Immunotherapy: RAPID ACCESS TO VIRUS-SPECIFIC T CELLS FOR ADOPTIVE IMMUNOTHERAPY FOR COMPASSIONATE USE IN AUSTRALIA

Background & Aim: Adoptive T cell immunotherapy holds great promise for the treatment of viral complications. Our group has been developing and trialling virus-specific T cell therapies for more than 20 years. Recently, we have generated a repository of multi-virus-specific T cells for our clinical trials. Unfortunately, for many patients with viral complications, there is no suitable trial through which to access these therapies. In Australia, the Therapeutic Goods Administration has a Special Access Scheme (SAS) to enable provision of unapproved therapies for compassionate use. Our research group is now a leading Australian provider of "off-the-shelf" and custom-grown allogeneic virus-specific T cells to hospitals for patients with no other treatment options. Methods, Results & Conclusion(s): We have generated a repository of multi-virus-specific T cells from 20 healthy donors, with up to 150 doses of T cells per donor generated from a single blood sample. Each product batch is thoroughly characterised in terms of viral antigen specificity, HLA restriction and alloreactivity. These T cells target a combination of Epstein-Barr virus, cytomegalovirus, BK polyomavirus, John Cunningham virus and adenovirus epitopes. We have also generated a repository of SARS-CoV-2-specific T cells and occasionally grow custom patient-specific batches of T cells from nominated donors, on request. Since 2008, we have provided virus-specific T cells to 15 hospitals across Australia, and the volume of supply requests has significantly increased in recent years, as clinicians have gained interest in adoptive immunotherapy. In 2022, we provided T cells for 26 patients via the SAS. The majority were experiencing post-transplant complications, including cytomegalovirus disease, BK virus-associated haemorrhagic cystitis and post-transplant lymphoproliferative disorder. Through our clinical trials, we have developed rigorous processes for T cell therapy manufacture and characterisation, in addition to a computer-based selection algorithm, which we apply to SAS cases. As these cases are not part of a clinical trial, concomitant therapy varies, and monitoring is not uniform. However, we have received reports of clinical benefit from adoptive T cell therapy. These include cases of reduction in viral load, improvement in symptoms, and complete resolution of infection. We believe that these promising T cell therapies should be available to hospitals through a nationally funded centre for cellular therapies for critically ill patients.Copyright © 2023 International Society for Cell & Gene Therapy

Clinical improvement 2 years after starting elexacaftor/tezacaftor/ivacaftor in patients with advanced lung disease

Background: With the introduction of new cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy (elexacaftor/tezacaftor/ ivacaftor), peoplewith CF experiencing severe lung disease can experience significant improvements in clinical symptoms. Method(s): This single-center institutional review board-approved retrospective chart review identified patients with advanced lung disease who met criteria for a compassionate use or expanded access program because of high risk of death or transplant need within 2 years. Clinical data collection for all patients began at baseline, 2 to 4 weeks after therapy initiation, and continued every 3 months for 2 years. Datawere collected on demographic characteristics, clinic progress notes, clinical labs, forced expiratory volume in 1 minute (FEV1),weight, body mass index, respiratory colonization, and hospitalizations after drug initiation. Patients also completed sinus and chest computed tomography (CT) to track clinical changes. Result(s): Eighteen people with CF (aged 15-49, 56% male) from a large midwestern CF center who initiated drug therapy between July and September 2019 in an inpatient hospital or clinic setting were identified. Clinical markers (Table 1) indicated that modulator therapy was well tolerated and not discontinued by any participant;safety lab values did not indicate medical concern or discontinuation. There were 90 admissions for the group in the 2 years before therapy and 17 admissions during the 2 years after, although seven of the posttherapy admissions were for nonrespiratory indications. Monitoring results indicated the safety of modulator therapy because there were no adverse clinical occurrences or laboratory events, and all patients presented with universal stabilization. There have been no deaths and no transplants. Unlike lumacaftor/ivacaftor, therewere no problems with chest tightness or any difficulty with troublesome increases in expectoration burden or choking during initiation of therapy. Most had significant reduction in or loss of spontaneous cough and sputum production. The impact on microbial colonization is unclear, because even in this severe group, inability to produce sputum on command led to considerable missing data in follow-up, leaving colonization status at follow-up unclear. Conclusion(s): This study focused on people with CF who qualified for modulator therapy based on advanced lung disease. Initiation of modulator therapy was deemed safe and resulted in objective positive changes in nutrition;cough;FEV1);and subjective reports of clinical status, level of activity, and reduction in burden of treatment. No evidence was found of difficulty managing the increased expectoration during initial therapy. Limitations were noted in missing data during the COVID-19 pandemic, small sample size, and delayed follow-up for drug monitoring.(Table Presented) Clinical indicators before and after modulator therapy *Completed post-drug initiation (earlier than 12 months), **24 months before and after therapy initiationCopyright © 2022, European Cystic Fibrosis Society. All rights reserved

Pay attention to the medication safety of patients during the period of coronavirus disease 2019 epidemic prevention.

The coronavirus disease 2019 (COVID-19) epidemic is facing the most critical situation. As of January 11, 2021, there have been nearly 90 million confirmed cases worldwide and nearly 2 million deaths. The local epidemic situation in China is sporadic and locally clustered, and the situation of epidemic prevention is difficult and complicated. In this situation, there are many problems in medication safety of patients, such as safety issues in off-label medication and compassionate medication of COVID-19 treatment, safety problems in the combination use of drugs for COVID-19 and drugs for other diseases, monitoring of adverse drug reactions in COVID-19 treatment, the safety issues in self-purchased drugs for prevention and treatment of COVID-19, and the medication safety in patients with other diseases during the epidemic. Therefore, it is necessary to pay more attention to the medication safety of patients to fight the epidemic scientifically and to win a greater victory in the fight against the COVID-19 epidemic at a smaller price.Copyright © 2021 Chinese Medical Association

Pharmacy services provided by clinical pharmacists for COVID-19 patients

Background: In December 2019, a respiratory illness due to a novel coronavirus, SARS-CoV-2, was first identified in Wuhan, China. SARS-CoV-2, termed COVID-19, is now a worldwide pandemic and has been identified in 216 countries and areas or territories (WHO, 2020). As of May 15th, 2020, there have been more than 4.2 million confirmed cases and 294,190 deaths worldwide. Purpose(s): Ensure patient safety, drug availability, and therapeutic efficacy for all COVID-19 patients. Implement a number of changes to urgently meet the institution's patient care needs. Method(s): Data were collected from a 62-year-old male patient admitted with severe COVID-19 to the intensive care unit in April 2020. The following pharmacy services were then provided: first, constant review and interpretation of new clinical data;second, patient eligibility assessment and obtaining medication through compassionate use protocols;third, evidence-based interventions (e.g. drug-drug interaction, drug-disease interaction, and dose adjustments);fourth, limit unnecessary nebuliser use. Last but not least, educate patients and the public on effective strategies to prevent acquisition and further spread of infection (e.g. social distancing, optimal hand hygiene, and personal protective equipment). Result(s): With standard care and the compassionate use of Hydroxychloroquine, Azithromycin, Zn supplements, and Tocilizumab under close monitoring, the patient successfully recovered and was discharged on May 4th, 2020. Conclusion(s): Pharmacists play a vital role within a multi-disciplinary healthcare team to optimise patient care during this COVID-19 pandemic.

