The Potential Use of Cyclosporine Ultrafine Solution Pressurised Metered-Dose Inhaler in the Treatment of COVID-19 Patients

Introduction: Serious COVID-19 respiratory problems start when the virus reaches the alveolar level, where type II cells get infected and die. Therefore, virus inhibition at the alveolar level would help prevent these respiratory complications. Method: A literature search was conducted to collect physicochemical properties of small molecule compounds that could be used for the COVID-19 treatment. Compounds with a low melting point were selected along with those soluble in ethanol, hydrogen-bond donors, and acceptors. Results : There are severe acute respiratory syndrome coronavirus inhibitors with physicochemical properties suitable for the formulation as an ultrafine pressurised metered-dose inhaler (pMDI). Mycophenolic acid, Debio 025, and cyclosporine A are prime candidates among these compounds. Cyclosporine A (hereafter cyclosporine) is a potent SARS-CoV-2 inhibitor, and it has been used for the treatment of COVID-19 patients, demonstrating an improved survival rate. Also, inhalation therapy of nebulised cyclosporine was tolerated, which was used for patients with lung transplants. Finally, cyclosporine has been formulated as a solution ultrafine pMDI. Although vaccine therapy has been started in most countries, inhalation therapies with non-immunological activities could minimise the spread of the disease and be used in vaccine-hesitant individuals. Conclusion: Ultrafine pMDI formulation of cyclosporine or Debio 025 should be investigated for the inhalation therapy of COVID-19.

980. Universal Lifelong Fungal Prophylaxis and Risk of Coccidioidomycosis in Lung Transplant Recipients Living in an Endemic Area

Background Previous studies suggested that 6-12 months of universal or targeted azole prophylaxis is effective in preventing coccidioidomycosis for various organ transplant recipients. However, limited reports have described outcomes with longer prophylactic durations or using mold-active azoles in lung transplant recipients. Therefore, the purpose of this study was to investigate the incidence of coccidioidomycosis and tolerability of universal lifelong azole therapy in this high-risk patient population. Methods This study was an IRB-approved, retrospective cohort study of lung transplant recipients transplanted from January 2013 through December 2018. Adult recipients who were initiated on azole antifungal prophylaxis were eligible for inclusion. Recipients who died or received pre-emptive or definitive treatment for coccidioidomycosis during the transplant admission, or who received a previous transplant were excluded from the study. Outcomes were assessed through December 2019 or until the time of coccidioidomycosis diagnosis, death, second transplant, or date lost to follow-up. Results Of 544 lung transplants completed between 2013-2018, 493 patients were included with a mean age at transplant of 62 ± 11; 57.3% were male, 88.6% were white, and 77.1% developed post-transplant diabetes. The majority of patients ( > 70%) lived in Arizona or California pre-transplant and at 1-year post-transplant, and most patients had primary transplant indication of COPD and/or pulmonary fibrosis (~75%). One proven coccidioidomycosis infection and one new asymptomatic seropositivity for Coccidioides (incidence 0.2% each) occurred during the study period with median follow-up duration of 31 months. Azole therapy changes were common but permanent discontinuation was rare (1.4%) with reasons for azole switch varying among the different agents as summarized in Table 1. Table 1. Comparison of azole antifungal exposures and reasons for discontinuation Conclusion Lifelong azole antifungal prophylaxis was well-tolerated and effectively protected lung transplant recipients at an Arizona transplant center against coccidioidomycosis. Thus, in the absence of documented intolerance or contraindication, universal lifelong azole antifungal prophylaxis should be considered for all lung transplant recipients residing in a coccidioidomycosis-endemic area. Disclosures Michael D. Nailor, PharmD, BCPS (AQ-ID), AbbVie (Consultant)Merck (Consultant)Shionogi (Consultant) Rajat Walia, MD, Astellas (Consultant, Speaker)

Factors for severe outcomes following SARS-CoV-2 infection in people with cystic fibrosis in Europe

BackgroundSARS-Co-V-2 infection in people with CF (pwCF) can lead to severe outcomes.MethodsIn this observational study, the European Cystic Fibrosis Society Patient Registry collected data on pwCF and SARS-CoV-2 infection to estimate incidence, describe clinical presentation and investigate factors associated with severe outcomes using multivariable analysis.ResultsUp to 31 December 2020, 26 countries reported information on 828 pwCF and SARS-CoV-2 infection. Incidence was 17.2 per 1000 pwCF (95% CI: 16.0–18.4). Median age was 24 years, 48.4% were male and 9.4% had lung transplants. SARS-CoV-2 incidence was higher in lung-transplanted (28.6 [95% CI: 22.7–35.5]) versus non-lung transplanted pwCF (16.6 [95% CI: 15.4–17.8]) (p=<0.001).SARS-CoV-2 infection caused symptomatic illness in 75.7%. Factors associated with symptomatic SARS-CoV-2 infection were age >40 years, at least one F508del mutation, and pancreatic insufficiency.Overall, 23.7% were admitted to hospital, 2.5% to intensive care. Regretfully 11 pwCF (1.4%) died. Hospitalisation, oxygen therapy, intensive care, respiratory support and death were 2–6-fold more frequent in lung-transplanted versus non-lung transplanted pwCF.Factors associated with hospitalisation and oxygen therapy were lung transplantation, CF-related diabetes (CFRD), moderate or severe lung disease and azithromycin use (often considered a surrogate marker for Pseudomonas aeruginosa infection and poorer lung function).ConclusionSARS-CoV-2 infection yielded high morbidity and hospitalisation in pwCF. PwCF with forced expiratory volume in one second (FEV1) <70% predicted, CFRD and those with lung transplants are at particular risk of more severe outcomes.

