Lung transplantation from controlled donation after circulatory death using simultaneous abdominal normothermic regional perfusion: A single center experience.

Despite the benefits of abdominal normothermic regional perfusion (A-NRP) for abdominal grafts in controlled donation after circulatory death (cDCD), there is limited information on the effect of A-NRP on the quality of the cDCD lungs. We aimed to study the effect of A-NRP in lungs obtained from cDCD and its impact on recipients´ outcomes. This is a study comparing outcomes of lung transplants (LT) from cDCD donors (September 2014 to December 2021) obtained using A-NRP as the abdominal preservation method. As controls, all lung recipients transplanted from donors after brain death (DBD) were considered. The primary outcomes were lung recipient 3-month, 1-year, and 5-year survival. A total of 269 LT were performed (60 cDCD and 209 DBD). There was no difference in survival at 3 months (98.3% cDCD vs. 93.7% DBD), 1 year (90.9% vs. 87.2%), and 5 years (68.7% vs. 69%). LT from the cDCD group had a higher rate of primary graft dysfunction grade 3 at 72 h (10% vs. 3.4%; p <  .001). This is the largest experience ever reported with the use of A-NRP combined with lung retrieval in cDCD donors. This combined method is safe for lung grafts presenting short-term survival outcomes equivalent to those transplanted through DBD.

Excellent long-term outcome with lungs obtained from uncontrolled donation after circulatory death.

We aimed to propose a simple and effective preservation method in lungs procured for transplantation from uncontrolled donation after circulatory death (uDCD) associated with excellent long-term results. Outcome measures for lung recipients were survival and primary graft dysfunction (PGD) grade 3. Survival was estimated using the Kaplan-Meier method. A total of 9 lung uDCDs were evaluated and 8 lung transplants were performed. Mean no-flow time was 9.8 minutes (standard deviation [SD] 8.6). Mean time from cardiac arrest to topical cooling was 96.8 minutes (SD 16.8). Preservation time was 159 minutes (SD 31). Ex vivo lung perfusion was used to assess lung function prior to transplantation in 2 cases. Mean recipient age was 60.8 years (SD 3.1), and mean total ischemic time was 678 minutes (SD 132). PGD grade 3 was observed in 2 cases (25%). The 1-month, 1-year, and 5-year survival rates were 100%, 87.5%, and 87.5%, respectively. Mean follow-up was 52 months. The logistic complexity of procuring lungs from uDCDs for transplantation requires the development of new strategies designed to facilitate this type of donation. A program based on strict selection criteria, using a simple and effective preservation technique, may recover lung grafts with excellent long-term posttransplant outcomes.

Evaluation of Two Different CMV-Immunoglobulin Regimens for Combined CMV Prophylaxis in High-Risk Patients following Lung Transplant.

BACKGROUND: The clinical benefits of the common off-label use of cytomegalovirus (CMV)-specific immunoglobulin (CMV-Ig) combined with antivirals in organ transplantation have not been previously assessed. The objective was to compare the risk of CMV infection and other post-transplantation outcomes between two CMV-Ig prophylaxis regimens in lung transplant recipients; Methods: Retrospective study of 124 donor CMV positive/recipient negative (D+/R-) patients receiving preventive ganciclovir/valganciclovir for 12 months, of whom 62 received adjunctive CMV-Ig as per label indication (short regimen [SR-Ig]; i.e., 7 doses over 2.5 months) and were compared to 62 who received an extended off-label regimen (ER-Ig) consisting of 17 doses over one year after transplantation. RESULTS: The incidence of CMV infection or disease, acute rejection, chronic lung allograft dysfunction, and survival did not differ between the two CMV-Ig schedules. Although the time to the first CMV infection after transplantation was shorter in the ER-Ig than in the SR-Ig adjunctive group (log-rank: p = 0.002), the risk was independently predicted by antiviral cessation (odds ratio = 3.74; 95% confidence interval = 1.04-13.51; p = 0.030), whereas the CMV-Ig schedule had no effect. CONCLUSIONS: Extending the adjunctive CMV-Ig prophylaxis beyond the manufacturer's recommendations up to one year does not confer additional clinical benefits regarding lung post-transplantation outcomes.