Favipiravir for symptomatic COVID-19: A nationwide observational cohort study.

INTRODUCTION: Favipiravir, an antiviral agent with activity against SARS-CoV-2, was made available to hospitals in Japan for off-label use among COVID-19 patients between 2020 and 2021. METHODS: A nationwide observational cohort study was conducted on patients who received favipiravir as part of clinical care between February 2020 and December 2021. Information was collected on demographics, comorbidities, severity of illness, use of favipiravir and other medications targeting COVID-19, adverse events, clinical status at 7 and 14 days and clinical outcome one month after admission to the hospital. RESULTS: A total of 17,508 hospitalized patients who received favipiravir were registered from 884 hospitals. In terms of demographics, 55.9% were age ≥60 years, and 62.3% were male. At least one of the four surveyed comorbidities was present in 45.5% of the patients. The rates of clinical improvement at 7 and 14 days were 72.4％ and 87.5%, 61.4% and 76.6%, and 45.4% and 59.5% for mild, moderate, and severe diseases, respectively. The case fatality rates within a month from hospitalization were 3.3%, 12.6%, and 29.1% for mild, moderate, and severe diseases, respectively. Significant correlations were observed between death and advanced age, male sex, moderate or severe disease, diabetes, cardiovascular diseases, and immunosuppression. Commonly reported adverse events included uric acid level increase or hyperuricemia (16.8%), liver function abnormalities (6.9%), and rash (1.0%). CONCLUSIONS: Favipiravir was well tolerated among COVID-19 patients. The study provides insights into the use of this agent at hospitals across Japan in the early phase of the pandemic.

Revisiting the Term "Compassionate Use" and Leadership of the World Health Organization in Resolving Confusion in the Age of COVID-19 and Beyond.

We discuss the term "compassionate use" (CU) as an example of terminology having a huge impact on drug regulation. CU is used in many confusing situations, and its meaning varies significantly. We ethically affirm the necessity of CU. We insist that CU should be properly placed in exceptional status. The regulation of CUs is much more lenient than that of clinical trials because of the difference in the purpose. Whether consciously or unconsciously, abuse results in confusion and is never acceptable. The World Health Organization (WHO) proposed not to use the previous term CU but to replace it with another one. WHO also proposed the term MEURI (monitored emergency use of unregistered and experimental interventions). However, this was extremely incomplete, and WHO used the term CU subsequently. The main purpose of the proposal needs to be thoroughly implemented. In the context of the COVID-19 pandemic and beyond, expectations regarding WHO's role and leadership in global health issues are rising. We hope that WHO will play a major role in promoting research ethics preparedness while discontinuing the use of confusing terms such as CU and will develop alternative terms and their content. We discuss the evaluation of MEURI, the Japanese version of CU, and appropriate and inappropriate terminology related to the therapeutic use of unapproved drugs. We also discuss the expected appearance of CU including its name. It is appropriate to target group/cohort patients and unapproved drugs in the late stage of development. It is also important to solve the problem of incentives for CUs of pharmaceutical companies that are rushing to obtain marketing approval. The UK's Early Access to Medicine Scheme has provided many suggestions. We believe that our opinion can contribute to WHO's efforts to resolve the confusion and promote research ethics preparedness in health emergencies.

