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.

Paraesophageal hernia repair with laparoscopic Toupet fundoplication: impact on pulmonary function, respiratory symptoms and quality of life.

BACKGROUND: Paraesophageal hiatal hernia (PEH) is characterized by protrusion of intra-abdominal organs into the posterior mediastinum. Respiratory symptoms and reduced pulmonary function have been described as possibly related to lung compression. OBJECTIVE: To assess the effect of laparoscopic Toupet fundoplication (LTF) for PEH repair on pulmonary function, measured with pulmonary function tests (PFTs), and respiratory symptoms. METHODS: Retrospective, single-center, cohort study (November 2015-2020). All patients that completed pre- and postoperative (12 months) PFTs assessment were included. The gastroesophageal reflux disease health-related quality of life (GERD-HRQL), reflux symptom index (RSI) and short form-36 (SF-36) were used. RESULTS: Overall, 71 patients were included. The median age was 67.1 years and the majority were females (78.8%). Baseline PFTs were within normal limits in 91% of patients. At 12 month follow-up, total lung capacity (TLC) (4.77 vs. 5.07 L; p = 0.0251), vital capacity (VC) (2.97 vs. 3.31 L; p = 0.0065), forced expiratory volume in one second (FEV1) (2.07 vs. 2.44 L; p < 0.001) and forced vital capacity (FVC) (2.78 vs. 3.19 L; p < 0.001) were significantly improved. No significant differences were found for diffusing capacity of lung for carbon monoxide (DLCO) (17.09 vs. 17.24; p = 0.734), and FEV1/FVC (0.77 vs. 0.77; p = 0.967). Interestingly, improvements were more pronounced in patients with large PEH (type IIIb and IV). At 12 month follow-up, both gastrointestinal and respiratory symptoms were significantly improved and 94% of patients were satisfied with the operation. The GERD-HRQL (18.1 ± 7.9 vs. 4.01 ± 2.4; p = 0.001), RSI (37.8 ± 9.7 vs. 10.6 ± 8.9; p < 0.001) and all SF-36 items were improved. CONCLUSIONS: LTF for the treatment of PEH is safe and seems to be effective up to 12 month follow-up with improved lung volumes, spirometry values, quality of life, gastrointestinal and respiratory symptoms.

An international multidisciplinary peer-driven consensus on the optimal use of hemostatic powders in surgical practice.

Bleeding is a consequence of insufficient hemostasis and excessive bleeding at a surgical site is associated with an increased risk of post-operative infection, transfusion and re-operation, in addition to increased hospital length of stay and costs. Surgeons employ a range of methods to achieve hemostasis, including topical hemostatic agents of differing composition and properties. Hemostatic powders are a sub-group of topical hemostats, which can be used in helping as adjuncts to manage troublesome bleeding in a variety of situations. As this technology is relatively new and potentially not well known by the broad surgical community, no specific guidelines or recommendations for the optimal use of hemostatic powders in surgery currently exist. A steering group throughout Europe of multidisciplinary surgeons, expert in hemostasis and hemostatics, identified from literature and from personal experience, five key topics. When to use hemostatic powder, the evidence for use, benefits of use, safety remarks and considerations in various surgical specialties. Thirty-seven statements were subsequently drawn from these five key topics. An online survey was sent to 128 high-volume surgeons working in breast surgery, gynaecological and obstetric surgery, general and emergency surgery, thoracic surgery and urological surgery in Europe to assess agreement (consensus) with these statements. Consensus was defined as high if ≥ 75% and very high if ≥ 90% of respondents agreed with a statement. A total of 79 responses were received and consensus among the surgical experts was very high in 27 (73%) statements, high in 8 (22%) statements and was not achieved in 2 (5%) statements. Based on the consensus scores, the steering group produced 16 key recommendations which they considered could improve patient outcomes by reducing post-operative bleeding and its associated complications using hemostatic powder.

Effects of bilateral lung transplantation on cardiac autonomic modulation and cardiorespiratory coupling: a prospective study.

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.

Lung Transplant From Donor With Tracheal Bronchus: Case Report and Literature Review.

Donor lung abnormalities are quite rare; one of them is the presence of bronchial anomalies, whose incidence range is from 0.1% to 0.5%. The upper right tracheal bronchus is one of the most frequent anatomic variations. We present a case of successful double lung transplant in a young female patient affected by cystic fibrosis from a donor with upper right tracheal bronchus, emerging 2 rings before the tracheal carina. During implantation of the left lung, we performed a double apical segmentectomy on back table; therefore, the right lung was implanted with the standard technique. Four cases of graft transplant characterized by the presence of tracheal bronchus are reported in the scientific literature; the authors report 4 different technical solutions to tackle the problem of anatomic anomaly. We report the first case of graft segmentectomy at back table suggesting a simple, safe, and time-sparing procedure. In conclusion, provided that the team has sufficient skill in reductive surgery at the back table and the anthropometric data are permissive, we stress the opportunity to downsize the graft in order to minimize anastomotic risks and save time.