Double-Lung Transplantation in a Patient with Pulmonary Type B Niemann-Pick Disease: A Valid Treatment Option.

Niemann-Pick disease is a rare autosomal recessive disease characterized by an abnormal intracellular lipid accumulation. Type B is later in onset and a less severe form of the disease, so affected people may survive in adulthood. Storage of sphingomyelin in pulmonary macrophages can lead to interstitial lung disease. There are very few published cases of lung transplantation in patients with Niemann-Pick disease, all of them described in the last 2 years. We present here one case of a 57-year-old man successfully treated with a double-lung transplant.

A prospective evaluation of phrenic nerve injury after lung transplantation: Incidence, risk factors, and analysis of the surgical procedure.

BACKGROUND: Phrenic nerve injury (PNI) is a complication of lung transplantation related to the surgical procedure and associated with increased morbidity. However, the incidence and risk factors, specifically regarding surgical techniques, have not been adequately studied. METHODS: We conducted a prospective single-center study over 4-years, in recipients of lung transplantation with a normal pretransplant phrenic nerve conduction study (PNCS). Diaphragm ultrasound and PNCS were performed in the first 21 postoperative days and PNI was defined when both tests were abnormal. Patients were followed up until hospital discharge. The association between transplant characteristics and PNI was analyzed by using logistic regression models. RESULTS: Two hundred eleven lung grafts implanted in 127 patients were included in the study. After lung transplantation, PNI was diagnosed in 43.3% of the subjects and 29% of the operated hemithorax. Regression logistic model showed that the variables related to PNI were female gender (p = 0.02), bilateral lung transplantation (BLT) (p = 0.001), right lung graft (p = 0.003), clamshell incision (p = 0.01), mediastinal adhesions (p = 0.002), longer operative time (p = 0.003), intraoperative extracorporeal support (p = 0.02), and blood transfusion (p = 0.003). Conversely, age >61 years (p = 0.008) and higher thoracic diameter (p = 0.04) were protective factors. The use of electrocautery, cardiac mechanical retractors, and diaphragmatic traction was not associated with PNI. Morbidity was increased without any difference in mortality. CONCLUSIONS: PNI is a frequent complication after lung transplantation, associated with higher morbidity. Mainly risk factors were age, BLT, female gender, and variables related to surgical difficulties. Lung graft in the right hemithorax and mediastinal adhesiolysis were the most relevant technical variables.

New Sequence Type ST3449 in Multidrug-Resistant Pseudomonas aeruginosa Isolates from a Cystic Fibrosis Patient.

Pseudomonas aeruginosa is one of the most critical bacterial pathogens associated with chronic infections in cystic fibrosis patients. Here we show the phenotypic and genotypic characterization of five consecutive multidrug-resistant isolates of P. aeruginosa collected during a month from a CF patient with end-stage lung disease and fatal outcome. The isolates exhibited distinct colony morphologies and pigmentation and differences in their capacity to produce biofilm and virulence potential evaluated in larvae of Galleria mellonella. Whole genome-sequencing showed that isolates belonged to a novel sequence type ST3449 and serotype O6. Analysis of their resistome demonstrated the presence of genes blaOXA-396, blaPAO, aph(3')-IIb, catB, crpP and fosA and new mutations in chromosomal genes conferring resistance to different antipseudomonal antibiotics. Genes exoS, exoT, exoY, toxA, lasI, rhlI and tse1 were among the 220 virulence genes detected. The different phenotypic and genotypic features found reveal the adaptation of clone ST3449 to the CF lung environment by a number of mutations affecting genes related with biofilm formation, quorum sensing and antimicrobial resistance. Most of these mutations are commonly found in CF isolates, which may give us important clues for future development of new drug targets to combat P. aeruginosa chronic infections.

Myeloid-Derived Suppressor Cells Are Increased in Lung Transplant Recipients and Regulated by Immunosuppressive Therapy.