POST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDER (PTLD) IN RENAL TRANSPLANT PATIENTS WITH COVID-19

SESSION TITLE: Pulmonary Issues in Transplantation Case Report Posters SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: Post-transplant lymphoproliferative disorder (PTLD) is a life-threatening complication after transplantation. While there is evidence that hematologic malignancy is associated with increased severity in COVID-19 infection, there is little description of PTLD and COVID-19. CASE PRESENTATION: A 68-year-old man and a 68-year-old female, both of whom had prior renal transplantation, were admitted to the hospital with COVID-19 pneumonia. Both patients were vaccinated against COVID-19, though were negative for spike protein antibodies. The man was treated with remdesivir and the woman was treated with remdesivir and dexamethasone. Both patients improved and were discharged. Within a month, both had recurrent symptoms of dyspnea and fever requiring re-admission. They were hypoxic, the man requiring high flow nasal cannula and the woman requiring nasal cannula to maintain SpO2>90%. They had positive COVID-19 PCR tests, with cycle threshold lower than in their initial admissions, as well as chest imaging with bilateral infiltrates. The man had a pleural effusion with cytology consistent with PTLD and perinephric mass and retroperitoneal lymphadenopathy with biopsy confirming PTLD. The woman had a renal sinus mass with biopsy confirming PTLD. Both patients were treated with another 5 days of remdesivir and started on dexamethasone. The medical team discussed monoclonal antibody treatment, but the patients did not meet EUA criteria and compassionate use request was denied. To treat PTLD, both were initiated on Rituximab, Cyclophosphamide, Hydroxydaunomycin, Oncovin, and Prednisone (R-CHOP). Since then, both patients have had complicated and prolonged hospital courses. The woman developed renal failure and severe C.diff colitis complicated by toxic megacolon requiring total colectomy. The man developed renal failure, CMV viremia, and pseudomonas UTI. The patients were able to be weaned to room air, though ultimately the woman had to be intubated due to poor mental status and remains on low oxygen settings. Both patients continue to be persistently positive for COVID-19 by PCR. DISCUSSION: This case illustrates diagnosis and treatment of PTLD in two patients with COVID-19 infection. Of particular interest was the use of Rituximab, an anti-CD-20 antibody which impairs humoral immunity, in the treatment of PTLD, as the drug has been associated with increased risk of severe COVID-19 infection. Rituximab was particularly concerning as both patients had persistent COVID-19 without development of immunity despite prior vaccination, and both continue to be positive despite two months of active infection. The patients had improvement of their respiratory status, though have had poor and complicated clinical courses with renal and infectious complications. CONCLUSIONS: Treatment of PTLD in patient's with active COVID-19 may impair ability to clear virus, though impact on outcomes is unclear. Reference #1: Simpson-Yap, S., de Brouwer, E., Kalincik, T., Rijke, N., Hillert, J. A., Walton, C., Edan, G., Moreau, Y., Spelman, T., Geys, L., Parciak, T., Gautrais, C., Lazovski, N., Pirmani, A., Ardeshirdavanai, A., Forsberg, L., Glaser, A., McBurney, R., Schmidt, H., … Peeters, L. (2021). Associations of Disease-Modifying Therapies With COVID-19 Severity in Multiple Sclerosis. Neurology, 97(19). https://doi.org/10.1212/WNL.0000000000012753 Reference #2: Andersen, K. M., Bates, B. A., Rashidi, E. S., Olex, A. L., Mannon, R. B., Patel, R. C., Singh, J., Sun, J., Auwaerter, P. G., Ng, D. K., Segal, J. B., Garibaldi, B. T., Mehta, H. B., Alexander, G. C., Haendel, M. A… Chute, C. G. (2022). Long-term use of immunosuppressive medicines and in-hospital COVID-19 outcomes: a retrospective cohort study using data from the National COVID Cohort Collaborative. The Lancet Rheumatology, 4(1). https://doi.org/10.1016/S2665-9913(21)00325-8 Reference #3: Passamonti, F., Cattaneo, C., Arcaini, L. Bruna, R., Cavo, M., Merli, F., Angelucci, E., Krampera, M., Cairoli, R., della Porta, M. G., Fracchiolla, N., Ladetto, M., Gambacorti Passerini, C., Salvini, M., Marchetti, M., Lemoli, R., Molteni, A., Busca, A., Cuneo, A., … Corradini, P. (2020). Clinical characteristics and risk factors associated with COVID-19 severity in patients with haematological malignancies in Italy: a retrospective, multicentre, cohort study. The Lancet Haematology, 7(10). https://doi.org/10.1016/S2352-3026(20)30251-9 DISCLOSURES: No relevant relationships by Ian Mahoney No relevant relationships by Caroline Motschwiller

ONE MORE FEATHER IN THE CAP (DECITABINE): YET ANOTHER CASE OF CHEMOTHERAPY-INDUCED LUNG INJURY

SESSION TITLE: Drug-Induced and Associated Critical Care Cases Posters 2 SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: Lung toxicity due to antineoplastic therapy is reported with both cytotoxic and molecularly targeted agents [1]. We present one such case of lung injury induced by capecitabine. CASE PRESENTATION: A 79-year-old female with history of triple negative infiltrating duct carcinoma of the right breast (status post mastectomy and adjuvant chemotherapy with docetaxel and cyclophosphamide 3 years prior) presented to the hospital with dyspnea on exertion following her fourth cycle of capecitabine therapy for breast cancer recurrence. Patient developed nausea, vomiting, and malaise with cycles 1, 2, and 3 of capecitabine therapy with onset of severe dyspnea on exertion, cough, and hypoxia following cycle 4. Computed tomography (CT) scan of the chest on admission showed consolidative opacities in the right upper, right middle, and anterior right lower lobe along with smaller opacities in the left lung apex and small subcentimeter nodules;no pulmonary embolism. Antibiotics were given for a short duration for suspected pneumonia without improvement. Capecitabine was held on discharge. She presented again to the emergency room with worsening shortness of breath, diarrhea, fatigue, and dizziness. COVID test was negative. Chest x-ray redemonstrated patchy airspace disease involving the right apical, lateral, mid lower lung field. Oral steroids were recommended for suspected organizing pneumonia, but the patient refused due to concerns about side effects. Her hospital course was complicated by Clostridium difficile infection (treated with oral vancomycin) and left lower extremity deep venous thrombosis (treated with anticoagulation). Subsequently she followed up with pulmonology outpatient. Repeat imaging showed evolving infiltrates in the same areas with elevated aspergillus IgG level (18.0 mcg/ml) and IgE (178 kU/L) but negative galactomannan and sputum bacterial/fungal/acid fast cultures. Oral steroids were initiated with clinical and symptomatic improvement. DISCUSSION: Capecitabine is a prodrug of fluorouracil (antimetabolite). It is used as a chemotherapy agent in multiple types of cancer including breast cancer. Respiratory side effects include cough (<7%) and bronchitis (<5%). Lung injury/pneumonitis is a rare complication with only a few cases reported to date [2,3]. The timing of symptoms with chemotherapy administration and the negative infectious work-up supports capecitabine as the inciting etiology of lung injury. Withholding chemotherapy and starting systemic steroids were effective treatments in this case of chemotherapy induced lung toxicity. CONCLUSIONS: Capecitabine induced lung injury is a rare but important entity and should always be kept in mind while evaluating dyspnea in cancer patients. Reference #1: Capri G, Chang J, et al. An open-label expanded access study of lapatinib and capecitabine in patients with HER2-overexpressing locally advanced or metastatic breast cancer. Ann Oncol. 2010;21(3):474. Epub 2009 Oct 8. DOI: 10.1093/annonc/mdp373 Reference #2: C. J. Benthin, G. Allada. Capecitabine-Induced Lung Injury. American Journal of Respiratory and Critical Care Medicine 2016;193:A1653. Reference #3: Andrew K Chan, Bok A Choo, John Glaholm. Pulmonary toxicity with oxaliplatin and capecitabine/5-Fluorouracil chemotherapy: a case report and review of the literature. Onkologie. 2011;34(8-9):443-6. doi: 10.1159/000331133. Epub 2011 Aug 19. DISCLOSURES: No relevant relationships by William Karkowsky No relevant relationships by Chahat Puri No relevant relationships by Sahib Singh

TIME TO EXPAND THE USE OF CASIRIVIMAB/IMDEVIMAB MONOCLONAL ANTIBODY THERAPY? A CASE OF COMPASSIONATE USE IN SEVERE COVID-19 PNEUMONIA

