Search

The prevalence of anti-SARS-CoV-2 antibodies in people with cystic fibrosis (CF) is largely unknown. We carried out a cross-sectional study between March and June 2021 with the aim of estimating the seroprevalence of anti-SARS-CoV-2 antibodies in two CF centres in Northern Italy. Total serum anti-SARS-CoV-2 (spike) antibodies levels were measured and values ≥0.8 U/mL were considered positive. Among 434 patients aged >12 years, 64 patients had a positive result (14.7%, 95% CI: 11.5–18.4), 36 (56.3%) without experiencing any COVID-19-related symptoms. Three out of 49 transplanted patients tested positive with an odds ratio for a positive result among transplanted as compared to non-transplanted patients of 0.35 (95% CI: 0.07–1.14). No significant differences were observed between sexes, age groups, socioeconomic status and lung disease severity. In conclusion, SARS-CoV-2 has infected a relatively high proportion of our patients but in most cases the infection was asymptomatic.

Introduction The clinical trajectory of post-operative acute kidney injury (AKI) following lung transplantation for cystic fibrosis is unknown. Methods Incidence and risk factors for post-operative AKI, acute kidney disease (AKD) and chronic kidney disease (CKD) were retrospectively analyzed in cystic fibrosis patients undergoing lung transplantation. Logistic regressions, Chi-square, Cuzick rank tests, and Cox-proportional hazard models were used. Results Eighty-three patients were included. Creatinine peaked 3[2–4] days after transplantation, with 15(18%), 15(18%), and 20(24%) patients having post-operative AKI stages 1, 2, and 3, while 15(18%), 19(23%) and 10(12%) developed AKD stage 1, stage 2 and 3, respectively. Higher AKI stage was associated with worsening AKD (p = 0.009) and CKD (p = 0.015) stages. Of the 50 patients with AKI, 32(66%) transitioned to AKD stage > 0, and then 27 (56%) to CKD stage > 1. Female sex, extracorporeal membrane oxygenation support as a bridge to lung transplant and at the end of the surgery, the use of intraoperative blood components, and cold-ischemia time were associated with increased risk of post-operative AKI and AKD. Higher AKI stage prolonged invasive mechanical ventilation (p = 0.0001), ICU stay (p = 0.0001), and hospital stay (p = 0.0001), and increased the incidence of primary graft dysfunction (p = 0.035). Both AKI and AKD stages > 2 worsened long-term survival with risk ratios of 3.71 (1.34–10.2), p = 0.0131 and 2.65(1.02–6.87), p = 0.0443, respectively. Discussion AKI is frequent in cystic fibrosis patients undergoing lung transplantation, it often evolves to AKD and to chronic kidney disease, thereby worsening short- and long-term outcomes. Graphical abstract

The acceptable duration of donor warm ischemia time (DWIT) after cardiocirculatory death (DCD) is still debated. We analyzed the biomolecular profile and function during ex vivo lung perfusion (EVLP) of DCD lungs and their correlation with lung transplantation (LuTx) outcomes. Donor data, procurement times, recipient outcomes, and graft function up to 1 year after LuTx were collected. During EVLP, the parameters of graft function and metabolism, perfusate samples to quantify inflammation, glycocalyx breakdown products, coagulation, and endothelial activation markers were obtained. Data were compared to a cohort of extended-criteria donors after brain death (EC-DBD). Eight DBD and seven DCD grafts transplanted after EVLP were analyzed. DCD’s DWIT was 201 [188;247] minutes. Donors differed only regarding the duration of mechanical ventilation that was longer in the EC-DBD group. No difference was observed in lung graft function during EVLP. At reperfusion, “wash-out” of inflammatory cells and microthrombi was predominant in DCD grafts. Perfusate biomolecular profile demonstrated marked endothelial activation, characterized by the presence of inflammatory mediators and glycocalyx breakdown products both in DCD and EC-DBD grafts. Early graft function after LuTx was similar between DCD and EC-DBD. DCD lungs exposed to prolonged DWIT represent a potential resource for donation if properly preserved and evaluated.

Highlights • An atypical clinical presentation of early antibody-mediated rejection in COVID era. • The radiological features mimicked SARS-CoV2 pneumonia, but tests were negative. • This is the first report of lung transplantation in the COVID era in Europe. • Decide whether to keep lung transplantation programmes open in a COVID Hospital., Introduction In addition to morbidity and mortality rate per se, COVID-19 outbreak leads to potential ‘side effects’, which are difficult to evaluate and predict. Lung transplantation is a consolidated treatment for end-stage chronic lung disease requiring significantly demanding management. Deciding whether to keep transplant programmes open during an epidemic of this size is not easy, as immunosuppressed subjects face the risk of infection and related mortality. Additionally, there is a chance for the patient’s standard care process to be compromised. Presentation of case We report the case of a patient undergoing bilateral lung transplantation during the explosion of COVID-19 epidemic in Lombardy; he died from definite early acute antibody-mediated rejection, clinically (persistent high fever, unresponsive to treatment) and radiologically mimicking viral pneumonia but persistently negative for SARS-CoV-2. Discussion The diagnosis was difficult given this atypical presentation, confounded by global scenario. Grafts were procured from a donation after circulatory death donor in an uncontrolled setting and a donor-recipient transmission was possible. Our institute became a COVID-Hospital right during the first post-transplantation days. Radiological imaging had the same features of SARS-CoV-2 pneumonia. Conclusions This is the first report of lung transplantation of the COVID-19 era in Europe. Our extremely fragile patient was COVID-19 free up to the end. Donor-recipient transmission is conceivable, but the risk should be assessed with respect to waiting list mortality. Ultimately, treating COVID-19 patients can be a resource-consuming activity but we decided to keep our centre open.