Lung transplantation remains as a primary treatment for end-stage lung diseases. Although remarkable improvement has been achieved due to the immunosuppressive protocols, long-term survival for lung transplant recipients (LTR) is still limited. In the last few decades, an increasing interest has grown in the study of dysregulation of immune mechanisms underlying allograft failure. In this regard, myeloid-derived suppressor cells (MDSCs) could play an important role in the promotion of graft tolerance due to their immune regulatory function. Here, we describe for the first time circulating subsets MDSCs from LTR at several time points and we evaluate the relationship of MDSCs with sort-term lung transplant outcomes. Although no effect of MDSCs subsets on short-term clinical events was observed, our results determine that Mo-MDSCs frequencies are increased after acute cellular rejection (ACR), suggesting a possible role for Mo-MDSCs in the development of chronic lung allograft dysfunction (CLAD). Therefore, whether MDSCs subsets play a role as biomarkers of chronic rejection remains unknown and requires further investigations. Also, the effects of the different immunosuppressive treatments on these subpopulations remain under research and further studies are needed to establish to what extend MDSCs immune modulation could be responsible for allograft acceptance.

Predictive Value of Immune Cell Functional Assay for Non-Cytomegalovirus Infection in Lung Transplant Recipients: A Multicenter Prospective Observational Study.

INTRODUCTION: Immune cell functional assay (ImmuKnow®) is a non-invasive method that measures the state of cellular immunity in immunosuppressed patients. We studied the prognostic value of the assay for predicting non-cytomegalovirus (CMV) infections in lung transplant recipients. METHODS: A multicenter prospective observational study of 92 patients followed up from 6 to 12 months after transplantation was performed. Immune cell functional assay was carried out at 6, 8, 10, and 12 months. RESULTS: Twenty-three patients (25%) developed 29 non-CMV infections between 6 and 12 months post-transplant. At 6 months, the immune response was moderate (ATP 225-525ng/mL) in 14 (15.2%) patients and low (ATP<225ng/mL) in 78 (84.8%); no patients had a strong response (ATP≥525ng/mL). Only 1 of 14 (7.1%) patients with a moderate response developed non-CMV infection in the following 6 months compared with 22 of 78 (28.2%) patients with low response, indicating sensitivity of 95.7%, specificity of 18.8%, positive predictive value (PPV) of 28.2%, and negative predictive value (NPV) of 92.9% (AUC 0.64; p=0.043). Similar acute rejection rates were recorded in patients with mean ATP≥225 vs. <225ng/mL during the study period (7.1% vs. 9.1%, p=0.81). CONCLUSION: Although ImmuKnow® does not seem useful to predict non-CMV infection, it could identify patients with a very low risk and help us define a target for an optimal immunosuppression.

Predictive Value of Immune Cell Functional Assay for Non-Cytomegalovirus Infection in Lung Transplant Recipients: A Multicenter Prospective Observational Study.

INTRODUCTION: Immune cell functional assay (ImmuKnow®) is a non-invasive method that measures the state of cellular immunity in immunosuppressed patients. We studied the prognostic value of the assay for predicting non-cytomegalovirus (CMV) infections in lung transplant recipients. METHODS: A multicenter prospective observational study of 92 patients followed up from 6 to 12 months after transplantation was performed. Immune cell functional assay was carried out at 6, 8, 10, and 12 months. RESULTS: Twenty-three patients (25%) developed 29 non-CMV infections between 6 and 12 months post-transplant. At 6 months, the immune response was moderate (ATP 225-525ng/mL) in 14 (15.2%) patients and low (ATP<225ng/mL) in 78 (84.8%); no patients had a strong response (ATP≥525ng/mL). Only 1 of 14 (7.1%) patients with a moderate response developed non-CMV infection in the following 6 months compared with 22 of 78 (28.2%) patients with low response, indicating sensitivity of 95.7%, specificity of 18.8%, positive predictive value (PPV) of 28.2%, and negative predictive value (NPV) of 92.9% (AUC 0.64; p=0.043). Similar acute rejection rates were recorded in patients with mean ATP≥225 vs. <225ng/mL during the study period (7.1% vs. 9.1%, p=0.81). CONCLUSION: Although ImmuKnow® does not seem useful to predict non-CMV infection, it could identify patients with a very low risk and help us define a target for an optimal immunosuppression.