SESSION TITLE: COVID-19 Case Report Posters 1 SESSION TYPE: Case Report Posters PRESENTED ON: 10/17/2022 12:15 pm - 01:15 pm INTRODUCTION: The FDA limits REGEN-COV (Casirivimab/Imdevimab) use to asymptomatic adults at high risk for progression to severe COVID-19 pneumonia or post-exposure prophylaxis. Here, we present a case of compassionate use of REGEN-COV in severe COVID-19 pneumonia. CASE PRESENTATION: A 76-year-old male with a medical history significant for COPD, Rheumatoid arthritis (treated with hydroxychloroquine and low dose steroids), and monoclonal gammopathy of undetermined significance (MGUS) presented with one week of fever, cough, and fatigue. He was febrile to 103 F, with normal oxygen saturation on admission. SARS-CoV-2 rapid molecular PCR was positive. He was started on Levofloxacin, but he did not meet the criteria for administration of dexamethasone, remdesivir, or monoclonal antibody (mAb) therapy. On day one of admission, he became hypoxemic and was subsequently started on dexamethasone and remdesivir. He was given convalescent plasma to address inadequate antibody response to COVID-19 immunization secondary to his chronic immunosuppressed/immunodeficient state. His hypoxemia continued to worsen, requiring high-flow nasal cannula oxygen (HFNC). A regimen of tocilizumab was also initiated. CT chest angiography ruled out pulmonary embolism but revealed diffuse bilateral patchy opacities. His oxygen requirements continued to increase with decreasing ROX index and hence was transferred to the Intensive Care Unit. Repeat PCR for SARS-COV-2 was significant for a high viral load. Approval for compassionate use of REGEN-COV was obtained and administered to the patient. Following administration, his symptoms improved significantly with the transition from HFNC to simple nasal cannula oxygen. Repeat PCR for SARS-CoV-2 also showed a remarkable decline of the viral load. He was transferred back to the medical floors and later to the skilled nursing facility once he was clinically more stable. DISCUSSION: In the United States, REGEN-COV (Casirivimab/Imdevimab) treatment has been approved for emergency use since November 2020. The combination of these two neutralizing immunoglobulin gamma 1 (IgG1) mAb attacks the spike protein of the SARS-CoV-2 virus and has been shown to effectively prevent the progression of symptomatic COVID-19 pneumonia and decrease the high viral load of SARS-CoV-2. It also reduces COVID-19 related hospitalization or death, especially in immunosuppressed patients. Our patient received dexamethasone, remdesivir, tocilizumab, and convalescent plasma as part of conventional COVID-19 treatment with continued worsening of COVID-19 pneumonia. However, the compassionate use of REGEN-COV led to rapid clinical improvement of the patient's symptoms and reduced the SARS-CoV-2 viral load. CONCLUSIONS: Hence, physicians and FDA should consider expanding the use of REGEN-COV mAB therapy to immunosuppressed patients with rapidly worsening COVID-19 pneumonia in adjunct to conventional COVID-19 treatment. Reference #1: Stein D, Oviedo-Orta E, Kampman WA, McGinniss J, Betts G, McDermott M, Holly B, Lancaster JM, Braunstein N, Yancopoulos GD, Weinreich DM. Compassionate Use of REGEN-COV ® in Patients with COVID-19 and Immunodeficiency-Associated Antibody Disorders. Clin Infect Dis. 2021 Dec 31:ciab1059. doi: 10.1093/cid/ciab1059. Epub ahead of print. PMID: 34971385;PMCID: PMC8755381. Reference #2: O'Brien MP, Forleo-Neto E, Musser BJ, Isa F, Chan KC, Sarkar N, Bar KJ, Barnabas RV, Barouch DH, Cohen MS, Hurt CB, Burwen DR, Marovich MA, Hou P, Heirman I, Davis JD, Turner KC, Ramesh D, Mahmood A, Hooper AT, Hamilton JD, Kim Y, Purcell LA, Baum A, Kyratsous CA, Krainson J, Perez-Perez R, Mohseni R, Kowal B, DiCioccio AT, Stahl N, Lipsich L, Braunstein N, Herman G, Yancopoulos GD, Weinreich DM;Covid-19 Phase 3 Prevention Trial Team. Subcutaneous REGEN-COV Antibody Combination to Prevent Covid-19. N Engl J Med. 2021 Sep 23;385(13):1184-1195. doi: 10.1056/NEJMoa2109682. Epub 2021 Aug 4. PMID: 34347950;PMCI : PMC8362593. Reference #3: Weinreich DM, Sivapalasingam S, Norton T, Ali S, Gao H, Bhore R, Xiao J, Hooper AT, Hamilton JD, Musser BJ, Rofail D, Hussein M, Im J, Atmodjo DY, Perry C, Pan C, Mahmood A, Hosain R, Davis JD, Turner KC, Baum A, Kyratsous CA, Kim Y, Cook A, Kampman W, Roque-Guerrero L, Acloque G, Aazami H, Cannon K, Simón-Campos JA, Bocchini JA, Kowal B, DiCioccio AT, Soo Y, Geba GP, Stahl N, Lipsich L, Braunstein N, Herman G, Yancopoulos GD;Trial Investigators. REGEN-COV Antibody Combination and Outcomes in Outpatients with Covid-19. N Engl J Med. 2021 Dec 2;385(23):e81. doi: 10.1056/NEJMoa2108163. Epub 2021 Sep 29. PMID: 34587383;PMCID: PMC8522800. DISCLOSURES: No relevant relationships by Mubashir Ayaz Ahmed No relevant relationships by Shayet Hossain Eshan No relevant relationships by Sami Hussein No relevant relationships by Khalid Hussein No relevant relationships by Kamalnath Sankaran Rajagopalan No relevant relationships by Chenyu Sun

