A Prospective Randomised, Controlled Trial Switching Sirolimus for Mycophenolate to Enhance Immunological Responses to Third Dose COVID-19 Vaccination in Kidney Transplant Recipients with Poor Baseline Humoral Immunity

Purpose: Kidney transplant recipients (KTR) have inadequate responses to 2-dose COVID vaccination schedules and are at increased risk of severe COVID-19. Formation of T cell memory following vaccination is regulated by mTOR complex 1. mTOR inhibitors have been used in pre-clinical models to boost vaccine-elicited cytotoxic T cell memory responses. In observational studies, KTR receiving mTOR inhibitors had improved serological neutralisation and SARS-CoV-2 reactive T cell responses to 2 doses of COVID-19 vaccine, including cytotoxic T cells and circulating T follicular helper cells. We performed a clinical trial in stable KTR using sirolimus as a substitute for mycophenolate prior to a 3rd dose of COVID-19 vaccine to enhance COVID-19 vaccine responses. Method(s): KTR receiving tacrolimus, mycophenylate and corticosteroid with inadequate response to 2 doses of a COVID vaccine (defined by anti-RBD IgG <100U/ mL) and no history of COVID infection were recruited from 2 Australian transplant centres. Patients were randomised in a 1:1 ratio to continue mycophenolate maintenance or switch to sirolimus (trough level target 6 ng/mL). All patients received a 3rd dose of BNT162b2 COVID-19 vaccine and had immunological responses measured 4-6 weeks later. Result(s): 54 patients were randomised to sirolimus switch (n = 28), or control (n = 26). Patients were 70% male, mean age 57.5 years (SD10.4), with mean graft age 6.2 years (SD 5.4). Mean serum trough concentrations of sirolimus and tacrolimus were 6.4 and 6.1 respectively. There have been no safety or tolerability issues in the sirolimus cohort with stable serum creatinine (mean 117.8 vs 119.3, p=0.6), and mild increase in urinary ACR (mean 5.4 vs 17.4, p=0.1). Final results including immunological testing will be collated March 2022. Conclusion(s): Sirolimus switch is safe and well-tolerated. This trial will determine whether the strategy of mTOR inhibitor therapy peri-vaccination can optimise vaccine immune responses against COVID-19 in KTR.

A Randomized, Controlled, Double-Blind Trial of Inulin to Boost Response to a Third COVID-19 Vaccine Dose in Kidney Transplant Recipients

Purpose: Kidney transplant recipients (KTR) commonly exhibit inadequate responses to 2-dose COVID-19 vaccination schedules and remain at increased risk of severe COVID-19. Gut dysbiosis is common among KTRs and has been associated with poor vaccine responses. We hypothesised that a dietary fibre supplement may correct dysbiosis and enhance responses to a third dose of COVID-19 vaccine in KTRs. Method(s): KTRs who had received 2 doses of a COVID-19 vaccine were recruited from 2 transplant programs in Australia. KTRs with an inadequate response (defined by anti-RBD <100U/mL) were randomised to receive inulin (fibre) or maltodextran (control), 10g dissolved in 200ml water twice daily for 4 weeks prior to, and 4 weeks after a 3rd vaccine, at which time vaccine response was measured by anti-RBD titre, vaccine-specific B and T cell responses, and changes in the gut microbiome. Patients and investigators were blinded to treatment assignment. COVID-19 infection was excluded by measurement of anti-nucleocapsid antigen. Result(s): Of 85 KTRs screened, 71 had baseline anti-RBD<100U/mL and were randomised to inulin (n=37) or control (n=34). Participants were 33% female, mean age 59 yrs (SD 11), with mean eGFR 56 ml/min/1.73m2 (SD 24.8), and were most commonly receiving tacrolimus, mycophenolate and prednisolone. All participants received a third dose of a mRNA COVID-19 vaccine after receiving a dietary supplement for 4 weeks. Week 8 assessment of vaccine response, supplement tolerability and change in microbiome are ongoing. Four participants tested positive for COVID-19 during the study. Conclusion(s): Gut dysbiosis is one potential contributor to the poor COVID-19 vaccine responses exhibited by KTRs. This trial will determine whether a simple dietary fibre supplement is well tolerated and effective in correcting gut dysbiosis and restoring vaccine responsiveness. Improved vaccine responses are urgently required to better protect KTRs from ongoing morbidity and mortality from COVID-19.

