Organ Transplantation from Donors with Active SARS-CoV-2 Infection: The Italian Experience

Purpose: In the present study we want to report safety and outcome of organ transplantation from donors with active SARS-CoV-2 infection in Italy. Method(s): In November 2020 the Italian CNT allowed the use of hearts and livers from asymptomatic donors with incidentally discovered active SARS-CoV-2 infection. Organ could be offered to candidates with asymptomatic or resolved COVID-19 or with a full COVID-19 vaccination (3 doses with documented seroconversion) and to Kidney transplant candidates with resolved COVID-19 or with a full course of anti-COVID-19 vaccination. After transplantation all recipients underwent SARS-CoV-2 RNA detection on respiratory secretions on a weekly basis for up to 4 weeks after transplantation. Result(s): From November 21, 2020 to January 23, 2022 we have performed 44 solid organ transplants (33 livers, including 3 split, 5 hearts and 6 kidneys), in 34 males, and 10 females, mean age 49.5 years, range 0-70), from 32 donors (18 males, mean age 47.9, range 14-82) with active SARS-CoV-2 infection and cause of death unrelated to COVID-19. None of the recipients developed a donor derived SARS-CoV-2 infection. Conclusion(s): We believe that the use of non-lung organs from donors with active SARS-CoV-2 infection in selected and consented recipients may contribute to safely increase the donors pool.

A Phase 2 Multicenter, Randomized, Controlled Study to Evaluate the Efficacy and Safety of Reparixin in Hospitalized Adult Patients with COVID-19 Pneumonia

Rationale: Severe coronavirus disease 2019 (COVID-19) is associated with significant morbidity attributed from the complications of acute respiratory distress syndrome. Poor outcomes in severe COVID-19 patients have been related to cytokine release syndrome, which may be mediated by CX- C chemokine ligand 8/interleukin 8 (CXCL8/IL-8) acting through C-X-C chemokine receptor types 1 and 2 (CXCR1/2). The aim of this clinical trial was to determine if CXCR 1/2 blockade by reparixin, an IL-8 inhibitor, can improve clinical outcomes in hospitalized patients with severe COVID-19 pneumonia. Methods: This was a Phase 2, open-label, adaptive, multicenter, randomized trial in hospitalized adult patients, conducted in Italy and Brazil, with severe COVID-19 pneumonia between May and November 2020. Eligible patients had respiratory distress (respiratory rate ≥30 breaths/minute without oxygen and/or partial arterial oxygen pressure (PaO2)/fraction of inspiration O2 (FiO2) >100 to <300 mmHg), pneumonia confirmed by chest imaging, and elevated inflammatory markers. Patients were randomized 2:1 to receive oral reparixin 1200mg three times daily or the standard of care (SOC) for up to 21 days. Patients were followed for up to seven days after the end of treatment. The primary endpoint was defined as a composite of clinical events: use of supplemental oxygen, need for mechanical ventilation, intensivecare unit admission, and/or use of rescue medication. This study was funded by Dompé Farmaceutici SpA (ClinicalTrials.gov: NCT04794803). Results: Fifty-five patients were enrolled and included in the final analysis comparing reparixin (n = 36) to the SOC (n = 19). The rate of clinical events was statistically significantly lower in the reparixin group compared to the SOC group (16.7% [95% CI: 6.4-32.8%] vs 42.1% [95% CI: 20.3-66.5%], p=0.02). After controlling for covariates, this statistical significance was maintained with a hazard ratio of 0.33 (95% CI, 0.11 to 0.99;p = 0.047). Reparixin treatment appeared to be well-tolerated with no discontinuation of therapy. Conclusions: In patients with severe COVID-19, reparixin led to a significant improvement in clinical outcomes when compared to the SOC. The results of this phase 2 study allowed progression to a Phase 3 clinical trial to further explore the efficacy and safety of reparixin for the treatment of severe COVID- 19.

Post-COVID-19 Lung Transplantation Italian Pivotal Protocol: Some Ethical Considerations.

SARS­CoV­2 mostly affects the respiratory system with clinical patterns ranging from the common cold to fatal pneumonia. During the first wave of the COVID-19 pandemic, owing to the high number of patients who were infected with SARS­CoV­2 and subsequently recovered, it has been shown that some patients with post-COVID-19 terminal respiratory failure need lung transplantation for survival. There is increasing evidence coming from worldwide observations that this procedure can be performed successfully in post-COVID-19 patients. However, owing to the scarcity of organs, there is a need to define the safety and efficacy of lung transplant for post-COVID-19 patients as compared to patients waiting for a lung transplant for other pre-existing conditions, in order to ensure that sound ethical criteria are applied in organ allocation. The Milan's Policlinic Lung Transplant Surgery Unit, with the revision of the National Second Opinion for Infectious Diseases and the contribution of the Italian Lung Transplant Centres and the Italian National Transplant Centre, set up a pivotal observational protocol for the lung transplant of patients infected and successively turned negative for SARS­CoV­2, albeit with lung consequences such as acute respiratory distress syndrome or some chronic interstitial lung disease. The protocol was revised and approved by the Italian National Institute of Health Ethics Committee. Description of the protocol and some ethical considerations are reported in this article.