PROLONGED COVID-19 INFECTION IN AN IMMUNOSUPPRESSED PATIENT TREATED WITH CASIRIVIMAB/IMDEVIMAB

SESSION TITLE: Drug-Induced Critical Care SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/19/2022 12:45 pm - 1:45 pm INTRODUCTION: We present a case of an immunosuppressed patient on rituximab who developed prolonged COVID-19 infection lasting over 6 months. CASE PRESENTATION: A 61-year-old male with a history of follicular lymphoma in remission on maintenance rituximab was hospitalized in December 2020 due to COVID-19 pneumonia. Chest X-ray demonstrated patchy bilateral airspace disease. He was treated with dexamethasone and remdesivir. His symptoms did not resolve upon discharge and in January 2021, he was referred to outpatient pulmonology with fevers, progressive dyspnea, and hypoxemia requiring 2 liters oxygen with activity. Computed tomography (CT) of the chest exhibited worsening bilateral ground-glass opacities compared to previous imaging. He had a bronchoscopy in February 2021 which showed negative cultures, except for persistent positive COVID-19 by PCR. He was subsequently started on a prednisone taper for presumed post-COVID-19 organizing pneumonia. Starting from February to May, he would have improvement in his fevers and dyspnea with high dose steroids, but worsening of symptoms with tapering of the dosage requiring two hospital admissions. During these admissions, he was treated with remdesivir and intravenous (IV) steroids, and discharged on steroid tapers. He also had two bronchoscopies in April and May that were positive for COVID-19 by PCR but otherwise had negative cultures. Serum COVID-19 anti-spike antibodies were also noted to be negative, while he remained positive for COVID-19 by nasal swab. With the lack of improvement with treatment for post-COVID-19 organizing pneumonia, Regeneron was trialed under the compassionate use guidelines for working diagnosis of persistent COVID-19 infection. He reported resolution of fevers, improvement in fatigue, and decreased oxygen requirements within 1 week of Regeneron administration. At 3 month follow up, his oxygen requirements were 1 liter with activity, he was afebrile, and COVID-19 anti-spike antibodies remained present. DISCUSSION: Medications such as rituximab diminish the immune system's ability to produce neutralizing antibodies to COVID-19 and may lead to a prolonged course of infection (1). Other case studies have demonstrated improvement with Regeneron in immunosuppressed patients (1, 2). CONCLUSIONS: We present a case of prolonged COVID-19 infection in the setting of immunosuppression while on maintenance rituximab for follicular lymphoma in remission. We believe this patient's case represents persistent COVID-19 infection and not re-infection due to persistent positive COVID-19 PCR, fevers, and absence of COVID-19 antibodies. This patient demonstrated dramatic improvement in his symptoms after Regeneron infusion. Monoclonal antibodies should be considered beyond accepted treatment windows in immunocompromised patients with prolonged COVID-19 symptoms. Reference #1: Velez I, Bermejo J, Perez J, Aguayo L, Ruiz M, Garcia-Erce J. Two patients with rituximab associated low gammaglobulin levels and relapsed COVID-19 infections treated with convalescent plasma. https://doi.org/10/1016/j.transcri.2021.103104 Reference #2: D'Abramo A, Vita S, Maffongelli G, Mariano A, Agrati C, Castilletti C, et al. Prolonged and Severe SARS-CoV-2 infection in patients under B-cell-depleting drug successfully treated: A tailored approach. Internal Journal of Infectious Diseases 2021;107 247-250 DISCLOSURES: No relevant relationships by Joseph Pitcher No relevant relationships by Subhan Toor

Compassionate use of pulmonary vasodilators in acute severe hypoxic respiratory failure due to COVID-19

Introduction: There have been over 200 million cases and 4.4 million deaths from Covid-19 worldwide. In the UK over half a million have required hospitalisation, with over 130,000 deaths. Although most experience a mild illness the mortality can be over 50% for those requiring mechanical ventilation.1 One potential treatment for severe hypoxaemia is inhaled pulmonary vasodilator (IPVD) therapy, either as nitric oxide (NO) or prostaglandin analogues. Despite the lack of robust evidence IPVDs are often considered recue treatments for refractory hypoxaemia.2,3 Given the disease severity in COVID-19 we implemented a protocol for the use of IPVDs on a compassionate basis for patients with severe hypoxaemia receiving otherwise maximal support. In this study we detail our findings and assess differences between survivors and non-survivors. Objectives: The primary outcome of this study was percentage changes in PaO2/FiO2 (PF) ratio and Alveolararterial (A-a) gradient at 2, 6, 12, 24, 48 and 72 hours following initiation of IPVD therapy. Secondary outcomes were differences in characteristics and response to therapy between survivors and non-survivors who received an IPVD. Methods: Data from a prospectively maintained research database of patients with SARS-CoV-2 admitted to the ICU at a large teaching hospital were analysed for the time period 14 March 2020 -11 February 2021. Patients aged 18 years or older who received an IPVD during their admission were eligible for inclusion. An IPVD was considered if the PF ratio was less than 13.3kPa despite rescue therapies (prone positioning, neuromuscular blockade, airway pressure release ventilation). Nitric oxide was commenced at 20ppm and titrated to response. If oxygenation improved Iloprost nebulisers were commenced at 10-30mcg four hourly and NO weaned. Results: Three-hundred eight patients with SARS-Cov-2 were admitted during the study period of whom 59 (19.2%) received IPVD therapy. Patients receiving an IPVD had a lower PF ratio (14.37 vs. 16.37kPa, p=0.002) and higher APACHE-II score (17 vs. 13, p=0.028) at admission compared to those who did not. Survival to ICU discharge was lower in patients receiving an IPVD (55.9% vs. 81.9%, p<0.001). The median PF ratio at commencing IPVD therapy was 11.33kPa (9.93-12.91) with a median of 6 days from admission to receiving an IPVD. At 72 hours the median improvement in PF ratio was 33.9% (-4.3-84.1). In patients receiving IPVDs there were no differences in other therapies received (steroids, prone ventilation, ECMO) between survivors (n=33) and non-survivors (n=26), with the exception of renal replacement therapy. At 72 hours changes in PF ratio (70.8 vs. -4.1%) and reduction in A-a gradient (44.7 vs. 14.8%) differed significantly between survivors and non-survivors (both p <0.001). Conclusion: The response to the compassionate use of IPVDs for patients with acute hypoxic respiratory failure due to Covid-19 differs significantly between survivors and non-survivors. Both NO and inhaled prostaglandins may offer therapeutic options for severe hypoxaemia due to COVID-19, with prostaglandins particularly attractive as they do not require specialist delivery systems. The use of inhaled prostaglandins, and NO where feasible, should be studied in both isolation and combination in adequately powered prospective randomised trials.

