Safety and Immunogenicity of the AntiCOVID19 Vaccines in a Cohort of Lung Transplant Recipients

Lung transplant recipients (LuTxR) are at greater risk of COVID-19 and have attenuated response to vaccinations. In Italy, immunocompromised patients received the indication to be administered mRNA vaccines only. We aimed to evaluate the safety and immunogenicity of these vaccines in our cohort of LuTxR;we are now presenting the preliminary data of their serologic responses. We conducted a single-center observational prospective study including all consecutive LuTxR who were administered two doses of mRNA antiCOVID19 vaccine at our institution in March 2021;NCT05116748. We investigated the incidence of systemic and local adverse events and, in order evaluate immunogenicity, we used ImmunoAssay in ECLIA for the quantitative detection of anti-protein S1 (spike) antibodies (including IgG) on venous blood samples at 60 and 80 (+/- 10) days from the vaccine administration. 116 patients were enrolled, 52 females. Table 1 summarizes the basic characteristics of our population. Figure 1 focalizes on different serologic responses based on immunosuppressive regimens. No serious adverse events were reported. The most common solicited adverse events were fever (52% of our patients), headache, fatigue, myalgia, chills, and injection-site pain. Our initial findings are reassuring. Humoral SARS-CoV-2 specific immunity in our cohort of patients tended to be stronger than expected. mRNA vaccines appeared to be safe in the transplant population, and have not raised serious concern about the possible onset of graft dysfunction or other serious adverse events in the first period after their administration. [ABSTRACT FROM AUTHOR] Copyright of Journal of Heart & Lung Transplantation is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Insights into the lung microenvironment after severe COVID-19

The SARS-CoV-2 is the betacoronavirus responsible for the coronavirus disease 2019 (COVID-19) pandemic. Severe COVID-19 affects approximately 10-15% of patients and results in prolonged morbidity and mortality. Little is known about the immunophenotypic changes of the lung parenchyma driven by the viral infection in patients who die of severe COVID-19. Ultrasound-guided lung biopsies (LB) were collected (IRB approval#1561/21) within few hours from death in 15 severe COVID-19 patients between November 2020 and January 2021, in two patients who underwent lung transplantation after COVID-19 and in one patient who had surgery for bacterial superinfection during COVID-19 disease. All samples underwent histologic and immunohistochemistry evaluation and molecular profiling using the nCounter Host Response and Coronavirus Panel plus. As controls, lungs from end-stage usual interstitial pneumonia (UIP;n=9) and from lobectomy for lung cancer (Norm;n=5) were used. Eleven lungs (61%) were positive for SARS-CoV-2 RNA. Signs of diffuse alveolar damage (DAD) were observed in 6 patients (30%). COVID-19 lungs showed a marked macrophage infiltration with M2 polarization compared with controls. Globally, COVID-19 lungs showed distinct molecular profiles from UIP or Norm lungs. Specifically, a marked upregulation of interferon-genes that was directly correlated with SARS-CoV-2 genes was seen in COVID-19 lungs. COVID-19-specific genes signatures (Log2FC >1.5;adj p<0.05) obtained using VENN diagram showed impairment of the STAT3-pathway accompanied by the upregulation of the NFkB signaling. Results herein provide new insights into lung alterations induced by severe COVID-19 and suggest novel potential targets for therapeutic intervention.

Telemonitoring: An Opportunity to Improve Multidisciplinary Care in Lung Transplanted Patients