Surveillance Transbronchial Biopsy Program to Evaluate Acute Rejection After Lung Transplantation: A Single Institution Experience.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Epstein-Barr Virus-Related Post-Transplant Lymphoproliferative Disorders in Cystic Fibrosis Lung Transplant Recipients: A Case Series.

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.

Lobar Lung Transplantation From Deceased Donor: Monocentric Experience.

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.

Lung Transplantation From Donors After Previous Cardiac Surgery: Ideal Graft in Marginal Donor?

Lung transplantation is a limited by donor pool shortage. Despite the efforts to extend the graft acceptability with recurrent donor criteria reformulations, previous cardiothoracic surgery is still considered a contraindication. A donor who underwent cardiac surgery could potentially provide an ideal lung but high intraoperative risks and intrinsic technical challenges are expected during the graft harvesting. The purpose of this study is to present our dedicated protocol and four clinical cases of successful lung procurements from donors who had a previous major cardiac surgery. One donor had ascending aortic root (AAR) substitution, another had mitral valve substitution, and two had coronary artery bypass surgery. The others' eligibility criteria for organ allocation, such as ABO compatibility, PaO2/FiO2 ratio, absence of aspiration, or sepsis were respected. In one of the cases with previous coronary bypass grafting, the donor had a veno-arterial extracorporeal membrane oxygenation support. Consequently, the grafts required an ex vivo lung perfusion evaluation. We report the technical details of procurement and postoperative courses of recipients. All procurements were uneventful, without lung damage or waste of abdominal organs related to catastrophic intraoperative events. All recipients had a successful clinical outcome. We believe that successful transplantation is achievable even in a complicated setting, such as cases involving donors with previous cardiac surgery frequently are. Facing lung donor shortage, we strongly support any effort to avoid the loss of possible acceptable lungs. In particular, previous major cardiac surgery does not strictly imply a poor quality of lungs as well as unsustainable graft procurement.

Lung Allocation Score: A Single-Center Simulation.

BACKGROUND: The lung allocation score (LAS) was introduced in the United States in May 2005 with the main goal of reducing the waiting list mortality of patients with end-stage lung diseases, but also to enhance the lung transplant benefit and improve the management of urgent candidates. Several papers have reported that LAS resulted in a reduction of the waiting list mortality but no significant survival benefit was noted. METHODS: We evaluate the usefulness of LAS as a predictor for lung transplantation outcome in 123 patients listed for lung transplantation in an Italian center. Primary endpoints were waiting list mortality and posttransplant mortality at 1 year; secondary endpoints included perioperative circulatory support, cardiopulmonary bypass, primary graft dysfunction, and long-term survival after transplantation. RESULTS: We observed the absence of correlation between LAS and waiting list mortality. The LAS did not affect the long-term survival in our population. CONCLUSIONS: High LAS was predictive of primary graft dysfunction of grade 3 in the first 72 hours after transplantation.

Successful Transplantation of Lungs From an Uncontrolled Donor After Circulatory Death Preserved In Situ by Alveolar Recruitment Maneuvers and Assessed by Ex Vivo Lung Perfusion.

We developed a protocol to procure lungs from uncontrolled donors after circulatory determination of death (NCT02061462). Subjects with cardiovascular collapse, treated on scene by a resuscitation team and transferred to the emergency room, are considered potential donors once declared dead. Exclusion criteria include unwitnessed collapse, no-flow period of >15 min and low flow >60 min. After death, lung preservation with recruitment maneuvers, continuous positive airway pressure, and protective mechanical ventilation is applied to the donor. After procurement, ex vivo lung perfusion (EVLP) is performed. From November 2014, 10 subjects were considered potential donors; one of these underwent the full process of procurement, EVLP, and transplantation. The donor was a 46-year-old male who died because of thoracic aortic dissection. Lungs were procured 4 h and 48 min after death, and deemed suitable for transplantation after EVLP. Lungs were then offered to a rapidly deteriorating recipient with cystic fibrosis (lung allocation score [LAS] 46) who consented to the transplant in this experimental setting. Six months after transplantation, the recipient is in good condition (forced expiratory volume in 1 s 85%) with no signs of rejection. This protocol allowed procurement of lungs from an uncontrolled donor after circulatory determination of death following an extended period of warm ischemia.

Clinical risk factors for primary graft dysfunction in a low-volume lung transplantation center.