Regulatory Science Challenges - Encouraging Innovation Through an Adaptive Regulatory System

ATMPs - a new era A boy from Hungary, Zente, was one and a half years old when the crowd-funding campaign to finance his life-saving medicine Zolgensma concluded with a happy end. He was the third European patient that received the new gene therapy, which replaces the function of the missing or nonworking survival motor neuron 1 (SMN1) gene with a new, working copy of a human SMN gene that helps motor neuron cells work properly and survive. From a European perspective, it has been almost 15 years by now since regulatory framework for advanced therapy medicinal products (ATMPs) had been established to ensure the free movement of these medicines within the European Union, to facilitate their access to the EU market, and to foster the competitiveness of European pharmaceutical companies in the field. Zolgensma has been approved in the EU in May 2020. The FDA expects it will be reviewing and approving up to 20 cell and gene therapies each year until 2025. Rapid development of technology and better understanding of the manufacturing challenges are not the only prerequisites of the growth. Assessment of products like Zolgensma requires very specific knowledge and often an adaptive approach from regulators. They have to gain enough experience and need to be able to summarize knowledge in guidelines that would help developers of products that are substantially different from traditional medicines. FDA issued seven new guidelines in January 2020, in which, for example, they highlight the importance of long-term follow-up for gene therapies that offer one-time fix for inherited diseases and where pre-market studies may have limited value. 2. Regulatory tools These examples may already show that rapid change in technology leads to new kinds of medicines that require a properly adapted regulatory system. Patients would expect state-of-the-art medicines within the shortest possible time frame, however, authorities are traditionally more cautious. Still, there are several various initiatives from the EMA and the FDA to foster early access to medicines. Some of these have been available for a longer time. EMA's accelerated assessment reduces the timeframe for review of innovative applications of medicines with major public health interest. Conditional marketing authorisation grants authorization before a complete dataset is available, and compassionate use allows the use of an unauthorized medicine for patients with an unmet medical need. A more recent regulatory tool of EMA is the priority medicines scheme (PRIME) that aims to enhance support for the development of medicines that are expected to make a real difference to patients. Early dialogue between EMA and the developers is a crucial part of the tool, together with accelerated assessment and continuous scientific advice and protocol assistance. Up to now, 282 applications for PRIME eligibility have been assessed by the CHMP of which 95 have received a green light. Most of the applicants are small and medium size enterprises, and the major therapeutic area is oncology. FDA has similar programs, such as the Fast Track, Breakthrough Therapy and Priority Review designations, and is also aiming to facilitate and accelerate development and marketing authorization of key medicines. By 2018, about 70% of new drug approvals by the FDA were expedited, compared to about 50% in 2010. The result is a growing pro-portion of medicines authorized with less premarket evidence, a trade-off, that most patients with fatal or debilitating disease would likely accept. Nevertheless, conditional approval requires a strong post-marketing attention from regulators, and lack of enough evidence sometimes leads to difficult decisions. In April 2019 a fast-tracked cancer drug, Lartruvo was withdrawn because a large study was not able to prove a favourable benefit-risk profile, which was established previously on a smaller patient population. The regulators approach is not expected to be changed, but experience from such cases would gradually be built into the decision-making process. In addition to this real world evidence (RWE) and patient recorded outcomes may also help in decision making. 3. Digital revolution The rapid development of biotechnology is not the only area where an adaptive regulatory approach is needed. Digital medicine is a new field, as smartphones and sensors open up new ways of generating data. For example, collecting and analysing RWE seems to be a good solution for single arm studies where randomized trials are not feasible. FDA has approved easy-to-use devices that are able to track several physiological systems of our body, which in turn can give a boost to developments in this field. In addition to these simpler devices, digital revolution in terms of artificial intelligence (AI) and cognitive machine learning is another challenge that our regulatory systems should tackle. It has been recently announced that a new drug candidate, a long-acting and potent serotonin 5-HT1A receptor agonist, which was created using an artificial intelligence platform, will enter into clinical study. There are also numerous radiological applications based on AI, including computer aideddetection and diagnosis software, where images are analysed, and clinically relevant findings suggested to aid diagnostic decisions. Many of these new developments require a tailored approach from regulators to find a way for authorization within the existing regulatory framework. The fact, that many of these new developments are carried out by academic research groups or small companies without extensive regulatory experience, adds an extra layer of difficulty. To meet this challenge, EMA and the Heads of Medicines Agencies have established the EU-Innovation Network, to support medicine innovation and early development. As a milestone of its function, beginning in 1 February 2020 a pilot for simultaneous scientific advice is starting, where the applicants will receive a consolidated advice from the participating agencies. Innovative products often require specific expertise;therefore this new form of advice is also extremely beneficial for regulators as they are able to learn from each other and broaden their knowledge. 4. Conclusions The rapid development of pharmaceutical and digital technology requires a concerted action from all stakeholders. Or, as we all experience, a global pandemic can be an important driving force of the evolution of regulatory policies. Appropriate usage of currently available regulatory tools and a continuous discussion between academia, industry and regulators would be the only way to ensure quick access to state-of-the-art, safe and efficacious medicines, and medical devices. It is clearly shown currently by the concerted action of various stakeholders and series of rolling reviews which led to the expedited authorization of COVID-19 vaccines.

Building a system for accepting COVID-19 cases by applying drug management at a cancer hospital

It was expected that the number of patients with COVID-19 requiring hospitalization would increase worldwide. In the context of the worsening pandemic, the Tokyo Metropolitan Government requested the National Cancer Center Hospital to accept patients with COVID-19. Upon acceptance of the request, six working groups (WGs), i.e., the administrative/medical cooperation group, COVID-19 medical care group, cancer medical care group, medical resource management group, staff work/health management group and infectious disease zoning group, were constituted at our cancer hospital. The objective was to provide appropriate medical care for both cancer patients and patients with COVID-19. A COVID-19-dedicated ward was set up with 23 beds for admission of moderate cases and 2 beds for severe cases. A COVID-19 medical care manual was prepared in collaboration with the COVID-19 treatment team and the infection control team. The Pharmacy Department devised a system by which the ward staff confirmed the drugs that the patients were taking and had brought with them at the time of admission to the COVID-19 ward. The Pharmaceutical Affairs Committee reviewed and approved "off-label use" and "limited patient-only use" of the therapeutic agents favipiravir and ciclesonide for COVID-19. In addition, since the treatment for COVID-19 was prescribed by doctors who were not infectious disease specialists, the pharmacists in the Pharmaceutical Information Section of the Pharmacy Department prepared a master list of drugs with information on each drug that could be prescribed to treat COVID-19, and established a drug-ordering sys¬tem so that there were no errors in the prescription. We accepted patients with COVID-19 for the first time at our hospital in April 2020. We report that we have been able to provide appropriate treatment by applying the in-hospital drug supply system that had been established in the past for cancer treatment. © 2021 Japan Society of Chemotherapy. All rights reserved.

