Simultaneous Lung and Kidney Transplant in a Young Patient with COVID-19

Purpose: Lung transplant is the last resort for COVID-19 refractory ARDS. Dual organ transplant is seen as a relative contraindication at many institutions. We describe a case of simultaneous Lung-Kidney transplant (SLK) in a patient with COVID-19 ARDS. Method(s): A 24-year-old patient with no PMH presented to an outside hospital with a week of shortness of breath, cough, and fever. Despite treatment with Remdesivir and dexamethasone, the patient developed hypoxemic respiratory failure with acute renal injury requiring ICU care and intubation, V-V ECMO, and dialysis. Additionally, Intravenous and inhaled Aviptadil were given under emergency use authorization. While oxygenation improved, the patient could not be weaned off ECMO. With a LAS score of 90.29, the patient underwent an SLK transplant on HD 53, requiring standard induction and maintenance immunosuppression therapy. The patient was treated post-operatively for PGD as well as for subclinical AMR. After successful inpatient rehabilitation, the patient was discharged home after four months and had a one-month follow-up on room air and normal creatinine clearance. Result(s): Patients with pre-existing renal dysfunction who have undergone lung transplants have a significantly higher one- and three-year mortality than patients with normal GFR. The patient's survival after SLK was similar to isolated lung transplants at one and five years, according to an analysis of the UNOS/OPTN database. Still, dual organ transplant in the COVID-19 ARDS population is considered a contraindication at many centers, given these patients' critical illness and frailty. However, the frailty in this population is reversible due to the rapid onset of disease in an otherwise previously healthy younger population with minimal comorbidities. Thus, multiorgan transplantation should be considered in such a patient population. Our patient received Aviptadil as part of an EIND to stabilize patients and improve oxygenation while waiting on the transplant list. Conclusion(s): We propose that SLK transplantation should be considered for carefully selected patients with COVID-19 ARDS.

Inhaled aviptadil for the possible treatment of COVID-19 in patients at high risk for ARDS: study protocol for a randomized, placebo-controlled, and multicenter trial.

BACKGROUND: Despite the fast establishment of new therapeutic agents in the management of COVID-19 and large-scale vaccination campaigns since the beginning of the SARS-CoV-2 pandemic in early 2020, severe disease courses still represent a threat, especially to patients with risk factors. This indicates the need for alternative strategies to prevent respiratory complications like acute respiratory distress syndrome (ARDS) associated with COVID-19. Aviptadil, a synthetic form of human vasoactive intestinal peptide, might be beneficial for COVID-19 patients at high risk of developing ARDS because of its ability to influence the regulation of exaggerated pro-inflammatory proteins and orchestrate the lung homeostasis. Aviptadil has recently been shown to considerably improve the prognosis of ARDS in COVID-19 when applied intravenously. An inhaled application of aviptadil has the advantages of achieving a higher concentration in the lung tissue, fast onset of activity, avoiding the hepatic first-pass metabolism, and the reduction of adverse effects. The overall objective of this project is to assess the efficacy and safety of inhaled aviptadil in patients hospitalized for COVID-19 at high risk of developing ARDS. METHODS: This multicenter, placebo-controlled, double-blinded, randomized trial with 132 adult patients hospitalized for COVID-19 and at high risk for ARDS (adapted early acute lung injury score ≥ 2 points) is conducted in five public hospitals in Europe. Key exclusion criteria are mechanical ventilation at baseline, need for intensive care at baseline, and severe hemodynamic instability. Patients are randomly allocated to either inhale 67 µg aviptadil or normal saline (three times a day for 10 days), in addition to standard care, stratified by center. The primary endpoint is time from hospitalization to clinical improvement, defined as either hospital discharge, or improvement of at least two levels on the nine-level scale for clinical status suggested by the World Health Organization. DISCUSSION: Treatment strategies for COVID-19 are still limited. In the context of upcoming new variants of SARS-CoV-2 and possible inefficacy of the available vaccines and antibody therapies, the investigation of alternative therapy options plays a crucial role in decreasing associated mortality and improving prognosis. Due to its unique immunomodulating properties also targeting the SARS-CoV-2 pathways, inhaled aviptadil may have the potential to prevent ARDS in COVID-19. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04536350 . Registered 02 September 2020.

A Safety Monitoring Framework for Critical Care Trials of Agents with Potential to Lower Blood Pressure