Primary graft dysfunction (PGD) is a severe acute lung injury syndrome following lung transplantation. Previous studies of clinical risk factors, including a multicenter prospective cohort trial, have identified a number of recipient, donor, and operative variables related to Grade 3 PGD. The aim of this study was to validate these risk factors in a lung transplantation center with a low volume of procedures. We conducted a retrospective cohort study of 45 consecutive lung transplantations performed between January 2011 and September 2013. PGD was defined according to the International Society for Heart and Lung Transplantation grading scale. Risk factors were evaluated independently and the significant confounders entered into multivariable logistic regression models. The overall incidence of Grade 3 PGD was 35.5% at T24, 17.7% at T48, and 15.5% at T72. The following risk factors were associated with Grade 3 PGD at the indicated time points: recipient female gender at T24 (P=.034), mixed diagnoses at T72 (P=.047), ECMO bridge-to-lung transplantation at T24 (P=.0004) and at T48 (P=.038), donor causes of death different from stroke and trauma at T24 (P=.019) and T72 (P=.014), blood transfusions during surgery at T24 (P=.001), intraoperative venoarterial ECMO T24 (P<.0001). Multivariate analysis at T24 identified recipient female gender and intraoperative venoarterial ECMO as risk factors (P=.010 and P=.018, respectively). This study demonstrated that risk factors for severe PGD in a low-volume center were similar to international reports in prevalence and type. ECMO bridge-to-lung transplantation emerged as a risk factor previously underestimated.

Variations of thoracoabdominal volumes after lung transplantation measured by opto-electronic plethysmography.

BACKGROUND: Lung function after lung transplantation (LTx) has been widely studied. On the contrary, the thoracoabdominal volume rearrangement after LTx has yet to be investigated. METHODS: Patients with cystic fibrosis and listed for double LTx at our institution were enrolled for the prospective study to explore the effects of LTx on the rearrangement of respiratory volumes in patients affected by cystic fibrosis, by utilizing the opto-electronic plethysmography (OEP), a noninvasive method to study the volume and motion of the human trunk. Rib cage and abdominal volumes were tested with OEP (OEP system, BTS, Milano, Italy). RESULTS: Eight patients were enrolled (male-to-female ratio: 1:3; mean age 29.3 ± 7.8 years). After LTx the volume changes analyzed with OEP revealed a significant decrease of the total lung capacity (TLC) as well as the functional residual capacity and residual volume when the chest wall volume was considered. Dividing the whole respiratory volume in the three compartments showed different trends. CONCLUSIONS: We consider OEP a particularly useful device in patients with severe respiratory disease, in that it allows a noninvasive estimate of the volume change of the chest wall. This study demonstrates a significant reduction of thoracoabdominal volumes in patients affected by cystic fibrosis treated with bilateral LTx. Abdomen and upper rib cage were congruent with the volume reduction, while the lower rib cage showed an opposite tendency.

Lung transplantation and posterior reversible encephalopathy syndrome: a case series.

Posterior reversible encephalopathy syndrome is a neurological problem characterized by headache, altered mental status, focal neurological deficits, visual disorders, and seizures. The disorder is related to a number of diseases including calcineurin inhibitor therapy in solid organ transplantation. The incidence of posterior reversible encephalopathy syndrome in lung transplantation patients is unclear; probably the majority of the cases are unreported. The authors have described a case series constituted of four patients presenting posterior reversible encephalopathy syndrome after bilateral lung transplantation. The cases had in common complicated surgery and a posttransplant course characterized by hypertension, hypomagnesemia and acidosis. Invasive mechanical ventilation, calcineurin inhibitor discontinuation, aggressive antihypertensive therapy, and electrolyte regulation led to near complete recovery of symptoms.

Early lung retransplantation in a patient affected by cystic fibrosis correlated with donor cause of death: a case report.

The relationship between donor cause of death and lung transplantation outcomes remains unclear. We report a case of lung transplantation in a young patient affected by cystic fibrosis. Immediately after lung reperfusion a pulmonary hypertension was observed that was intractable with maximal medical therapy requiring surgical resection of the left lower lobe which became congested after a few days. The donor had died from suicidal hanging; the authors attributed the posttransplantation pulmonary hypertension which is an uncommon form of primary graft dysfunction to this cause of death. The patient was treated with early bilateral lung retransplantation which required a long, troublesome hospital stay. In conclusion, the authors warn against the use of lungs from donors who die due to hanging even when the gas exchanges were ideal.

Late lung retransplantation using extracorporeal membrane oxygenation as a bridge: case report.