Purpose: Telemedicine has been successfully employed in a wide range of specialties. We hereby present the results of a pivotal study we ran in our centre just before the COVID19 pandemic. Methods: This was a prospective study including all adult cystic fibrosis patients who underwent lung transplant (LuTx) from September 2017 to August 2019. Patients were randomized into two groups;patients assigned to the first arm (intervention) received a home medical assistant (HMA) system device, to which a pulse oximeter and a spirometer with reusable turbine were integrated;they were asked to perform a spirometry and register their SpO2 at rest and on effort on a twice-weekly basis. All the data were digitally transmitted to our centre, where physiotherapists and physicians were able to analyse them real-time. Both the groups received traditional hospital-based follow-up. Results: 32 patients were enrolled, 16 in each group. No statistically significant difference was found between the two groups (see Table 1).With reference to the telemonitoring group:- Adherence to telemonitoring significantly decreased during the 12months period of follow up (see figure 1).- Hospital reported data were consistent with the last being registered with the HMA device.- Of note, two patients were requested to anticipate their hospital routine visit because of a FEV1 decrease being reported on their HMA device, in order to rule out possible acute lung allograft dysfunction.- 13 out of 16 patients reported a high degree of satisfaction with the telemonitoring experience. Conclusion: The COVID19 pandemic highlighted the necessity to investigate alternative practices to treat chronically ill individuals. In our study, telemonitoring proved to be a valuable tool to improve quality health care to LuTx recipients, especially for those who live far from the transplant centre. We are now implementing this approach scheduling online video consultations. Further research should be focused on standardizing quality of telemedicine services.

COVID19 in Lung Transplanted Patients: Chronicles from an Italian Epicenter

Purpose Lombardy was one of the hardest hit regions in Italy during the COVID19 pandemic. We hereby report our experience with SARS-CoV2 infection in lung transplant recipients. Methods We retrospectively collected clinical data on all the consecutive cases of COVID19 in our centre, based in Milan, from March 2020 to August 2021. Diagnosis was always confirmed by a positive nucleic acid amplification test (RT-PCR) for SARS-CoV-2 on nasopharyngeal swab and/or tracheal aspirate. Results 21 patients were diagnosed with COVID19. Figure 1 summarizes the clinical course of these individuals. We reduced immunosuppressive regimen in all these patients, typically holding the antiproliferative agent and augmenting steroids;when hospitalized, everybody received initial empiric antibiotic treatment with piperacillin/tazobactam and high-dose LMWH. Hydroxychloroquine was used only in the "first wave" (4 patients). One patient was compassionately administered anakinra and remdesivir as a “rescue therapy”. Lymphocitopenia was a common presenting sign (14 patients, 66%). Aspergillus co-infection occurred in 5 patients (24%). Mortality rate was 29%;4 out of these 6 patients were affected by CLAD and 3 had chronic kidney disease. Of note, in March 2021, we tested all our patients for anti-SARS-CoV-2 nucleocapsid antibodies before starting vaccinations: we found three additional seropositive patients, who were not included in the present analysis, but had been presumably affected by an asymptomatic/mild form of the disease. Conclusion Apart from immunosuppression, the majority of our patients presented at least one risk factor for mortality in COVID-19 (diabetes, chronic kidney disease, arterial hypertension) and, for this reason, we felt that they should be hospitalized to enable close monitoring and prompt management of possible complications and deterioration. Clinical course seemed favorable in only two thirds of our patients but, for the time being, none of these individuals showed sign of new-onset CLAD after COVID19.

SARS-CoV-2 infection in cystic fibrosis during the first pandemic wave in Italy: a multi-centre prospective study with a control group

Background: Patients with cystic fibrosis (CF) are at high risk of developing severe forms of viral respiratory infections. This study aimed at comparing symptoms and clinical course of SARS-CoV2 infection with other respiratory infections in patients with CF. Methods: We carried out a prospective multicentre cohort study within the Italian CF Society involving 32 CF centres following 6,597 patients. CF centres were contacted to collect baseline and follow-up data of all patients who had reported symptoms suggestive of COVID-19 or who had had contact with a positive/suspected case between the end of February and July 2020. Symptoms and clinical course of the infection were compared between patients who tested positive by molecular testing (cases) and those who tested negative (controls). Results: Thirty patients were reported from the centres, 16 of whom tested positive and 14 negative. Fever, cough, asthenia and dyspnea were the most frequently reported symptoms and their frequency were not significant different between groups. Eight cases (50%) were hospitalised but none required ICU admission. Two adults with a history of lung transplant required non-invasive ventilation;none required ICU admission. All patients fully recovered without short-term sequelae. Changes in FEV1 (percent of predicted) after recovery were not significantly different between groups (median, interquartile range: 3.0%, –1.5, 5.5 among cases and –3.0%, –8.5, 6.3 among controls, P = 0.48). Conclusions: Symptoms and clinical course of SARS-CoV-2 infection in our patients was not significantly different from other respiratory infections. The clinical course of COVID-19 was relatively favourable, however CF patients with severely impaired respiratory function and organ transplant may develop complications and a negative outcome. The study is ongoing, and we are recruiting patients during the second wave of the pandemic.