Highlights • Lung donation after cardiac death is a valuable option to fight organ shortage. • Grafts from an extended uncontrolled DCD donor were transplanted. • The recipient was a high-risk fragile patient with cystic fibrosis. • Ex-vivo lung perfusion has a pivotal role in graft function evaluation. • Good results were achieved despite several relative contraindications., Introduction Lung donation after circulatory death (DCD) has proved to be an effective strategy for expanding the donor pool, but is still considered challenging. We report a successful case of lung procurement from an extended-criteria uncontrolled DCD. Presentation of case We evaluated the lungs of an uncontrolled DCD from a hospital without extracorporeal membrane oxygenation (ECMO) program. The donor was a non-smoker 20-year old male with a history of cardiomyopathy, cardiocirculatory arrests, and Lennox-Gastaut syndrome. Cardiac arrest occurred in a swimming pool, and bronchoscopy showed signs of inhalation. We employed our usual normothermic in-situ open-ventilated lung approach. After retrieval, lungs were stored on ice, then evaluated with ex-vivo lung perfusion (EVLP) and judged suitable for transplantation. The recipient was a 26-year old female with cystic fibrosis on long-term oxygen therapy, on the waitlist for up to 21 months due to her anthropomorphic characteristics. She required central VA-ECMO support during bilateral lung transplantation. Primary graft dysfunction (PGD) within the first 72 h reached grade 3; post-operative peripheral VV-ECMO support was discontinued two days after surgery. The patient was discharged 28 days after surgery; she is alive two years after transplantation with no signs of rejection nor anastomotic complications. Discussion Despite the spreading use of lungs from controlled DCD, perplexities remain on uncontrolled DCD, namely: severe PDG, postoperative mortality, airway complications. Conclusion Our case report suggests that good results can be achieved with uncontrolled DCD despite the presence of relative contraindications: inhalation of water, prolonged ischemic times and recipient in poor conditions.

Outcomes after transplantation of lungs (LuTX) treated with ex-vivo lung perfusion (EVLP) are debated. In a single-center 8 years of retrospective analysis, we compared: donors' and recipients' characteristics, gas exchange and lung mechanics at ICU admission, 3, 6, and 12 months, and patients' survival of LuTX from standard donors compared with EVLP-treated grafts. A total of 193 LuTX were performed. Thirty-one LuTX, out of 50 EVLP procedures, were carried out: 7 from nonheart beating and 24 from extended criteria brain-dead donors. Recipients' characteristics were similar. At ICU admission, compared with standard donors, EVLP patients had worse PaO2 /FiO2 [276 (206; 374) vs. 204 (133; 245) mmHg, P < 0.05], more frequent extracorporeal support (18% vs. 32%, P = 0.053) and longer mechanical ventilation duration [28 days of ventilator-free days: 27 (24; 28) vs. 26 (19; 27), P < 0.05]. ICU length of stay [4 (2; 9) vs. 6 (3; 12) days, P = 0.208], 28-day survival (99% vs. 97%, P = 0.735), and 1-year respiratory function were similar between groups. Log-rank analysis (median follow-up 2.5 years) demonstrated similar patients' survival (P = 0.439) and time free of chronic lung allograft disease (P = 0.484). The EVLP program increased by 16% the number of LuTX. Compared to standard donors, EVLP patients had worse respiratory function immediately after LuTX but similar early and mid-term outcomes.

Aims Primary graft dysfunction (PGD) is a form of acute lung injury, that occurs after lung transplantation (LTx), characterized by pulmonary oedema and diffuse alveolar damage. Pulmonary hypertension is a well-known risk factor for PGD and some invasive and non-invasive studies showed an association between PGD and altered left heart filling pressure. Despite the cardiopulmonary haemodynamic seems to be mainly involved in the pathogenesis of PGD, no reliable predictive parameter has been demonstrated. The aim of our study is to test whether pulmonary arterial pressure and left diastolic function may be considered in the risk PGD stratification. Methods and results we retrospectively analyzed the results of right heart catheterization (RHC) performed in occasion of the assessment for the LTx eligibility. All patients have been assessed at the Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico of Milan (Italy) from 2006 to 2018. We included all form of respiratory diseases except for cystic fibrosis. PGD was defined as PaO2/FIO2 Conclusion s our data confirmed that pulmonary circulation plays a crucial role in the prediction of PGD and elevated mPAP is the one of the main risk factors. Of note, despite in both group PAWP in was within normal values (

Patients with cystic fibrosis awaiting lung transplantation for end-stage respiratory failure have high prevalence of reduced bone mineral density and fragility fracture. Suboptimal 25-hydroxyvitamin D levels could significantly contribute to the development of cystic fibrosis-related bone disease. The assessment of the prevalence of cystic fibrosis-related bone disease (CFBD) and its associated risk factors in young adults with cystic fibrosis (CF) awaiting lung transplantation for end-stage respiratory failure. Clinical characteristics, bone mineral density (BMD), the parameters of calcium metabolism, including vitamin D (25OHVitD) levels, and the presence of fragility fractures were evaluated in 42 CF patients (24 females, age 34.0 ± 8.4 years) consecutively referred as lung transplant candidates. Mean 25OHVitD levels (54.9 ± 26.2 nmol/L) were below the reference range and hypovitaminosis D (25OHVitD

There is no unanimity in the literature regarding the value of transbronchial biopsies (TBBs) performed at a scheduled time after lung transplantation (surveillance TBBs [SBs]), compared to biopsies performed for suspected clinical acute rejection (clinically indicated TBBs [CIBs]). This study exposes an assessment of our experience over the last 4 years through a retrospective analysis of the data collected.In our center, SBs are performed at 3, 6, and 12 months after a transplant. Data from 110 patients who underwent a TBB were collected from January 2013 to November 2017. Clinical and functional data along with the histologic results and complications were collected.Overall 251 procedures were performed: 223 for surveillance purposes and 28 for clinical indications. The SBs diagnostic rate was 84%. A grade 2 acute rejection (AR) was detected in 9 asymptomatic patients, all of whom were medically treated, with downgrading of AR documented in all cases. The rate of medical intervention in the SB group was 8%. The CIBs diagnostic rate was 96%. The rate of AR detected by CIBs was significantly higher than by SBs (36% versus 4%; P .0001). Overall the major complication rate was 4%; no patients required transfusions and no mortality occurred in the patient cohort.The surveillance protocol did not eliminate the necessity of CIBs, but in 8% of patients early rejection was histologically assessed. The correlation between histologic and clinical data allows a more careful approach to transplanted patients.