Sirolimus Use is Associated with an Improved Immune Response to COVID-19 Vaccination in Kidney Transplant Recipients

Purpose: Kidney transplant recipients (KTRs) are highly vulnerable to severe COVID-19, however are poorly protected by vaccination. Additional vaccine doses have achieved limited improvements in serological neutralisation or T cell response. A novel strategy to boost vaccine response is needed. Method(s): KTRs (n=80) and healthy cohabitants (HCs;n=80) were recruited from a transplant centre in South Australia to undergo a 2-dose vaccination schedule with BNT162b2 or ChAdOx1. KTRs were most commonly receiving the standard-of-care (SOC) triple therapy: tacrolimus, mycophenolate mofetil, prednisolone. Following 2 vaccine doses (median 21 days;IQR 21-24), spike-specific IgG and T cell responses (by IFNgamma ELISpot) were measured to assess vaccine immunogenicity, and live virus neutralisation and anti-receptor binding domain (RBD) IgG (Elecsys, Roche) were evaluated as correlates of protection from infection and disease. In an extended cohort comparing SOC (n=15) and sirolimus-inclusive (n=15) protocols, function and phenotype of antigen-specific T cells were further interrogated by flow cytometry. Result(s): Vaccine immunogenicity was profoundly reduced in KTRs, with a >1,000- fold lower median anti-spike IgG titre, and >10-fold lower median antiviral T cell response relative to HCs. Thresholds for protective anti-RBD IgG (100 U/mL) and serological neutralisation (50% neutralisation at a serum dilution of 1/40) were achieved by 6.7% and 10.9% of KTRs, respectively, and by 100% of cohabitants. In an extended cohort, patients on mTOR inhibitors (mTORi;sirolimus or everolimus) achieved 4-fold higher rates of serological neutralisation than those on SOC therapy (34.6% vs 7.9%). Remarkably, sirolimus use was associated with a median antiviral T cell response 55-fold greater than SOC therapy, and 5-fold greater than HCs. SARSCoV- 2-specific CD4+ and CD8+ T cells in these patients were highly polyfunctional and formed robust central memory out to 3 months post second vaccine dose. Conclusion(s): These data underscore priority vaccination of cohabitants as an effective strategy to protect KTRs, and support a randomised controlled trial of immunosuppression modification with sirolimus as a strategy to directly improve vaccine responses in KTRs.

Analysis of the impacts of the COVID-19 pandemic on the drinking milk supply chain in Austria by means of a business process modelling and System Dynamics approach

Dairy farming is an important branch of agricultural production for the supply of the Austrian population with domestic food. This paper examines the impact of the COVID-19 pandemic on the Austrian drinking milk supply chain. For this purpose, a tripartite approach was chosen consisting of a process description using Business Process Model and Notation (BPMN), a qualitative System Dynamics analysis with a Causal Loop Diagram (CLD), and the use case of the COVID-19 pandemic in the year 2020 in Austria. The results show that the drinking milk supply chain is complex and consists of many individual process steps. However, the number of locations that are passed through during drinking milk production is rather small. The CLD revealed that reinforcing feedback loops occur in the provision of packaging material and the availability of dairy staff. Analysis of the use case showed that the system of dairy production in Austria is stable in the tested scenario, and that the supply chains preserved their function also during the pandemic. Dairies with diverse product ranges were able to react more easily to the massively changed demand situation. The insights gained by this research may be used to increase the resilience of the drinking milk supply chain. Furthermore, the methodological approach can be transferred and used to analyse the supply chains of other foods. © 2021 Johanna Singer et al., published by Sciendo.