Lung Allograft Dysfunction in a COVID-19 Transplanted Patient is Associated with a Peculiar Immunopathological Phenotype

Purpose Lung transplantation (LT) after severe SARS-CoV-2 infection is emerging as a life-saving medical procedure for selected patients who experience acute respiratory distress syndrome (ARDS). We present the first immunopathological evaluation of a lung allograft rejection in a patient who underwent LT because of irreversible ARDS related to COVID-19. Methods Two male patients with irreversible ARDS caused by COVID-19 underwent bilateral LT at our Institution. A surveillance transbronchial biopsy (TBB) was performed 2 months after LT in the first patient (Pt#1), while the second patient (Pt#2) died because of allograft rejection at day 62 post LT and explanted lungs were retrieved. CT imaging of the lungs was performed three days before death. Morphological examination was performed by H&E, whereas the immunophenotyping was performed by immunohistochemistry. Results Imaging and morphological examination of Pt#2 lungs indicated the presence of a graft dysfunction with features of a restrictive, widespread usual interstitial pneumonia-like syndrome (Fig. 1A, B). The immunophenotyping showed that B-lymphocytes (CD20-positive) were nearly absent, CD8-T-cells were not particularly expanded (mean positive cells within the lung stroma=13.8%;Fig. 1C), and the CD4/CD8 ratio was not decreased (Fig. 1D). The T-regs (Foxp3-positive) were 6% of the overall population (Fig. 1E). Analysis of the immune checkpoint molecules PD1, Tigit, CTLA4 and PDL1 showed that the expression of PD-L1 alone was highly increased in vases and in alveolar cells of rejected lungs, whereas it was nearly undetectable in the TBB from Pt#1 (Fig. 1F, G). Conclusion PDL1 expression in vases was previously documented as a sign of indirect ARDS. Together with our preliminary data, we can hypothesize that PDL1 may play a role in tissue effacement and graft failure, possibly indicating poor allograft prognosis.

Lung Transplantation for Acute Respiratory Distress Syndrome Related to COVID-19: The Lesson Learned from the First Two Cases

Purpose The respiratory system, and namely the lung, is undoubtedly the preferential target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The clinical pictures are extremely various, up to the intensive care unit (ICU) admission for acute respiratory distress syndrome (ARDS). Lung transplantation (LT) is a consolidate therapeutic option for end-stage chronic respiratory diseases. Its role in an acute setting is questionable, particularly due to lack of experiences, donor shortage, and the difficulty to fully evaluate the potential recipient. We report our preliminary experience with the first two cases of LT for SARS-CoV-2 related ARDS, trying to provide some food for thought. Methods We retrospectively analysed our first two cases of bilateral LT for ARDS after COVID-19. We recorded data on pre-transplantation clinical course, transplantation management and outcomes. Results The two patients had a similar clinical evolution of COVID-19. Transplantations were successful in both cases;the first patient is alive and in good condition 5 months after transplantation, while the second died 62 days after surgery. Table 1 shows clinical details and relevant time-points. Conclusion Our experience showed that LT for COVID-19 is feasible. Importantly, observing a dedicated protocol made the procedure safe for the healthcare staff involved. On the other hand, our second unsuccessful case poses relevant questions: first of all, lung transplantation should be reserved to highly selected patient, after careful clinical, infective as well as psychiatric evaluation. The ethical aspects should also be considered in this situation, with regard to the centre rate mortality on waiting list. Anyway, the potential role of LT in the acute and sub-acute/chronic settings suggests the need for maintaining LT centre active during pandemic. Finally, COVID-19, once more, imposes to share clinical experiences.