Pleuroparenchymal fibroelastosis (PPFE) is a rare condition, characterized by predominantly upper-lobe pleural and subjacent parenchymal fibrosis, the latter being intra-alveolar with accompanying elastosis of the alveolar walls that leads a clinical progression to respiratory failure. This condition may not be as rare as it seems to be, because nowadays the increasing awareness among specialists is raising the number of new diagnoses. Limited data are available about the prognosis, both for secondary and idiopathic forms. Nevertheless, the idiopathic form seems to be rapidly progressive and no treatment can control the disease, which is why management is challenging. Since the disease was characterized, PPFE cases have been reported in the literature, but most have been secondary rather than idiopathic. Of these, few have successfully undergone lung transplantation as a treatment of end-stage respiratory failure. We here report a successful case of a 38-year-old man affected by idiopathic PPFE who underwent bilateral lung transplantation after extracorporeal membrane oxygenation bridging for an abrupt transition to critical clinical conditions. After a complex postoperative course and a first year characterized by acute rejection, the patient is alive at 5 years with a good quality of life. Our experience confirms that lung transplantation would be a valuable treatment option in case of end-stage idiopathic PPFE cases.

Background Solid organ transplantation is associated with a higher risk of Epstein-Barr virus (EBV)–related lymphoproliferative disease due to immunosuppressive regimen. Little evidence is currently available on post-transplant lymphoproliferative disorders (PTLDs) in the lung transplant (LuTx) setting, particularly in cystic fibrosis (CF) recipients. Methods We retrospectively analyzed all the cases of PTLDs that occurred in our LuTx center between January 2015 and December 2017. We reviewed clinical and radiologic data, donor and recipient EBV serostatus, immunosuppressive therapy, histologic data, and follow-up of these patients. Results A total of 77 LuTxs were performed at our center in the study period; 39 (50.6%) patients had CF; 4 developed EBV-related PTLDs. They were all young (17–26 years) CF patients with high serum EBV DNA load. Disease onset was within the first 3 months after LuTx. In 3 cases presentation was associated with fever and infection-like symptoms, whereas in 1 case radiologic suspicion arose unexpectedly from a CT scan performed for different clinical reasons. Diagnosis was reached through lung biopsy in all cases. All patients received rituximab, cyclophosphamide, doxorubicin hydrochloride (hydroxydaunomycin), vincristine sulfate (Oncovin), and prednisone with variable response and complications. Conclusion In our experience, the early development of EBV-related PTLD was a highly aggressive, life-threatening condition, which exclusively affected young CF patients in the early post-transplant period. The rate of this complication was relatively high in our population. Diagnosis with lung biopsy is crucial in all suspected cases and regular monitoring of EBV DNA levels is of utmost importance given the high correlation with PTLDs in patients at increased risk.

Background Although cardiac autonomic modulation has been studied in several respiratory diseases, the evidence is limited on lung transplantation, particularly on its acute and chronic effects. Thus, we aimed to evaluate cardiac autonomic modulation before and after bilateral lung transplantation (BLT) through a prospective study on patients enrolled while awaiting transplant. Methods Twenty-two patients on the waiting list for lung transplantation (11 women, age 33 [24–51] years) were enrolled in a prospective study at Ospedale Maggiore Policlinico Hospital in Milan, Italy. To evaluate cardiac autonomic modulation, ten minutes ECG and respiration were recorded at different time points before (T0) and 15 days (T1) and 6 months (T2) after bilateral lung transplantation. As to the analysis of cardiac autonomic modulation, heart rate variability (HRV) was assessed using spectral and symbolic analysis. Entropy-derived measures were used to evaluate complexity of cardiac autonomic modulation. Comparisons of autonomic indices at different time points were performed. Results BLT reduced HRV total power, HRV complexity and vagal modulation, while it increased sympathetic modulation in the acute phase (T1) compared to baseline (T0). The HRV alterations remained stable after 6 months (T2). Conclusion BLT reduced global variability and complexity of cardiac autonomic modulation in acute phases, and these alterations remain stable after 6 months from surgery. After BLT, a sympathetic predominance and a vagal withdrawal could be a characteristic autonomic pattern in this population.

Acute and chronic graft rejection remains the major problem in clinical surveillance of lung-transplanted patients and early detection of complications is of capital importance to allow the optimal therapeutic option. The aim of this study was to investigate the role of quantitative non contrast-enhanced magnetic resonance imaging (MRI) as a non-ionizing imaging modality to assess ventilation impairment in patients who have undergone lung transplantation, in comparison with quantitative computed tomography (CT) and spirometry.Ten lung-transplanted patients (39 ±12 years, forced-expiratory volume in 1 second (FEV1) = 81 ± 27%, forced vital capacity (FVC) = 87 ± 27%) were acquired in breath-hold at full-expiration and full-inspiration with 1.5T MRI and CT. Maps of expiratory-inspiratory difference in MR signal-intensity and CT-density were computed to estimate regional ventilation. Based on expiratory, inspiratory, and expiratory-inspiratory difference values, each pixel was classified as healthy (H), low ventilation (LV), air trapping (AT), and consolidation (C) and the percent extent of each class was quantified.Overall, expiratory-inspiratory difference in MR signal-intensity correlated to CT-density (r = 0.64, p0.0001) and to FEV1 (ρ = 0.71, p = 0.02). The linear correlation between MRI and CT functional maps considering all the four classes is r = 0.93 (p0.0001). MRI percent volumes of H, AT, and C correlated to FEV1 %pred, with the highest correlation reported for AT (ρ = -0.82).Results demonstrated a good agreement between MRI and CT ventilation imaging and between the corresponding percent volumes of lung damage. Quantitative MRI may represent an accurate non-ionizing imaging technique for longitudinal monitoring of lung transplant recipients.

