplant Recipient: A Case Report

Pulmonary mucormycosis is a rare but opportunistic fungal infection that complicates immunosuppressed solid organ transplant recipients. Although antifungal medication is the remedial dependence in management of pulmonary mucormycosis, early surgical intervention provides advantage over medical treatment alone. However, major impairments and complications such as altered pulmonary and physical function induced by surgery are known to occur. We report the case of a 25-year-old male post renal transplantation on immunosuppression who developed invasive pulmonary mucormycosis in right middle and lower lobe. Liposomal Amphotericin B therapy provided insufficient infection control and lesion invaded the adjacent chest wall, ribs and intercostal muscles. After right pneumonectomy combined with anterior chest wall resection, the initial post-operative physiotherapy assessment was carried out. The patient was found to have productive cough, dyspnoea, chest pain, reduced chest expansion and excursion, limited range of motion of shoulder on affected side and limited activities of daily living. Six weeks of inpatient physiotherapy regime was given which included breathing exercises, thoracic mobility exercises, incentive spirometry, active range of motion exercises, positioning, bed mobility and early ambulation. Follow up assessment showed reduced pain intensity and improvement in oxygen saturation, dyspnoea, Timed up and go test (TUG) time, handgrip strength, activities of daily living and quality of life [Short form 36 (SF-36)]. Keywords: Pneumonectomy, Thoracic Surgery, Renal Transplant, Physiotherapy

Nicotinamide for Skin-Cancer Chemoprevention in Transplant Recipients

BackgroundImmunosuppressed organ-transplant recipients have an increased incidence of, and mortality from, skin cancer. Nicotinamide (vitamin B3) enhances the repair of ultraviolet (UV) radiation–induced DNA damage, reduces the cutaneous immunosuppressive effects of UV radiation, and reduces the incidence of keratinocyte cancers (including squamous-cell and basal-cell carcinomas) and actinic keratoses among high-risk immunocompetent patients. Whether oral nicotinamide is useful for skin-cancer chemoprevention in organ-transplant recipients is unclear.MethodsIn this phase 3 trial, we randomly assigned, in a 1:1 ratio, organ-transplant recipients who had had at least two keratinocyte cancers in the past 5 years to receive 500 mg of nicotinamide or placebo twice daily for 12 months. Participants were examined for skin lesions by dermatologists at 3-month intervals for 12 months. The primary end point was the number of new keratinocyte cancers during the 12-month intervention period. Secondary end points included the numbers of squamous-cell and basal-cell carcinomas during the 12-month intervention period, the number of actinic keratoses until 6 months after randomization, safety, and quality of life.ResultsA total of 158 participants were enrolled, with 79 assigned to the nicotinamide group and 79 to the placebo group. The trial was stopped early owing to poor recruitment. At 12 months, there were 207 new keratinocyte cancers in the nicotinamide group and 210 in the placebo group (rate ratio, 1.0; 95% confidence interval, 0.8 to 1.3; P=0.96). No significant between-group differences in squamous-cell and basal-cell carcinoma counts, actinic keratosis counts, or quality-of-life scores were observed. Adverse events and changes in blood or urine laboratory variables were similar in the two groups.ConclusionsIn this 12-month, placebo-controlled trial, oral nicotinamide therapy did not lead to lower numbers of keratinocyte cancers or actinic keratoses in immunosuppressed solid-organ transplant recipients. (Funded by the National Health and Medical Research Council; ONTRANS Australian New Zealand Clinical Trials Registry number, ACTRN12617000599370.)

Relationship of Post-Transplant Lymphoproliferative Disorders (PTLD) Subtypes and Clinical Outcome in Pediatric Heart Transplant Recipients: A Retrospective Single Institutional Analysis/Experience of 558 Patients.

Post-transplant lymphoproliferative disorders (PTLD) are heterogenous lymphoproliferative disorders that develop as a consequence of immunosuppression in transplant recipients. We sought to determine if subtypes of PTLD correlated with different outcomes. We performed a retrospective review of PTLD occurring in pediatric heart transplant recipients. A total of 558 children and infants underwent cardiac transplantation at our institution between 1985 and 2019 and were followed until March 2021. Forty-nine of 558 patients developed PTLD (8.8%). As compared to older children (>one year of age), infant recipients (<three months of age) were less likely to develop PTLD. Monomorphic PTLDs (M-PTLD, 61%) was the most common subtype at initial diagnosis, followed by non-destructive (21%), polymorphic (14%), and classic Hodgkin lymphoma (cHL, 4%). Patients who underwent transplantation at a young age (<three months) had significantly lower rates of M-PTLD or cHL and a longer time from transplant to PTLD diagnosis as compared to children older than one year at transplant (p = 0.04). Although not reaching statistical significance, patients with a shorter time to PTLD diagnosis showed a trend toward higher rates of M-PTLD or cHL. As expected, the overall survival (OS) of patients with M-PTLD or cHL was significantly lower than patients with non-destructive or polymorphic PTLD.

Delta-Omicron recombinant escapes therapeutic antibody neutralization

The emergence of recombinant viruses is a threat to public health, as recombination may integrate variant-specific features that together result in escape from treatment or immunity. The selective advantages of recombinant SARS-CoV-2 isolates over their parental lineages remain unknown. We identified a Delta-Omicron (AY.45-BA.1) recombinant in an immunosuppressed transplant recipient treated with monoclonal antibody Sotrovimab. The single recombination breakpoint is located in the spike N-terminal domain adjacent to the Sotrovimab binding site. While Delta and BA.1 are sensitive to Sotrovimab neutralization, the Delta-Omicron recombinant is highly resistant. To our knowledge, this is the first described instance of recombination between circulating SARS-CoV-2 variants as a functional mechanism of resistance to treatment and immune escape.