RATIONALE: Based on encouraging preliminary data, we undertook a randomized, placebo-controlled trial of synthetic vasoactive intestinal peptide (aviptadil) for treatment of COVID-19 acute respiratory distress syndrome (ARDS). Aviptadil may cause vasodilation and resultant hypotension. Given the high background incidence of hypotension from many causes (e.g., sedatives, sepsis, positive pressure ventilation) in critically ill patients, an ascertainment and grading strategy for postrandomization hypotension capable of distinguishing “signal” from “noise” is essential to the trial's conduct and interpretation. METHODS: We evaluated whether existing adverse event (AE) severity frameworks were adequate to characterize hypotension occurring in critically ill patients. Based on these findings, we developed and implemented a customized framework for hypotension-related safety monitoring and outcome collection during the Therapeutics for Severely Ill Inpatients with COVID-19 (TESICO) trial of aviptadil for COVID-19 ARDS (NCT04843761). RESULTS: Hypotension severity assigned to COVID-19 ARDS patients by existing AE frameworks - largely developed for outpatients - appeared misaligned with the frameworks' own generic/conceptual severity criteria. Existing frameworks' hypotension-specific AE grading tables lacked necessary detail and reporting guidance, over-graded mild hypotension, and missed safety signals suggested by increasing vasopressor requirements. We therefore developed a novel hypotension AE grading table aligned with conceptual AE severity criteria for critically ill patients (Figure). In addition to general severity criteria, the table adds criteria specific to the investigational agent's peri-infusion period and provides guidance for evaluating the “seriousness” of a hypotensive event in the context of subjects' preexisting critical illness. In combination with detailed reporting on the components of AE events, the study's protocol committee, sponsor, and data safety monitoring board approved the customized table for use in outcome measurement as well as real-time safety monitoring and AE reporting. We implemented a strategy to efficiently collect the hypotension-related data required for safety monitoring and allow automated hypotension AE grading according to both the adopted schema and existing AE frameworks. CONCLUSIONS: We developed a framework acceptable to diverse stakeholders for hypotension safety monitoring in COVID-19 ARDS patients receiving aviptadil or placebo. The monitoring framework will be validated in the ongoing TESICO trial and could be adapted for other trials of vasoactive investigational agents targeting critically ill patients. Comprehensive AE grading criteria designed specifically for critically ill patients could improve trials' ability to meaningfully monitor and report safety outcomes in this population.

RECOVERY and SURVIVAL in COVID-19 RESPIRATORY FAILURE, WHEN TREATED with AVIPTADIL

Background: COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Vasoactive Intestinal Peptide (VIP) blocks replication of the SARS-CoV-2 virus in alveolar type II cells, inhibits cytokine synthesis, prevents cytopathy, and up regulates surfactant production. Synthetic VIP-aviptadil is a novel strategy to treat patients with COVID-19 and respiratory failure. Methods: This was a prospective, multicenter, randomized, placebo-controlled trial with 196 patients, nasal swab PCR+ for COVID-19 receiving intensive care at 10 U.S. hospitals (6 tertiary care and 4 regional hospitals) to determine if intravenous aviptadil is superior to placebo in achieving recovery from respiratory failure and survival at 60 days post treatment. The analysis was by modified intent to treat (ITT) using a pre-specified logistic regression model. The primary pre-specified endpoint was being alive with no respiratory failure at day 60. Results: There were 213 subjects screened, with 203 eligible and 196 randomized and treated. Baseline characteristics were comparable except for worse NIAID severity for aviptadil (Table 1). All subjects were followed up to 60 days. A favorable trend (OR 1.63;P=.14) was seen for the primary endpoint at 60 days with significance achieved after adjusting for hospital setting. Overall, there was 2.0-fold increased odds of survival (95% CI 1.05-3.88;P<.035) for aviptadil at Day 60 controlling for baseline NIAID score. Odds of survival increased to over 4-fold after adjusting for site of care (Tertiary care vs regional hospital, OR 4.35 (95% CI 1.91, 9.90;P<.035). Logistic regression indicated aviptadil treated patients were also significantly more likely to be discharged earlier than placebo-treated patients (p=0.01). The most common adverse events noted were diarrhea (32.8% vs. 1.5%) and hypotension (26% vs.21.5%) for aviptadil vs. placebo. Additional adverse events occurring more frequently in aviptadil treated patients included acute kidney injury (23.7% vs 20%), hyperkalemia (12.2% vs 6.2%), and atrial fibrillation (11.5% vs 4.6%). Multiple organ dysfunction syndrome (6.9% vs 13.8%) and respiratory failure (12.2% vs 13.8%) occurred more commonly in placebo-treated patients. Conclusion: Treatment with aviptadil demonstrates efficacy in improving the likelihood of recovering from respiratory failure, surviving to 60 days, and reducing hospital stay in critically ill patients with respiratory failure caused by COVID-19.

Anticipated pharmacological role of Aviptadil on COVID-19.

Vasoactive intestinal peptide (VIP) is a neuropeptide that is produced by the lymphoid cells and plays a major role in immunological functions for controlling the homeostasis of the immune system. VIP has been identified as a potent anti-inflammatory factor, in boosting both innate and adaptive immunity. Since December 2019, SARS-Cov-2 was found responsible for the disease COVID-19 which has spread worldwide. No specific therapies or 100% effective vaccines are yet available for the treatment of COVID-19. Drug repositioning may offer a strategy and several drugs have been repurposed, including lopinavir/ritonavir, remdesivir, favipiravir, and tocilizumab. This paper describes the main pharmacological properties of synthetic VIP drug (Aviptadil) which is now under clinical trials. A patented formulation of vasoactive intestinal polypeptide (VIP), named RLF-100 (Aviptadil), was developed and finally got approved for human trials by FDA in 2001 and in European medicines agency in 2005. It was awarded Orphan Drug Designation in 2001 by the US FDA for the treatment of acute respiratory distress syndrome and for the treatment of pulmonary arterial hypertension in 2005. Investigational new drug (IND) licenses for human trials of Aviptadil was guaranteed by both the US FDA and EMEA. Preliminary clinical trials seem to support Aviptadil's benefit. However, such drugs like Aviptadil in COVID-19 patients have peculiar safety profiles. Thus, adequate clinical trials are necessary for these compounds.