Despite the promising results achieved so far in long-term survival after lung transplantation (LuTx), airway complications (ACs) still arise in the post-operative period. Early diagnosis and prompt treatment of ACs play a critical role in preventing their onset. Specifically, large bronchi ischemia has been recognized as a triggering factor for ACs. Autofluorescence bronchoscopy, which was first introduced for early cancer diagnosis, displays ischemic mucosae as red spots, while normal vascularized mucosae appear in green. The aim of this study is to investigate whether a significant correlation exists between ACs and the red/green (RG) ratio detected on scheduled autofluorescence bronchoscopy up to 1 year after LuTx. This prospective, observational, single-center cohort study initially considered patients who underwent LuTx between July 2014 and February 2016. All patients underwent concomitant white-light and autofluorescence bronchoscopy at baseline (immediately after LuTx), on POD7, POD14, POD21, POD28, POD45, 3 months, 6 months, and 1 year after LuTx. An autofluorescence image of the first bronchial carina distal to the anastomosis was captured and analyzed using histograms for red and green pixels; the R/G ratio was then recorded. Potential ACs were classified according according to the presence of a white-light following the MDS (macroscopic aspect, diameter and suture) criteria. The authors assessed the association between the R/G ratio and the ACs occurrence using a generalized estimating equations model. Thirty-one patients met the inclusion criteria and were therefore selected. Out of a total of 53 bronchial anastomoses, 8 developed complications (late bronchial stenosis), with an average onset time of 201 days after LuTx. ACs showed a similar baseline covariate value when compared to anastomoses that involved no complication. Generalized estimating equations regression indicated a clear association over time between the R/G ratio and the rise of complications (p = 0.023). The authors observed a significant correlation between post-anastomotic stenosis and the delayed decrease of the R/G ratio. Preliminary outcomes suggest that autofluorescence bronchoscopy may be an effective and manageable diagnostic tool, proving complementary to other instruments for early diagnosis of ACs after LuTx. Further research is needed to confirm and detail preliminary findings.

Introduction the effect of bone-active drugs on the risk of fragility fractures (Fx), bone mineral density (BMD) and trabecular bone score (TBS) changes in patients receiving lung transplantation (LTx) is largely unknown. This study assessed the bone-active drugs effect in patients undergoing LTx both with (CF) and without (nCF) cystic-fibrosis. Methods We evaluated incident Fx, both clinical and morphometric vertebral Fx by spinal X-ray, BMD and trabecular bone score (TBS) in 117 patients (CF=50, nCF n = 67) before and 24-months after LTx. A bone-active therapy was proposed to all LTx candidates. Results 83.8% of patients started a bone-active drug. Lumbar-spine (LS) T-score improved significantly only in treated patients (-1.4 ± 1.0 vs -2.0±1.0, p = 0.0001), whereas femur BMD and TBS remained stable in treated and not treated subjects. The rate of incident Fx was 15.3%, with no difference between treated and not treated patients. After LTx, LS T-score improved significantly only in nCF group (-1.3 ± 1.0 vs -1.8 ± 1.1, p = 0.0001), while femur remained stable in both nCF and CF groups. Patients with CF showed a significant Z-TBS increase (-3.6 ± 1.7 vs -3.0 ± 1.7, p = 0.019) and a lower Fx incidence as compared with nCF patients (4.1% vs 24.2%, p =0.003). Incident Fx were associated with nCF diagnosis (OR 7.300, CI95% 1.385–38.461, p = 0.019) regardless of prevalent Fx, previous glucocorticoid therapy and bone-active therapy introduced at least 6 months before LTx. Conclusions A prompt medical intervention helps in preventing BMD loss after LTx. As compared with nCF patients, CF patients show a TBS increase and a lower Fx risk after LTx.

Objective: The bilateral anterolateral thoracotomy without sternal splitting is considered the preferable approach for bilateral lung transplantation, mainly for the reported lower rate of sternal complications and better respiratory function in the early postoperative period. We evaluate the influence of the incision on vital capacity within one-year follow up. Methods: 133 double lung transplantations were done since January 2013 (85 cystic fibrosis, 36 interstitial lung diseases, 12 COPD). We retrospectively analysed spirometry performed before (pre), one month (post1), 6 months (post 6) and one year (post 12) after the transplantation. Forced vital capacity (FVC) was considered both as percentage predicted and as absolute value. Results: The majority of patients received clamshell incision (64.6%, n=86). Age was similar between the clamshell (38.2 years) and the bilateral anterolateral thoracotomy (40.5 years, p= 0.365) groups, while the former was characterized by higher LAS (39.3 vs 35.1, p=0.035). FVC was similar between the two groups before surgery, but it was systematically lower in the clamshell group in the three considered follow-ups (Figure1). Conclusions: The clamshell incision results in more postoperative lung restriction as compared with bilateral anterolateral thoracotomy; we note that this effect persists throughout the first year.