Dysfunctional lactate metabolism in human alveolar type II cells from idiopathic pulmonary fibrosis lung explant tissue

Background Idiopathic Pulmonary Fibrosis (IPF) is the most common and progressive form of the interstitial lung diseases, leading most patients to require lung transplants to survive. Despite the relatively well-defined role of the fibroblast in the progression of IPF, it is the alveolar type II epithelial cell (AEC2) that is now considered the initiation site of damage, driver of disease, and the most efficacious therapeutic target for long-term resolution. Based on our previous studies, we hypothesize that altered lactate metabolism in AEC2 plays a pivotal role in IPF development and progression, affecting key cellular and molecular interactions within the pulmonary microenvironment. Methods AEC2s isolated from human patient specimens of non-fibrotic and IPF lungs were used for metabolic measurements, lactate dehydrogenase (LDH) analyses and siRNA-mediated knockdown experiments. Results AEC2s isolated from human IPF lung explant tissues had lower rates of oxidative metabolism and were more glycolytic lactate-producing cells than were AEC2 from control, non-fibrotic lung explant tissues. Consistent with this shift in metabolism, patient-derived IPF AEC2s exhibited LDH tetramers that have higher ratios of LDHA:LDHB (i.e., favoring pyruvate to lactate conversion) than control AEC2s. Experimental manipulation of LDHA subunit expression in IPF AEC2s restored the bioenergetic profile characteristic of AEC2 from non-fibrotic lungs. Conclusions These results are consistent with the concept that altered lactate metabolism may be an underlying feature of AEC2 dysfunction in IPF and may be a novel and important target for therapeutic treatment.

PHENOMENON OF DEMIKHOV. At N.V. Sklifosovsky Institute (1960–1986). Paradigm shift in homologous organ transplantation: from overcoming biological incompatibility to artificial immunological tolerance (1960–1970)

The analysis of literature on experimental and clinical transplantation for the period of the 1968–1969 demonstrated that in the period from 1960 to 1970 the world transplantation saw a paradigm change in the field of homoorgan transplant: instead of overcoming the incompatibility between the donor organ and the recipient's body by using biological and physiological methods to influence the organ, which V.P. Demikhov had been dealing with for many years; surgeons and scientists, first abroad, and then in the USSR started developing and applying the creation of artificial immunological tolerance by using various physical, chemical and biological methods to impact recipient's body. The change of paradigms significantly influenced the implementation of organ transplantation techniques in clinic, including those of vital organs, and the further development of clinical transplantology. The data on the first heart transplants in 1968 and lung transplants in 1963–1970 have been presented.

The frequency of rare and monogenic diseases in pediatric organ transplant recipients in Italy

Background Rare diseases are chronic and life-threatening disorders affecting < 1 person every 2,000. For most of them, clinical symptoms and signs can be observed at birth or childhood. Approximately 80% of all rare diseases have a genetic background and most of them are monogenic conditions. In addition, while the majority of these diseases is still incurable, early diagnosis and specific treatment can improve patients’ quality of life. Transplantation is among the therapeutic options and represents the definitive treatment for end-stage organ failure, both in children and adults. The aim of this paper was to analyze, in a large cohort of Italian patients, the main rare genetic diseases that led to organ transplantation, specifically pointing the attention on the pediatric cohort. Results To the purpose of our analysis, we considered heart, lung, liver and kidney transplants included in the Transplant Registry (TR) of the Italian National Transplantation Center in the 2002–2019 timeframe. Overall, 49,404 recipients were enrolled in the cohort, 5.1% of whom in the pediatric age. For 40,909 (82.8%) transplant recipients, a disease diagnosis was available, of which 38,615 in the adult cohort, while 8,495 patients (17.2%) were undiagnosed. There were 128 disease categories, and of these, 117 were listed in the main rare disease databases. In the pediatric cohort, 2,294 (5.6%) patients had a disease diagnosis: of the 2,126 (92.7%) patients affected by a rare disease, 1,402 (61.1%) presented with a monogenic condition. As expected, the frequencies of pathologies leading to organ failure were different between the pediatric and the adult cohort. Moreover, the pediatric group was characterized, compared to the adult one, by an overall better survival of the graft at ten years after transplant, with the only exception of lung transplants. When comparing survival considering rare vs non-rare diseases or rare and monogenic vs rare non-monogenic conditions, no differences were highlighted for kidney and lung transplants, while rare diseases had a better survival in liver as opposed to heart transplants. Conclusions This work represents the first national survey analyzing the main genetic causes and frequencies of rare and/or monogenic diseases leading to organ failure and requiring transplantation both in adults and children.