Acute Kidney Injury and Renal Replacement Therapy in COVID-19 Versus Other Respiratory Viruses: A Systematic Review and Meta-Analysis.

BACKGROUND: Acute kidney injury (AKI) is a potentially fatal complication of Coronavirus Disease-2019 (COVID-19). Binding of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, to its viral receptor, angiotensin converting enzyme 2 (ACE2), results in viral entry and may cause AKI. OBJECTIVES: We performed a systematic review and meta-analysis of the frequencies of AKI and renal replacement therapy (RRT) in critically ill COVID-19 patients and compared those frequencies with patients who were infected by respiratory viruses that bind or downregulate ACE2 (ACE2-associated viruses) and viruses that do not bind nor downregulate ACE2 (non-ACE2-associated viruses). DESIGN: Systematic review and meta-analysis. SETTING: Observational studies on COVID-19 and other respiratory viral infections reporting AKI and RRT were included. The exclusion criteria were non-English articles, non-peer-reviewed articles, review articles, studies that included patients under the age of 18, studies including fewer than 10 patients, and studies not reporting AKI and RRT rates. PATIENTS: Adult COVID-19, Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS), and influenza patients. MEASUREMENTS: We extracted the following data from the included studies: author, year, study location, age, sex, race, diabetes mellitus, hypertension, chronic kidney disease, shock, vasopressor use, mortality, intensive care unit (ICU) admission, ICU mortality, AKI, and RRT. METHODS: We systematically searched PubMed and EMBASE for articles reporting AKI or RRT. AKI was defined by authors of included studies. Critical illness was defined by ICU admission. We performed a random effects meta-analysis to calculate pooled estimates for the AKI and RRT rate within each virus group using a random intercept logistic regression model. RESULTS: Of 23 655 hospitalized, critically ill COVID-19 patients, AKI frequencies were not significantly different between COVID-19 patients (51%, 95% confidence interval [CI]: 44%-57%) and critically ill patients infected with ACE2-associated (56%, 95% CI: 37%-74%, P = .610) or non-ACE2-associated viruses (63%, 95% CI: 43%-79%, P = .255). Pooled RRT rates were also not significantly different between critically ill, hospitalized patients with COVID-19 (20%, 95% CI: 16%-24%) and ACE2-associated viruses (18%, 95% CI: 8%-33%, P = .747). RRT rates for both COVID-19 and ACE2-associated viruses were significantly different (P < .001 for both) from non-ACE2-associated viruses (49%, 95% CI: 44%-54%). After adjusting for shock or vasopressor use, AKI and RRT rates were not significantly different between groups. LIMITATIONS: Limitations of this study include the heterogeneity of definitions of AKI that were used across different virus studies. We could not match severity of infection or do propensity matching across studies. Most of the included studies were conducted in retrospective fashion. Last, we did not include non-English publications. CONCLUSIONS: Our findings suggest that viral ACE2 association does not significantly alter the rates of AKI and RRT among critically ill patients admitted to the ICU. However, the rate of RRT is lower in patients with COVID-19 or ACE2-associated viruses when compared with patients infected with non-ACE2-binding viruses, which might partly be due to the lower frequencies of shock and use of vasopressors in these two virus groups. Prospective studies are necessary to demonstrate whether modulation of the ACE2 axis with Renin-Angiotensin System inhibitors impacts the rates of AKI and whether they are beneficial or harmful in COVID-19 patients.