Background and Aims Acute kidney Injury (AKI) occurs in more than 50% of patients after lung transplantation (LTx). Our aim was to describe the incidence, risk factors and outcomes associated with AKI after LTx in a retrospective monocentric cohort study. Method We studied all recipients of LTx (> 16 years of age) occurring at Ospedale Maggiore Policlinico Milano between Jan 1st 2015 and Dec 31st 2017. AKI was defined according to KDIGO classification, eGFR was calculated according to CKD (Chronic Kidney Disease) Epidemiology Collaboration formula and CKD was defined by an eGFR< 60 ml/min per 1.73 m2. Chi square, Fisher exact test, t.-test and logistic regression were used to define risk factors for AKI in the early post-surgical period and for CKD at 1 and 2 years after LTx. AKI-related survival was estimated using Kaplan Meyer model. Results Of 78 LTx patients enrolled in our Center, 50% of patients was affected by cystic fibrosis. Median age at transplant was 43 years (27-55); median follow- up was 31 months (20-40). Survival rate was 80.77% at 1 year, 69.23% at 2 years and 66.67% on Dec 31st 2019 (last follow-up). AKI occurred in 42 (53.85%) patients within the first week after LTx, respectively grade I and II in 12 each (15.38%) and grade III in 18 (23.08%) patients. Pre-transplant low albumin levels and hypertension were independently associated with AKI at univariate and multivariate (p= 0.0018 and 0.0004 respectively) analysis. Pre-transplant low albumin levels, pre-transplant ECMO-use, hypertension, ECMO-use during transplant surgery were associated with severe AKI in univariate analysis but only pre-transplant hypertension and ECMO-use during transplant surgery were independently associated in the multivariate one (p=0.0266 and 0.0463 respectively). Survival was significantly reduced in patients affected by AKI (p=0.035); this observation became strongly significant when only mild and moderate (grade I and II) AKI was considered (p=0.0071). CKD was diagnosed in 38.09% of patients at 1 year and 35.18% at 2 years. While numerous risk factors were related to the occurrence of CKD at 1 and 2 years after LTx at univariate analysis, only grade III AKI remained independently associated with CKD at multivariate analysis (p= 0.0081 for 1 year-CKD, p=0.0154 for 2 year-CKD). Conclusions In our population, AKI after LTx occurred in about half of the patients and was predicted by history of hypertension, low albumin levels and hemodynamic instability during the surgery. Mild-moderate AKI, often clinically underestimated, was strongly associated with reduced survival. Severe forms of AKI were predictive of occurrence of CKD.

Limited data are currently available regarding the course of COVID-19 in lung and solid organ transplant recipients. We hereby present four cases of SARS-CoV-2 pneumonia in lung transplant recipients from our center, set in Milan, Italy. We reduced immunosuppressive regimen in all these patients, typically holding the antiproliferative agent and augmenting steroids; everybody received hydroxychloroquine, initial empiric antibiotic treatment with piperacillin/tazobactam, and high-dose low molecular weight heparin. Clinical course seemed favorable in three of our patients, but one of them deteriorated after 10 days of hospitalization, probably due to an acute form of graft dysfunction triggered both by COVID-19 and a nosocomial bacterial infection, and eventually died. Although short-term prognosis could be considered benign in the majority of our patients, we should carefully monitor these individuals in order to detect early sign of clinical deterioration and graft dysfunction in the next few months.

Although the literature demonstrates that cardiac autonomic control (CAC) might be impaired in patients with chronic pulmonary diseases, the interplay between CAC and disease severity in end-stage lung disease has not been studied yet. We investigated the effects of end-stage lung disease on CAC through the analysis of heart rate variability (HRV) among patients awaiting lung transplantation. Forty-nine patients on the waiting list for lung transplantation (LTx, 19 men, age 38 &plusmn, 15 years) and 49 healthy non-smoking controls (HC, 22 men, age 40 &plusmn, 16 years) were enrolled in a case&ndash, control study at Policlinico Hospital in Milan, Italy. LTx patients were divided into two groups, according to disease severity evaluated by the Lung Allocation Score (LAS). To assess CAC, electrocardiogram (ECG) and respiration were recorded at rest for 10 min in supine position and for 10 min during active standing. Spectral analysis identified low and high frequencies (LF, sympathetic, and HF, vagal). Symbolic analysis identified three patterns, i.e., 0V% (sympathetic) and 2UV% and 2LV% (vagal). Compared to HCs, LTx patients showed higher markers of sympathetic modulation and lower markers of vagal modulation. However, more severely affected LTx patients, compared to less severely affected ones, showed an autonomic profile characterized by loss of sympathetic modulation and predominant vagal modulation. This pattern can be due to a loss of sympathetic rhythmic oscillation and a subsequent prevalent respiratory modulation of heart rate in severely affected patients.

BACKGROUND Lung transplantation is a complex but effective treatment of end-stage pulmonary disease. Among the post-operative complications, phrenic nerve injury, and consequent diaphragmatic dysfunction are known to occur but are hitherto poorly described. We aimed to investigate the effect of lung transplantation on diaphragmatic function with a multimodal approach. METHODS A total of 30 patients were studied at 4 time points: pre-operatively, at discharge after surgery, and after approximately 6 and subsequently 12 months post surgery. The diaphragmatic function was studied in terms of geometry (assessed by the radius of the diaphragmatic curvature delineated on chest X-ray), weakness (considering changes in forced vital capacity when the patient shifted from upright to supine position), force (maximal pressure during sniff), mobility (excursion of the dome of the diaphragm delineated by ultrasound), contractility (thickening fraction assessed by ultrasound), electrical activity (latency and area of compound muscle action potential during electrical stimulation of phrenic nerve), and kinematics (relative contribution of the abdominal compartment to tidal volume). RESULTS Despite good clinical recovery (indicated by spirometry and 6 minutes walking test), a reduction of the diaphragmatic function was detected at discharge; it persisted 6 months later to recover fully 1 year after transplantation. Diaphragmatic dysfunction was demonstrated in terms of force, weakness, electrical activity, and kinematics. Our data suggest that the dysfunction was caused by phrenic nerve neurapraxia or moderate axonotmesis, potentially as a consequence of the surgical procedure (i.e., the use of ice and pericardium manipulation). CONCLUSIONS The occurrence of diaphragmatic dysfunction in patients with a good clinical recovery indicates that the evaluation of diaphragmatic function should be included in the post-operative assessment after lung transplantation.