Current and Emerging Therapies to Combat Cystic Fibrosis Lung Infections

The ultimate aim of any antimicrobial treatment is a better infection outcome for the patient. Here, we review the current state of treatment for bacterial infections in cystic fibrosis (CF) lung while also investigating potential new treatments being developed to see how they may change the dynamics of antimicrobial therapy. Treatment with antibiotics coupled with regular physical therapy has been shown to reduce exacerbations and may eradicate some strains. Therapies such as hypertonic saline and inhaled PulmozymeTM (DNase-I) improve mucus clearance, while modifier drugs, singly and more successfully in combination, re-open certain mutant forms of the cystic fibrosis transmembrane conductance regulator (CFTR) to enable ion passage. No current method, however, completely eradicates infection, mainly due to bacterial survival within biofilm aggregates. Lung transplants increase lifespan, but reinfection is a continuing problem. CFTR modifiers normalise ion transport for the affected mutations, but there is conflicting evidence on bacterial clearance. Emerging treatments combine antibiotics with novel compounds including quorum-sensing inhibitors, antioxidants, and enzymes, or with bacteriophages, aiming to disrupt the biofilm matrix and improve antibiotic access. Other treatments involve bacteriophages that target, infect and kill bacteria. These novel therapeutic approaches are showing good promise in vitro, and a few have made the leap to in vivo testing.

Experience with Alpha-1 Proteinase Replacement Post-Lung Transplantation in Alpha-1 Antitrypsin Deficiency: A Single Center Case Series

Alpha-1 antitrypsin deficiency (AATD) accounts for approximately 5% of lung transplants (LTx) performed annually. No studies have addressed the potential benefit of ongoing alpha-1 proteinase inhibitor (A1-PI) replacement to AATD patients post-LTx. Our primary objective was to assess potential benefits of continually administering A1-PI from pre- to post-transplantation for AATD LTx recipients. A retrospective case series was performed on AATD LTx recipients between 2002 and 2018. Data reviewed included date of A1-PI initiation, pulmonary function tests, and surveillance bronchoscopies. Endpoints included the change of forced expiratory volume in one-second (FEV1), infective episodes, chronic lung allograft dysfunction (CLAD), and acute rejection episodes. Out of the 13 AATD LTx recipients, 6 continually received A1-PI beginning prior to transplant (Group 1), and 7 were re-introduced to Α1-PI a number of years after LTx (Group 2). After two years, Group 1 experienced a median FEV1% predicted decline of 0.0%, and Group 2 experienced a median decline of 15.0%. No differences noted in frequency of infective episodes. One patient in Group 1 developed CLAD about 2.5 years post-LTx, whereas all Group 2 patients developed CLAD at a mean of 5.4 years post-LTx. No Group 1 patients experienced acute lung rejection episodes noted from surveillance bronchoscopies, corresponding data not available for Group 2. We report that the continual use of Α1-PI in AATD LTx recipients is associated with better maintenance and stabilization of lung function and potentially less acute lung rejection episodes early post-LTx. Prospective studies should be performed to confirm possible benefits.

Expression of SARS-CoV-2 Entry Factors in Human Alveolar Type II Cells in Aging and Emphysema

Alveolar type II (ATII) cells proliferate and restore the injured epithelium. It has been described that SARS-CoV-2 infection causes diffuse alveolar damage in the lungs. However, host factors facilitating virus infection in ATII cells are not well known. We determined the SARS-CoV-2-related genes and protein expression using RT-PCR and Western blotting, respectively, in ATII cells isolated from young and elderly non-smokers, smokers, and ex-smokers. Cells were also obtained from lung transplants of emphysema patients. ACE2 has been identified as the receptor for SARS-CoV-2, and we found significantly increased levels in young and elderly smokers and emphysema patients. The viral entry depends on TMPRSS2 protease activity, and a higher expression was detected in elderly smokers and ex-smokers and emphysema patients. Both ACE2 and TMPRSS2 mRNA levels were higher in this disease in comparison with non-smokers. CD209L serves as a receptor for SARS-CoV-2, and we found increased levels in ATII cells obtained from smokers and in emphysema patients. Also, our data suggest CD209L regulation by miR142. Endoplasmic reticulum stress was detected in ATII cells in this disease. Our results suggest that upregulation of SARS-CoV-2 entry factors in ATII cells in aging, smokers, and emphysema patients may facilitate infection.