MISE EN CONTEXTE: L'insuffisance rénale aiguë (IRA) est une complication potentiellement mortelle de la maladie à coronavirus-2019 (COVID-19). Obligatoire du Coronavirus 2 du Syndrome Respiratoire Aigu Sévère (SARS-CoV-2), le virus responsable du COVID-19, à son récepteur, l'enzyme de conversion de l'angiotensine 2 (ACE2), entraîne une entrée virale et peut provoquer une IRA. OBJECTIFS DE L'ÉTUDE: Nous avons effectué une revue systématique et une méta-analyse des fréquences de l'IRA et de la thérapie de remplacement renal (RRT) chez les patients COVID-19 gravement malades et a comparé ces fréquences avec les patients qui ont été infectés par des voies respiratoires virus qui lient ou régulent négativement l'ACE2 (virus associés à l'ACE2) et les virus qui ne régulent pas négativement ni ne lient l'ACE2 (virus non associés à l'ACE2). CADRE ET TYPE D'ÉTUDE: Revue systématique et méta-analyse. Des études d'observation sur le COVID-19 et d'autres infections virales respiratoires signalant une AKI et une RRT ont été incluses. Les critères d'exclusion étaient des articles non anglophones, des articles non évalués par des pairs, des articles de revue, des études incluant des patients moins de 18 ans, les études incluant moins de 10 patients et les études ne rapportant pas les taux d'IRA et de RRT. PATIENTS: Adultes COVID-19, syndrome respiratoire aigu sévère (SRAS), syndrome respiratoire du Moyen-Orient (MERS) et malades de la grippe. MESURES: Nous avons extrait les données suivantes des études incluses : auteur, année, lieu de l'étude, âge, sexe, race, diabète sucré, hypertension, maladie rénale chronique, état de choc, utilisation de vasopresseurs, mortalité, admission en unité de soins intensifs (USI), Mortalité en soins intensifs, AKI et RRT. MÉTHODOLOGIE: Nous avons systématiquement recherché dans PubMed et EMBASE les articles rapportant AKI ou RRT. AKI a été défini par les auteurs des études incluses. La maladie grave a été définie par l'admission aux soins intensifs. Nous avons effectué une méta-analyse à effets aléatoires pour calculer estimations regroupées pour le taux d'IRA et de RRT au sein de chaque groupe de virus à l'aide d'un modèle de régression logistique d'interception aléatoire. RÉSULTATS: Sur 23 655 patients hospitalisés et gravement malades COVID-19, les fréquences AKI n'étaient pas significativement différentes entre patients COVID-19 (51 %, intervalle de confiance à 95 % [IC] : 44 %-57 %) et patients gravement malades infectés par l'ACE2 associé (56 %, IC à 95 % : 37 % à 74 %, P = 0,610) ou des virus non associés à l'ACE2 (63 %, IC à 95 % : 43 % à 79 %, P = 0,255). Tarifs RRT groupés n'étaient pas non plus significativement différents entre les patients hospitalisés gravement malades atteints de COVID-19 (20 %, IC à 95 % : 16 % à 24 %) et virus associés à l'ACE2 (18 %, IC à 95 % : 8 % à 33 %, P = 0,747). Taux de RRT pour les virus associés au COVID-19 et à l'ACE2 étaient significativement différents (P < 0,001 pour les deux) des virus non associés à l'ACE2 (49 %, IC à 95 % : 44 % à 54 %). Après ajustement pour le choc ou l'utilisation de vasopresseurs, les taux d'IRA et de RRT n'étaient pas significativement différents entre les groupes. LIMITES DE L'ÉTUDE: Les limites de cette étude incluent l'hétérogénéité des définitions de l'IRA qui ont été utilisées pour différents virus études. Nous n'avons pas pu faire correspondre la gravité de l'infection ou faire une correspondance de propension entre les études. La plupart des études incluses ont été menées de manière rétrospective. Enfin, nous n'avons pas inclus les publications non anglophones. CONCLUSIONS: Nos résultats suggèrent que l'association virale ACE2 ne modifie pas de manière significative les taux d'IRA et de RRT parmi les patients gravement malades admis aux soins intensifs. Cependant, le taux de RRT est plus faible chez les patients atteints de COVID-19 ou associés à l'ACE2 virus par rapport aux patients infectés par des virus ne se liant pas à l'ACE2, ce qui pourrait être dû en partie à la plus faible fréquences de choc et utilisation de vasopresseurs dans ces deux groupes de virus. Des études prospectives sont nécessaires pour démontrer si la modulation de l'axe ACE2 avec les inhibiteurs du système rénine-angiotensine a un impact sur les taux d'IRA et si ells sont bénéfiques ou nocifs chez les patients COVID-19.