Introduction Lung transplantation is considered a therapeutic option in selected patients affected by end-stage pulmonary disease. The mortality on the waiting list is mainly attributed to the shortage of the donor pool available for transplantation. There are various strategies to overcome this shortage; one of them is lobar transplantation. Methods The aim of the current study was to analyze the outcome of lobar lung transplantation from deceased donors in our Lung Transplant Center. Overall survival, perioperative mortality and morbidity, problem on bronchial anastomosis, and chronic rejection were prospectively recorded in a 5-year time-frame. Results From November 2010 to October 2015, we performed 100 lung transplantations; 6 of which (6%) were lobar transplantations from deceased donors. Three recipients were on an emergency list due to preoperative extracorporeal support. The causes of lobectomy leading to lobar transplantation were: size mismatch (3), iatrogenic vascular damage (2), and chronic atelectasis (1). One patient died 5 months after surgery for sepsis; and 5 patients were alive at the study end (median follow-up: 17.5 months). Prevalence of grade 3 primary graft dysfunction at 72 hours was 50%. One patient developed bronchial stenosis. No cases of chronic rejection were recorded. Conclusions Lobar transplantation can be considered a valid tool to overcome the donor pool shortage in selected cases; such a technique has proved particularly useful in critically ill patients who were scheduled in an emergency transplant program.

Purpose Transbronchial biopsy (TBB) using forceps is the standard procedure to establish the presence of allograft rejection after lung transplantation. However, inadequate tissue samples, high degree of interobservers variability and possible complications seems to prevent many centers in scheduling TBB in lung transplant follow-up. Despite transbronchial cryobiopsies (TCB) yield large specimens, few studies addressed the use of this technique. We aimed to analyze the diagnostic yield and complications rate of TCB in a surveillance program for lung transplant patients. Methods This is a retrospective comparative study with historical control. Eligible for inclusion were adults subjected to scheduled transbronchial biopsy at 3, 6 and 12 months after lung transplantation. A single pathologist classified the biopsy according to ISHLT scale. Results From 2018, 54 consecutive patients underwent TCB; previous 110 consecutive patients underwent TBB. The study group received 75 procedures versus 223 in the historical group. The diagnostic yield for acute rejection of TCB and TBB were 100% and 83%, respectively (p Conclusion TCB showed high diagnostic yield in a surveillance program for lung transplant patients; despite the low clinical impact, the complication rate is not negligible. These good results have led us to implement an interventional crossover trial on TCB versus TBB.

Purpose Antibody mediated rejection (AMR) has recently emerged as an important risk factor for lung allograft dysfunction and mortality. Several clinical protocols have been proposed to try to remove donor specific antibodies (DSA) and prevent their future development, including intravenous immunoglobulin (IVIG), therapeutic plasma exchange (TPE), rituximab and other. Unlike traditional TPE, immunoadsorption (IAS) is a blood-purification technique that enables the selective removal of immunoglobulins from separated plasma through high-affinity adsorbers; advantageously, IAS does not remove other plasma components such as fibrinogen and compounds of the coagulation cascade, reducing potential adverse effects. Our centre implemented a multimodality strategy including steroids, immunoadsorbption, IVIG and Rituximab. Methods All adult lung transplant (LuTx) recipients receiving a diagnosis of AMR (based on 2016 ISHLT consensus definition), were considered eligible to receive this treatment: pulsed methylprednisolone (10 mg/Kg), 5 cycles of IAS, IVIG (2 g/Kg) and rituximab (375 mg/m^2). Of note, C4d staining is not currently available at our institution. Results Between 2016 and 2018, four patients received multimodality antibody directed therapy for AMR after LuTx. Details can be found in table 1. 2 out of the 4 patients qualified for chronic lung allograft dysfunction (CLAD) prior to protocol start (patient 1 and 3). No adverse events were registered during IAS procedures, but patient 3 suffered transfusion related acute lung injury while receiving IVIG. However, patient 3′s death was attributed to progressive allograft failure and not to the therapy itself. Conclusion Following this treatment, while the total number of the original DSA and the value of MFI of the originally observed DSA decreased, clinical outcomes were variable: 2 patients are experiencing long term clinical stability, but the others rapidly progressed to severe CLAD.

Purpose We hereby report our real-life experience with extracorporeal photopheresis (ECP) for CLAD. Methods This was an observational retrospective study on LuTx adult patients who received a diagnosis of chronic lung allograft dysfunction (CLAD) from January 2008 to December 2018. They were referred to an ECP Service on a regional basis. Both automated closed and open loop devices were used. Results Over the period considered, 42 patients were diagnosed with CLAD, 10 (24%) restrictive allograft syndrome (RAS) and 32 BOS. Of those 42, 6 individuals were considered ineligible to initiate ECP due to their excessively compromised conditions; they all died soon after (less than 6 months). The rest (36 patients) were scheduled to receive ECP treatments. Median time from CLAD diagnosis to ECP initiation was 2 (1; 4) months. Median rate of FEV1 decline in the first 6 months was -13 mL/month; however, 11 (31%) did not respond (FEV1 decreased > 10% from ECP initiation). 14 (38%) patients were hospitalized at least once for respiratory infection. The majority of treated patients (21, 58%) reported a good quality of life and worked or were fit to work. 6 patients died, 5 of CLAD-related death. 3 individuals received a re-transplant, and 2 continued with ECP even afterwards. Given also that the majority of patients at our centre are affected by cystic fibrosis (24, 58% of this cohort), one of the major problems with performing ECP was represented by the lack of good vascular access; 4 patients needed a long term catheter insertion. In one of these patients early termination of treatment was decided after a sepsis due to S. epidermidis starting from her Tesio access. No other significant adverse event occurred. No difference was observed between closed and open loop devices. Conclusion Our data seem to further support the efficacy and safety of ECP to treat CLAD, not only in terms of pulmonary function but also of survival and quality of life. Vascular access related problems were the major issue. Several limits to be acknowledged: retrospective nature, single centre, no control group.