Lung retransplantation is the only therapeutic option for acute and chronic graft failure, but only a few cases have been described to have been performed with extracorporeal membrane oxygenation (ECMO) support. We describe the successful case of a 46-year-old man treated with right lung transplantation and left lung retransplantation supported by venovenous ECMO. Lung retransplantation is the only therapeutic option to treat severe primary graft dysfunction, major technical problems, and refractory chronic rejection following pulmonary transplantation. Despite a number of comprehensive studies on lung retransplantation, only a few works have addressed the use of extracorporeal membrane oxygenation (ECMO) as a bridge to the surgical reoperation. Herein we have presented a patient treated with pulmonary bilateral retransplantation subsequent to ECMO therapy for progressive deterioration of pulmonary function in single lung transplantation.

Primary pulmonary glomangioma: a coin lesion negative on PET study. Case report and literature review.

Glomus tumor is an uncommon perivascular lesion usually located in the dermis of the extremities. It rarely involves the respiratory tract or the lungs. We present the clinical and pathological features of a 39-year-old man who was evaluated for an incidental radiological finding of a pulmonary nodule. A chest computed tomography (CT) confirmed the presence of an upper left lobe coin lesion. Bronchoscopy and 18F-fluoro-2-deoxyglucose positron emission tomography (FDG-PET) were negative. An intraoperative frozen section examination was interpreted as a neuroendocrine tumor; therefore a left upper lobectomy with lymphadenectomy was performed. An immunohistochemical examination supported the diagnosis of a primary pulmonary glomangioma. The patient was free of disease at the 51-month follow-up. Due to its uncertain behavior we stress the usefulness of typical lung resection, lymph node dissection, and accurate follow-up.

Bridge to lung transplantation by venovenous extracorporeal membrane oxygenation: a lesson learned on the first four cases.

Extracorporeal membrane oxygenation (ECMO) is the only therapeutic option for patients with ventilation-refractory hypercapnia while awaiting lung transplantation. Moreover, there is increasing success using ECMO for definitive respiratory failure in formerly healthy patients. This report describes the use of membrane oxygenation as a bridge to lung transplantation in 2 patients on the waiting list and in 2 previously healthy patients. Our experience showed that coagulation management, critical illness myopathy, and psychological disorders were the most critical problems. One patient died at 2 days after transplantation, 1 at 3 months, and 2 returned to their pretransplantation activities. We concluded that ECMO is an adequate bridge to lung transplantation but, especially in formerly healthy patients, an awake procedure is advisable for a successful outcome.

Non-invasive continuous positive airway pressure in monolateral lung transplant patient with pneumonia and IPF.

Patients who undergo lung transplantation are prone to develop lower respiratory tract infections, leading to severe acute respiratory failure (ARF). Endotracheal intubation may not be indicated in these patients in light of a higher rate of mortality due to infections. The application of non-invasive ventilation could play a role in bridging these patients through the episode of ARF waiting for medical treatment to have effect. We report the evidence of morphological and physiological effects of the application of non-invasive continuous positive airway pressure during ARF sustained by pneumonia in a patient who underwent left lung transplantation because of idiopathic pulmonary fibrosis (IPF). We studied the effects of the application of positive end-expiratory pressure on both the right native lung affected by IPF and the transplanted lung affected by pneumonia.

Immunocytochemical detection of occult tumor cells in the bone marrow: prognostic impact on early stages of lung cancer.

OBJECTIVES: This study was designed to verify the prognostic impact of occult tumor cells in the bone marrow of stage I and II non-small-cell lung cancer patients using cytokeratin as a micrometastatic marker. METHODS: One hundred and fifty-two patients with stage I and II non-small-cell lung cancer, who underwent radical surgery by pulmonary lobectomy, were entered into the study. Bone marrow from fragments of resected ribs, and primary tumors were stained by anti-cytokeratin 18 antibody. Fourteen bone marrow specimens from patients without malignancy were used as a control group. Cancer recurrence was the study end point. RESULTS: All the primary tumors were positive for cytokeratin; occult tumor cells were detected in 38 bone marrow specimens (25%). The prevalence of the occult tumor cells was not related to age, gender, tumor stage, histological differentiation or grade. The mean follow-up time was 35.3 months; 68 patients developed recurrence; the mean time for recurrence was 21.2 months. The general disease-free interval was not related to the presence of occult tumor cells in the bone marrow. This result did not change when grouping the patients by tumor stage. The stage was the best predictor of cancer recurrence (Cox proportional hazards model ratio: 2.09; p = 0.0026). CONCLUSIONS: This study confirms that immunocytochemical analysis detects occult tumor cells in the bone marrow of at least 25% of patients surgically treated for stage I and II non-small-cell lung cancer. These occult tumor cells do not have any impact on the disease-free interval.