Respiratory disease, and treatment / thematic poster session mortality rate in lung transplant recipients infected with COVID-19

Rationale: The emergence of the novel SARS-CoV-2 has caused a global pandemic costing the lives of thousands of people. In the US, COVID-19 is now the third leading cause of death among those aged 45 through 84. Lung transplant (LTx) recipients may be at increased risk for fulminant novel SARS-CoV-2 COVID-19 infection due to their immunosuppressed state. Within solid organ transplant (SOT) recipients, the reported mortality rate has ranged from 5% to 40%. Observational studies of LTx recipients have noted a mortality rate of 10% to 34%. To further understand the mortality rate in LTx recipients, we retrospectively evaluated LTx patients at our center with COVID-19. Method: We identified LTx recipients infected with COVID-19 by nasopharyngeal swab at our institution in the Bay Area. Baseline demographics and clinical data were obtained through review of the electronic medical record (EMR) from 3/20/2020 to 12/18/20. Results: Eighteen LTx recipients were diagnosed with COVID-19 infection. The mean age was 55.1 years (SD ± 3.0) and the majority were male (Table 1). Eightynine percent of patients had 2 or more comorbidities, which included hypertension, diabetes, coronary artery disease, and chronic kidney disease. Clinical presentation ranged from mild to severe, 11% of patients were monitored at home and 89% required hospitalization. Of those hospitalized, 50% were treated in the intensive care unit (ICU). The survival rate of COVID-19 in this population was 94%. One patient who recovered from COVID-19 later died in hospice care related to other comorbidities. Conclusion: Lung transplant recipients infected with COVID-19 were mostly male and most had two or more comorbidities. Most patients had severe infection requiring hospitalization and of these, half necessitated ICU level care. The overall survival rate, however, was higher than has been reported in LTx recipients at other centers. Favorable survival outcomes may be due to disease education and prompt access to healthcare in this LTx population. Additionally, during this study period, the Bay Area did not experience the same overwhelming surge of COVID-19 cases that has been seen in other regions of the United States. Further studies are needed to evaluate factors affecting COVID-19 mortality rate in LTx patients. .

COVID-19 Disease in Lung Transplant Recipients: A Case Series

Purpose Lung transplant (LTx) recipients may be at increased risk for fulminant novel SARS-CoV-2 COVID-19 infection due to their immunosuppressed state. Additional risk factors, outcomes, and optimal management of COVID-19 in LTx recipients is unknown. Methods We identified LTx recipients infected with COVID-19 by nasopharyngeal swab in our institution. Baseline demographics and clinical data were obtained through review of the electronic medical record (EMR) from 3/20/2020 to 10/25/2020. Results Ten LTx recipients were diagnosed with COVID-19 infection. Disease course and management details are described in Table 1. Mean age was 57.5 ± 8 years, 50% were women (n = 5), and 70% self-identified as Latinx, 66% had a high school diploma or lower education. Medicare or Medicaid was the primary insurance in 60% (n = 6). Mean household size was 3.2 ± 1.5 persons. Forty percent (n = 4) had mild symptoms that progressed to fulminant hypoxemic respiratory failure at 9-10 days from symptom onset. Ninety percent (n = 9) required hospitalization with an average length of stay 14.8 ± 12. Sixty percent (n = 6) were treated in the intensive care unit (ICU), 40% (n = 4) requiring mechanical ventilation. COVID-19 specific therapies included remdesivir (80%, n = 8), dexamethasone (60%, n = 6), and convalescent plasma (50%, n = 5). Mycophenolate mofetil (MMF) was reduced or held in 60% (n = 6) of recipients. One recipient who recovered later died in hospice care from other comorbidities. Conclusion Most LTx recipients infected with COVID-19 had severe complications, with a high proportion requiring ICU admission and mechanical ventilation. Though, mortality was relatively low. Adjustments to immunosuppression included reduction in MMF and steroid augmentation. Similar to the general US population, there is a disproportionate impact of COVID-19 infection in Latinx LTx recipients that may be related to social factors such as residing in multi-generational households.