BACKGROUND Scedosporium species and Lomentospora prolificans (S/L) are the second most common causes of invasive mold infections following Aspergillus in lung transplant recipients. METHODS We assessed the current practices on management of S/L colonization/infection of the lower respiratory tract before and after lung transplantation in a large number of lung transplant centers through an international practice survey from October 2016 to March 2017. RESULTS A total of 51 respondents from 45 lung transplant centers (17 countries, 4 continents) answered the survey (response rate 58%). S/L colonization was estimated to be detected in candidates by 48% of centers. Only 18% of the centers used a specific medium to detect S/L colonization. Scedosporium spp. colonization was a contraindication to transplantation in 10% of centers whereas L prolificans was a contraindication in 31%; 22% of centers declared having had 1-5 recipients infected with S/L in the past 5 years. CONCLUSIONS This survey gives an overview of the current practices regarding S/L colonization and infection in lung transplant centers worldwide and underscores the need of S/L culture procedure standardization before implementing prospective studies.

Background Predictors and outcomes of intraoperative extracorporeal membrane oxygenation (ECMO) during lung transplantation (LUTX) for cystic fibrosis (CF) are unknown. Methods We retrospectively collected the clinical data at enlistment of the CF patients who underwent double LUTX from January 2013 to December 2018 at an Italian tertiary referral center. We compared blood transfusions, incidence of primary graft dysfunction (PGD), duration of mechanical ventilation, intensive care unit (ICU) length of stay (LOS), hospital LOS and survival of ECMO and non-ECMO patients. Chi-square, Kruskal-Wallis, and log-rank tests were used. Results Twenty-eight (40%) of the 70 included patients needed intraoperative central veno-arterial ECMO with postoperative veno-venous prolongation in 6 subjects. Lower right ventricle ejection fraction (p = 0.013, OR 0.92(0.86–0.98)), higher oxygen requirement (p = 0.026, OR 1.39(1.01–1.90)), lower body surface area (p = 0.044, OR 0.05(0.00–1.03)), and CF-related diabetes (p = 0.044, OR 2.81(1.03–7.66)) were associated with intraoperative ECMO. Compared to non-ECMO patients, ECMO patients needed almost fivefold intraoperative transfusion (2227 mL vs. 570 mL, p 0 at 72 h more frequently (16/57% vs. 12/28%, p = 0.017, OR 3.33(1.22–9.09)). Mechanical ventilation, ICU LOS and hospital LOS were significantly longer in ECMO patients. Survival at follow-up (651(326–1277) days) of ECMO and non-ECMO patients was 78% vs. 83%, respectively (OR 0.73 (0.21–2.46), p = 0.616, log-rank test p = 0.498). Conclusion : Pre-operative risk assessment and clinical planning should be done according to the predictors above. While undeniably useful as a life-saving procedure, ECMO during LUTX for CF is associated with worsened short-term outcomes. ECMO should be implemented weighing its risk and benefits.

Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Survivors of acute respiratory distress syndrome (ARDS) have long-term impairment of pulmonary function and health-related quality of life, but little is known of outcomes of ARDS survivors treated with extracorporeal membrane oxygenation. The aim of this study was to compare long-term outcomes of ARDS patients treated with or without extracorporeal membrane oxygenation. Methods A prospective, observational study of adults with ARDS (January 2013 to December 2015) was conducted at a single center. One year after discharge, survivors underwent pulmonary function tests, computed tomography of the chest, and health-related quality-of-life questionnaires. Results Eighty-four patients (34 extracorporeal membrane oxygenation, 50 non–extracorporeal membrane oxygenation) were studied; both groups had similar characteristics at baseline, but comorbidity was more common in non–extracorporeal membrane oxygenation (23 of 50 vs. 4 of 34, 46% vs. 12%, P < 0.001), and severity of hypoxemia was greater in extracorporeal membrane oxygenation (median Pao2/Fio2 72 [interquartile range, 50 to 103] vs. 114 [87 to 133] mm Hg, P < 0.001) and respiratory compliance worse. At 1 yr, survival was similar (22/33 vs. 28/47, 66% vs. 59%; P = 0.52), and pulmonary function and computed tomography were almost normal in both groups. Non–extracorporeal membrane oxygenation patients had lower health-related quality-of-life scores and higher rates of posttraumatic stress disorder. Conclusions Despite more severe respiratory failure at admission, 1-yr survival of extracorporeal membrane oxygenation patients was not different from that of non–extracorporeal membrane oxygenation patients; each group had almost full recovery of lung function, but non–extracorporeal membrane oxygenation patients had greater impairment of health-related quality of life.

Background: Regional analysis by computed tomography (CT) is an attractive technique to interpret lung patterns after transplantation (LTx). We evaluated the application of CT functional mask derived parameters to determine whether development of primary graft dysfunction (PGD) is associated with short and/or long-term postoperative evidences of pulmonary function alterations. Methods: A total of 38 patients who underwent bilateral LTx were evaluated at 24, 48 and 72 hours after the end of surgery to establish PGD occurrence and grading. CT scans at 3 and 12 months after LTx were analyzed to measure specific gas volume (SV g ) changes normalized on expiratory SV gEXP of the whole lung (ΔSV g /SV gEXP ) and to obtain functional masks of density variation, namely maps of low ventilation (LV), consolidation (C), air trapping (AT) and healthy parenchyma (H). Results: Our main result was the evidence of a marked decrease in ΔSV g /SV gEXP in all subjects, irrespectively on PGD, at each time point after LTx, indicating a high degree of ventilation defects versus healthy. High percentages of LV were found in all subjects while percentages of AT and C were negligible. Conclusions: We demonstrate that quantification of ventilation defects by CT functional mask offers insights into the correlation between PGD and pulmonary function after LTx at short and mid-term.