Preliminary analysis of an expanded access study of the fixed-dose combination of pertuzumab (P) and trastuzumab (H) for subcutaneous injection (PH FDC SC) for athome administration (admin) in patients (pts) with HER2-positive (HER2+) breast cancer (BC) during the COVID-19 pandemic

Background: Standard of care for HER2+ early/first-line metastatic BC (EBC/MBC) is P + H and concurrent chemotherapy (CT);PH FDC SC offers faster, more convenient admin vs intravenous (IV) P + H. COVID-19 has caused unprecedented strain on healthcare systems and disruption to cancer care;treatment (Tx) at home may: enable pts to continue cancer Tx;reduce exposure to COVID-19;free up hospital resources. This study's main objectives: to enable continuity of care during COVID-19;to assess safety of PH FDC SC given at home. Methods: This is an ongoing single-arm, hybrid, decentralized clinical trial (NCT04395508). Pts with HER2+ EBC/MBC who completed concurrent CT with P + H IV and are receiving/about to receive maintenance P + H IV, PH FDC SC, or H SC are switched to PH FDC SC given at home by a home health nursing provider (HHNP) until disease progression, unacceptable toxicity, pt withdrawal, or physician recommendation (pts with EBC will complete ≤18 cycles). The study endpoint is safety. A subset of pts took part in HARRIET, a substudy of at-home cardiac surveillance with artificial intelligence-guided cardiac ultrasound and optional 6L ECG acquired by an HHNP. Results: Data for 114 pts (1 male) were available at cutoff (Jan 19, 2022): 18 (16%) completed Tx;20 (18%) discontinued;76 (67%) remain on study;79 (69%) had a COVID-19 vaccine while on study. Median age was 49 years;pts were balanced between EBC (n = 55, 48%) and MBC (n = 59, 52%);received a median of 6 (EBC) and 8 (MBC) cycles;and were from metropolitan (n = 109), urban (n = 4), and rural (n = 1) areas. 11 pts tested COVID-19-positive during the Tx phase: 8 continued Tx after appropriate COVID-19 Tx and/or quarantine. Safety is summarized in the table. No new adverse events (AEs) emerged due to home admin. AEs of special interest were grade (gr) 1-2: admin-related reactions (n = 76, 67%), hypersensitivity (n = 5, 4%), cardiac dysfunction (n = 4, 4%), except 1 case of gr ≥3 diarrhea. AEs leading to study Tx discontinuation or interruption/dose reduction occurred in 3 (3%) and 15 (13%) pts. A subset of 7 pts completed at-home cardiac surveillance testing;quantitative assessment of left ventricular ejection fraction was feasible in 3 (43%);5 (71%) preferred at-home surveillance to clinic. Conclusions: In this preliminary analysis, safety of PH FDC SC at home was consistent with the established P + H safety profile, indicating that PH FDC SC at home is a viable option for continuing BC care during and beyond COVID-19.

Trends in intravenous antibiotic prescriptions pre- and postintroduction of Kaftrio® in a large UK adult cystic fibrosis centre

Background: Since the introduction of Kaftrio® in 2020, people with CF (pwCF) have reported significant health improvements. Real-world experiences over the last 2 years suggest that pwCF are using fewer antibiotics. Evidence has confirmed this is the case with nebulised antibiotics, however it is unclear what the impact has been on intravenous antibiotics (IVABx). Objective: To investigate IVABx use in pwCF, in our centre, pre and post Kaftrio® commencement. Method: Retrospective data was collected from our internal pharmacy database on number of IVABx dose units issued pre and post the widespread use of Kaftrio®. Results: Since Jan 2020, 282 pwCF, 81% of our cohort, have commenced on Kaftrio®;initially via clinical trials and compassionate use programmes, then more widely from August 2020 following its UK licence. (Table Presented) Pharmacy data shows overall IVABx prescriptions have reduced consistently since 2019 with a trend towards less inpatient therapy. Conclusion: Data suggests that the use of IVABx has reduced in our centre since the introduction of Kaftrio®. Other factors which may have influenced IVABx usage during this period include the COVID-19 pandemic, which led to pwCF “shielding” for several months during 2020, providing protection from community acquired infections and potentially increasing anxiety levels around seeking in-patient healthcare. CFHealthHub has also been vital during this time, supporting pwCF to increase their adherence to longterm nebulised treatments. Further work is needed to investigate the trends of antibiotic usage (nebulised and IV) beyond the pandemic and the effect on the long-term health outcomes of pwCF.

COVID-IRIS: Immune reconstitution after G-CSF administration for neutropenia during acute COVID-19 infection

Background: Immune reconstitution inflammatory syndrome (IRIS) is a rapid inflammatory response with immune recovery, most commonly observed following antiretroviral therapy initiation in people with HIV and underlying opportunistic infections. To date there is one reported case of COVID-associated IRIS in a neutropenic patient treated with granulocyte colony-stimulating factor (G-CSF). Here we describe a second case of COVID-associated IRIS in a patient with history of follicular lymphoma who received G-CSF during acute COVID-19 infection. Case: A 64-year-old woman with history of follicular lymphoma and autologous stem cell transplant one year prior presented with dyspnea, diarrhea, and fever, and tested positive for SARS-CoV-2. She had received three doses of the Pfizer BioNTech vaccine. She was admitted to the hospital for acute hypoxic respiratory failure and treated with remdesivir 100mg, dexamethasone 6mg, and 2 L/min supplemental oxygen via nasal cannula for five days. Twelve days after discharge, the patient returned with persistent diarrhea, fatigue, fever, and an oxygen saturation of 87% on room air. She again tested positive for SARS-CoV-2 by PCR. She was admitted to the intensive care unit for high-flow nasal cannula (HFNC) with oxygen at 30 L/min and 50% FiO2 and treated with methylprednisolone 1 mg/kg daily. On admission, her D-dimer was 3943 ng/mL, C-reactive protein 136 mg/L, absolute neutrophil count (ANC) 767/mcL, platelets 84/mcL. Her chest CT scan was negative for pulmonary embolism but demonstrated bilateral ground glass opacities characteristic of COVID-19 pneumonia. Her ANC reached a nadir of 186 on day 3 at which point G-CSF (filgrastim 300 mcg/day) was administered for three days with subsequent neutrophil recovery. On day 6, in light of a negative test for COVID antibodies, she received high-dose monoclonal antibodies through a compassionate use program. At that time, her oxygen requirements were stable and inflammatory markers had decreased to CRP 25 and D-Dimer 940. However, her oxygen requirements and inflammatory markers rapidly increased thereafter, with HFNC settings up to 60L/80%, D-dimer 27754, and CRP 135. After a repeat chest CT on day 8 showed worsened ground glass opacities throughout all lung fields, her steroid dose was increased to methylprednisolone 2 mg/kg daily out of concern for COVID-associated IRIS following G-CSF administration. Her oxygen requirement and inflammatory markers declined over the following 2-3 days and she was transferred out of the ICU. Discussion: We present here an unusual case of COVID-associated IRIS after G-CSF administration in a transplant patient with COVID-19 pneumonia. Given the increased risk of infection and severe illness in immunosuppressed patients despite vaccination, it is important for providers to be aware of complications associated with adjunct therapies such as G-CSF in this vulnerable population.