Implementation of a Chatbot Mobile Health Intervention with Home Spirometry to Monitor Lung Transplant Recipients Remotely

Purpose The COVID-19 pandemic accelerated the need to develop remote monitoring of graft function in lung transplant (LT) recipients. While home spirometry has been used previously in LT, long-term engagement has been poor. We aimed to improve engagement and allow efficient data and symptom collection using Bluetooth enabled home spirometers coupled with a digital chatbot. Methods We implemented an automated, chat-based mobile health intervention via text message or email paired with Bluetooth-enabled hand-held spirometers. The chatbot engaged LT recipients weekly in a personalized, automated chat with symptom assessment, education modules, and spirometer data collection. Clinical team members received automatic notification of concerning symptoms or FEV1 declines of >10%. The correlation between home spirometry FEV1 values and lab-based values were assessed with Pearson's coefficient. Results We mailed home spirometers to 424 patients. Between 5/4/2020 and 10/21/2020, 311 patients enrolled in the automated chat and, of these, 273 patients submitted ≥1 FEV1 measure, (median 13;IQR 6-23) over 24 weeks. The largest drop in FEV1 engagement came after the first week in each patient's chat experience;65% of those that submitted an FEV1 at baseline entered a value at week one and 72% at week two. However, after this initial decline, engagement remained stable through 24 weeks (57-72%, Figure 1.A). Home spirometry FEV1 correlated closely with in-lab spirometry (rho = 0.94) (Figure 1.B) Conclusion

Radical radiotherapy (RT) and chemoradiotherapy (CRT) in non-small cell lung cancer (NSCLC): Outcomes from a regional cancer network

Background: This is a retrospective review of outcomes and predictive factors for radical RT for NSCLC in our network. Technological advancement in RT has enabled treatment of larger tumours. SOCCAR (55Gy in 20 fractions) is the most used regime at our centre. This is a timely review in the context of COVID-19, with a renewed interest in shorter RT schedules. Methods: Data for patients who received RT or CRT for Stage I-III NSCLC from 2016-2018 (prior to introduction of adjuvant Durvalumab – NICE approved in 2018) was reviewed at North Middlesex University Hospital, London. Data included smoking history, lung function, planning parameters (PTV, Mean heart dose (MHD), V20 and V5 lung), relapses and deaths. Outcomes were demonstrated as overall survival (OS) and progression free survival (PFS) through Kaplan-Meier analyses. Progression was defined from follow-up imaging or clinical documentation. Results: 90 patients were analysed. Median follow-up time was 16 months. Median age was 72. 60 patients received 55Gy (66%) and 30 received 60-66Gy (33%). 32 patients received concurrent CRT (cCRT-36%), 13 received sequential CRT (sCRT-14%) and 45 received RT alone (50%). 21 patients had early disease (Stage I+II,23%) and 69 had Stage III disease (77%). Median PTV was 304 mm3 and median MHD was 6.65Gy. For all patients, median OS (mOS) was 23 months. Median PFS (mPFS) was 12 months. 1, 2 and 3 year OSR was 72%, 47% and 30% respectively. In those aged over 70, mOS was 23 months and mPFS was 12. For cCRT, mOS was 26 months and mPFS was 14. For sCRT, mOS was 13 months and mPFS was 13. RT alone mOS was 22 months and mPFS was 10. mOS for the cCRT group using 60-66Gy was 26 months and was not reached for 55Gy. mPFS for 60-66Gy and 55Gy was 12 and 15 months respectively. In those aged over 70-1,2 and 3 year OSR was 83%,70% and 50% respectively. FEV1% predicted was associated with OS (HR 0.98, 95% CI 0.97-0.99, p=0.04). Further analysis was performed looking at smoking history, performance status, pathology and gender. Conclusions: Our data confirms that cCRT is an effective treatment for NSCLC (regardless of schedule and age) with comparable outcomes to contemporary CRT trials. Patient screening and regimen choice is key to good outcomes, as apparent in the trends within our data. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.