Purpose The outcome of lung transplantion (LuTx) suffers from a high rejection rate, and there are still huge gaps of knowledge about immune-mediated rejection mechanisms. Acute rejection (AR) can lead to chronic lung allograft dysfunction (CLAD), the main cause of poor survival and low quality of life. The standardized morphologic evaluation of rejection is based on histopathologic diagnostic criteria at a given time-point, but it has a limited prognostic value towards clinical outcome and the likelihood to develop CLAD. We analyzed immune-check point proteins in lung tissues of patients who received a LuTx and who were or were not undergoing rejection in the attempt to define novel immunological markers that could predict rejection. Methods We conducted an observational retrospective study on eight consecutive explanted grafts for chronic rejection and on transbronchial cryobiopsies (TCB) obtained from 24 consecutive patients during the first year LuTx follow-up. A broad spectrum of immunohistochemical analysis was carried out (PD1/CD279, PDL1/CD274, CTLA4/CD152, CD4, CD8, hFoxp3, TIGIT, TOX, B-Cell-Specific Activator Protein). Of those TCB-patients we recorded at least 1 year follow up of survival, infections and rejections (acute and chronic) rate. Results Exhausted (PD1+/TOX+) as well as Treg (PD1+/FOXP3+) lymphocytes were significantly reduced in restrictive allograft syndrome (RAS)-compared to bronchiolitis-obliterans-syndrome (BOS)-rejected lungs. PD1-expressing T-lymphocytes in TCBs correlated (sensitivity 0.69; specificity 1) with the presence of AR and were highly suggestive of CLAD development (sensitivity 0.86; specificity 0.82; overall 10 times higher risk of developing CLAD) at one-year follow-up. Conclusion Results herein for the first time show the importance of immunological checkpoints in the setting of LuTx rejection and indicate that the evaluation of the expression of such proteins could offer a distinct prognostic advantage in monitoring the onset of AR in patients who underwent LuTx. Longitudinal analyses in ampler cohorts will be needed to confirm these data.

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.

Supplemental Digital Content is available in the text., Background. Primary graft dysfunction, infections, and acute rejection (AR) worsen lung transplantation (LTx) outcome and patient survival. Despite significant efforts, reliable biomarkers of acute lung allograft dysfunction are lacking. To address this issue, we profiled the bronchoalveolar lavage (BAL) miRNome in LTx patients. Methods. BAL-microRNAs (miRNAs) from 16 patients were collected 7 days (T0), 15 days (T1), and 3 months (T2) after bilateral LTx and profiled on low-density array. Unsupervised and supervised analyses were used to identify miRNAs associated with clinical features, pneumonia, or AR. Prognostic markers were identified using the Cox model. Targeted signaling pathways were predicted in silico. A second series of 11 patients were used to validate AR-associated miRNAs. Results. Variation in BAL-miRNAs was associated with acute lung allograft dysfunction. Increased levels of miR-23b-3p at T2 were detected in patients with pneumonia, whereas let-7f-5p, miR-146b-3p, miR-22-5p, miR-29c-5p, miR-362-5p, and miR-452-5p were upregulated at T2 in patients with AR. miR-148b-5p and miR-744-3p distinguished LTx patients with AR in both cohorts. Low miR-148b-5p and high miR-744-3p expression levels were significantly associated with a shorter time to AR either within the first year after LTx or during follow-up. Combination of the 2 miRNAs identified LTx patients with higher AR risk independently of clinical variables. Conclusions. Our data provide new insights into the roles of BAL-miRNAs in regulating the pulmonary environment after transplantation and suggest that these miRNAs could serve as biomarkers of early- or mid-stage events. If validated, these findings could pave the way to a personalized clinical approach in LTx patients.

Purpose In a previous study on miRNA profiling in bronchoalveolar lavage (BAL) fluid of lung transplanted (LTx) patients we obtained signatures of deregulated miRNAs associated to acute lung allograft dysfunction (ALAD). Now we extended this analysis to chronic dysfunction (CLAD) and to pathways potentially modulated by AR- or CLAD-miRNAs. Methods BALs were obtained from 16 patients who underwent bilateral LTx at our Institution. Mean follow-up time was 21 months (range 17-25). MiRNAs expression in BAL samples collected 7 days (T0), 15 days (T1) and 3 months (T2) after LTx was analyzed using TLDA. The association of miRNAs with pneumonia, acute rejection (AR) or CLAD was examined using ANOVA or Cox regression. The false discovery rate was applied for multiple comparison correction. miRNAs targets were search with miRTarget Link and imported in STRING or WebGestalt databases for functional annotation. Potential targets expression was analyzed by immunohistochemistry (IHC) on transbrochial biopsies. Results We identified one, 9 and 4 BAL-miRNAs whose upregulation is associated with pneumonia, AR or CLAD respectively (Fig. 1A-C). At T1, six BAL-miRNAs predicted CLAD by Cox model. Pathways prediction revealed that AR- or CLAD-miRNAs regulated cell dedifferentiation or WNT signaling, respectively, through the modulation of Sp1 or Bcl2 and cMYC factors (Fig. 1D,E). By IHC, Sp1 was more expressed in biopsies from patients with AR (Fig. 1F) whereas Bcl2 was predominantly detected in lungs from patients with CLAD (Fig. 1G). Conclusion Our results, although preliminary, uncover novel miRNAs-networks involved in AR and CLAD pathogenesis.