Compassionate Use of an Anti-C5 Inhibitor, Nomacopan, Positively Influenced the Course and Progression of Disease in Covid-19

Background Originally derived from tick-saliva, nomacopan is a first-in-class dual inhibitor of leukotriene B4 (LTB4) and complement C5. Nomacopan (Coversin) is currently in Phase III development for bullous pemphigoid and HSCT-TMA. In this study, we used nomacopan to treat a small cohort of COVID-19 patients on a compassionate basis. We concurrently present data from a study of biomarkers within a larger cohort of COVID-19 patients, where hyperinflammatory pathways due to complement are highlighted. Methods Patients, healthy-controls and sub-groups recruited to this study are summarised in Figure 1. Betweengroup comparisons in demographic, clinical and biomarker levels were carried out using Kruskal-Wallis and rank-Wilcoxon tests. ROX. SpO2Seven patients (six males and one female) in the CORONET study were treated with nomacopan (1st initial subcutaneous-dose: 45mg of nomacopan (t1/2 = 2.5 hrs), + 2 doses;45 mg, 12-hourly. Subsequently, patients were administered 45mg, od for 12 days. Antibiotic prophylaxis was co-administered. Results ROX indices for patients at enrolment within the CASCADE and CORONET studies were lower than that for normal-healthy individuals, with SpO2 <93%, admitted to ICU or COVID-19 Unit with suspected COVID-19 pneumonia and not on invasive mechanical ventilation on recruitment. Average values for SOFA and NEWS scores were significantly different (p<0.05) between the clinical severities. Values for SOFA and NEWS score were not available for the CORONET study patients.CH50, sC5b-9, C5, C5a, C3, and C3a levels were elevated significantly in CASCADE patients (p<0.05, C.I. 95%).Of the seven patients in the CORONET study, six survived, one (female) died, due to unforeseen circumstances (three days delay to get treatment delivered) from start of symptom onset before starting nomacopan treatment. Conclusion The result of this combined study shows that COVID-19 patients, admitted to hospital with significant symptoms of respiratory difficulty, demonstrated increased circulating levels of components of the complement cascade, potentially linked to lung damage leading to fatality. Interestingly, C5-levels (target of nomacopan) was increased, validating the rationale for anti-C5 treatment of COVID-19 patients. Nomacopan treatment was associated with no noticeable adverse event and without highly elevated as associated with normal C5 and C5a levels. (Figure Presented).

A RECOMBINANT BIO-HDL (CER-001) CAN PREVENT SARS-COV2-INDUCED RENAL DYSFUNCTION BY RESTORING SR-BI SIGNALLING

BACKGROUND AND AIMS: Replication of the enveloped SARS-COV2 virus can alter lipidomic composition and metabolism of infected cells [1]. These alterations commonly result in a decline in HDL, total cholesterol and LDL, and an increase in triglyceride levels in COVID-19 patients. Furthermore, the 'cytokine storm' subsequent to release of inflammatory cytokines can severely impair lipid homeostasis. Importantly, decreased HDL-cholesterol correlates with severity of COVID-19 infection and represents a significant prognostic factor in predicting poor clinical outcomes [2]. Similarly, it has been observed that COVID-19 patients' recovery is accompanied by a rise in serum HDL levels. Pharmacological intervention that aims to restore ApoA-1 or functional HDL particles may have beneficial roles for clinical outcome of COVID-19 patients and has recently been approved for compassionate use [3]. SARS-CoV 2 spike proteins S1 and S2 can bind free cholesterol and HDL-bound cholesterol, facilitating virus entry by binding the ACE2 co-receptor Scavenger Receptor-BI (SR-BI) [4]. When activated at the trans-membrane level, SR-BI signalling culminates in Ser1173-eNOS phosphorylation with both anti-inflammatory and anti-apoptotic effect. We hypothesized that SARS-COV2 binding promoted SR-BI internalization, so that it could not exert its essential protective function. Therefore, the aim of this study is to evaluate the effects of CER-001, a mimetic HDL, in antagonizing this process. METHOD: Endothelial and tubular (RPTEC) cells were exposed to S1, S2 and S1 + S2 (50-250 nM) with or without CER-001 (CER-001 50-500 ug/mL) and cholesterol (10-50 uM). Apoptosis tests (MTT and AnnV/PI) were performed. Internalization of SR-BI, ACE2 with S1 and activation of eNOS was evaluated by FACS analysis. SR-BI and ACE2 expression were evaluated on kidney biopsies from COVID-19 patients. RESULTS: At concentrations used, the exposition of S1, S2 and S1 + S2 in the presence of CER-001 and cholesterol did not induce apoptosis of endothelial cells and RPTEC. Endothelial and tubular cells stimulated by S1, in presence of cholesterol, showed an increased intracellular level of SR-BI and ACE-2, with significantly reduced eNOS phosphorylation compared to baseline (P < 0.05). The treatment with CER-001 reversed trans-membrane SR-BI levels and eNOS phosphorylation to baseline values. The detection of S1 spike protein by endothelial cells immunohistochemistry revealed an increased level in S1-exposed cells with cholesterol and reduced S1 intracellular positive staining in CER-001-exposed cells (P < 0.05). Interestingly, S1-exposed cells without cholesterol appeared not to be capable of mediating S1 spike protein internalization. Consistent with in vitro results, analysis of renal biopsies from COVID-19 patients with proteinuria showed increased SR-BI and ACE-2 cytoplasmic signals and reduced expression at the apical domain of injured tubules. CONCLUSION: Our data confirmed the key role of lipid profile in SARS-COV2 infection, evaluating the molecular signalling involved in HDL metabolism and inflammatory processes, and could offer new therapeutic strategies for COVID-19 patients. (Figure Presented).