Short-term evaluation of alemtuzumab to ocrelizumab switch in MS patients with disease activity after alemtuzumab: An Italian multicentric study

Objective: To evaluate efficacy and Safety of multiple sclerosis (MS) patients (pts) who switched to ocrelizumab (OCR) due to persistence of disease activity after two courses of alemtuzumab (ALM) Background: The management of MS pts who show disease activity after 2 ALM courses represents an unsolved issue Design/Methods: MS patients who switched from ALM to OCR from March 2019 to March 2020 were retro-A nd prospectively recruited from different Italian MS Centers. Clinical, immunological and neuroradiological data about ALM treatment period, ALM-OCR interval and OCR treatment period were collected Results: 23 MS pts [mean age: 35.7(6.8);female, 40.1%;Relapsing Remitting, (RR): 75.8%, active Secondary progressive, (aSP): 24.2%;mean time interval (days) from II ALM course 87.4(108);cumulative number of relapses: 21;mean number of new T2 and Gd+ lesions: 4.1(4.5) and 1.6(3.1);median EDSS:3(range 1-7)]. The mean follow-up (FU) from OCR start: 7.9±7.4 months. 4 (17.4%) pts had a relapse after OCR start (1 during the interval between first and the second OCR infusion and 3 pts after 3, 11 and 15 months from OCR start. 4 (17.4%) pts showed only radiological activity at 3 (n=2), 4 (n=1) and 9 months (n=1). Infusion Associated Reactions occurrence was lower than ALM courses (p<0.05) ;mild upper airways (n=1), urinary infections (n=1), appendicectomy (n=1) and fever due to probable Sars-Cov2 infection (n=1). No pts showed T CD4+ cell count <200 cell/mm3 at 3, 6-months and 1-year FU;B CD19+ cell depletion (<5 cell/mm3) was confirmed at 3, 6-months and 1-year FU with the exception of 1 pt (B CD19+ count 12 cells/mm3 at 6 month FU (n=12 pts)). 10 (43.4%) pts developed hypogammaglobulinemia without infectious events. No ALM-related new complications occurred. Conclusions: Short-term FU suggests that the switch to OCR in MS after 2 ALM courses is characterized by a good safety and efficacy profile.

Short-term evaluation of alemtuzumab to ocrelizumab switch in MS patients with disease activity after alemtuzumab: An italian multicentric study

Background: the management of MS patients (pts) who show disease activity after 2 alemtuzumab (ALM) courses represents an unsolved issue. No real-life data about the switch to ocrelizumab (OCR) have been reported yet. Objectives: To describe efficacy and safety outcome of OCR patients switching from ALM due to persistence of disease activity after ALM Methods: MS pts who switched from ALM to OCR from March 2019 to March 2020 were retro- and prospectively recruited from different Italian MS Centers. Clinical, immunological and neuroradiological data about ALM treatment period, ALM-OCR interval and OCR treatment period were collected. Results: we recruited 23 MS pts [mean age: 35.7(SD±6.8);female, 40.1%;Relapsing Remitting, (RR): 75.8%, active Secondary progressive, (aSP): 24.2%;mean time interval (days) from II ALM course: 87.4(SD±108);cumulative number of relapses: 21;mean number of new T2 and Gd+ lesions: 4.1(SD±4.5) and 1.6(SD±3.1);median EDSS:3(range 1-7)]. The mean follow-up (FU) from OCR start was 7.9±7.4 months. Efficacy: 4 (17.4%) pts had a relapse after OCR start (1 pt relapsed between the first and the second OCR infusion and 3 pts after 3, 11 and 15 months from OCR start respectively), with complete recovery after steroid treatment. 4 (17.4%) pts showed radiological activity with no clinical correlates at 3 months (n=2), 4 months (n=1) and 9 months (n=1). EDSS was stable except for 1 aSP patient who showed 1-year disability progression. Safety: I) Infusion Associated Reactions (IARs) occurrence was significantly lower with respect to alemtuzumab courses (p<0.05);(ii) infections: mild upper airways (n=1), urinary infections (n=1), appendicectomy (n=1) and fever due to probable Sars-Cov2 infection (n=1). For 12 pts, data about immunophenotype were available. Of them, no pts showed T CD4+ cell count decrease <200 cell/mm3 at 3, 6-months and 1-year FU;complete B CD19+ cell depletion (<5 cell/mm3) was confirmed at 3, 6-months and 1-year FU. 10 (43.4%) pts developed hypogammaglobulinemia without developing associated infectious events. C) Autoimmunity: no alemtuzumab-related new complications occurred. Conclusions: short-term FU seems to suggest that the switch to OCR in MS patients who showed disease activity after 2 ALM courses is characterized by a good safety and efficacy profile, although clinical and neuroradiological activity can be detected both in an early and in a later phase of treatment. Longer followup is warranted and recruitment is still ongoing.