Efficacy and safety of the combination of reduced duration prophylaxis followed by immuno-guided prophylaxis to prevent cytomegalovirus disease in lung transplant recipients (CYTOCOR STUDY): an open-label, randomised, non-inferiority clinical trial.

INTRODUCTION: Prolonged use of antivirals to prevent the development of cytomegalovirus (CMV) disease in lung transplant patients has been shown to have significant side effects, for which alternatives are being sought to reduce their use. The monitoring of cell immunity against CMV could be an alternative as it has shown to be useful in identifying transplant patients at low risk of infection, who could benefit from shorter prophylaxis. The aim of the CYTOCOR study is to demonstrate that the combination of a reduced prophylaxis strategy with subsequent CMV-specific immunological monitoring would allow CMV infection to be controlled in lung transplant patients as effectively as the usual strategy (prophylaxis followed by pre-emptive therapy), while reducing the side effects of antivirals due to the shorter duration of prophylaxis. METHODS AND ANALYSIS: Phase III randomised, open, multicentre, parallel, non-inferiority clinical trial to study the efficacy and safety of the combination of a prophylaxis strategy up to month +3 post-transplant followed by immuno-guided prophylaxis using the QuantiFERON-CMV technique up to month +12 post-transplant to prevent CMV disease in CMV-seropositive lung transplant recipients. This strategy will be compared with a combination of a usual prophylaxis strategy up to month +6 post-transplant followed by pre-emptive therapy up to month +12. To study the incidence of CMV disease, patients will be followed up to 18 months post-transplantation. A total of 150 patients are expected to be recruited for the study. ETHICS AND PUBLIC DISSEMINATION: The clinical trial has been approved by the Research Ethics Committees and authorised by the Spanish Agency of Medicines and Medical Devices (AEMPS).If the hypothesis of this clinical trial is verified, the dissemination of the results could change clinical practice by increasing knowledge about the safety and efficacy of discontinuing valganciclovir prophylaxis in lung transplant recipients. TRIAL REGISTRATION NUMBER: NCT03699254.

Diagnosis of Idiopathic Pulmonary Fibrosis: Differential Diagnosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fibrotic interstitial lung disease of unknown origin with a characteristic imaging and histologic pattern called usual interstitial pneumonia (UIP). The diagnosis of IPF is a complex procedure that requires the support of various specialists, who must integrate clinical, radiological, and histological data. The multidisciplinary team (MDT) has become the new gold standard to diagnose and manage the disease, increasing the accuracy and agreement of the diagnosis between different centers. It is mandatory to exclude nonspecific interstitial pneumonia or other diseases that can cause the UIP pattern, particularly drugs or exposure diseases, including chronic hypersensitivity pneumonitis or systemic autoimmune disease. The role of the MDT is also to decide who could need a biopsy or to review patient diagnoses at regular intervals in those with additional information or unexpected evolution. This review provides updated information to achieve a proper IPF diagnosis.

Polymeric chemosensor for the detection and quantification of chloride in human sweat. Application to the diagnosis of cystic fibrosis.

We have developed a new extremely hydrophilic polymeric film suitable for the detection and quantification of chloride in human sweat directly on the skin. The film, or membrane, has chemically anchored 6-methoxyquinoline groups as chloride responsive fluorescent motifs. We have prepared the sensory material from a standard vinyl copolymer, by a convenient and easy solid-phase reaction. The sensory material has a water swelling percentage of 700%, facilitating an immediate detection of chloride, is reusable for at least 6 cycles and can be handled without care by unskilled persons. The initially high fluorescence of the material decreases in the presence of chloride, allowing the quantification of chloride concentration by using the colour definition of a digital picture or a fluorimeter. The suitability of the material to perform quantitative chloride analysis of human sweat by putting it in contact with the skin offers promise for its application in the sweat test used for the diagnosis of cystic fibrosis (CF).

Screening for Latent Tuberculosis Infection in Patients who are Candidate for Biological Therapies in Spain? A Multidisciplinary Survey. / ¿Cómo realizamos el cribado de infección tuberculosa latente en pacientes candidatos a terapias biológicas en España? Una encuesta multidisciplinar.

INTRODUCTION: Treatment with biological therapies increases the incidence of tuberculous disease. The introduction of systematic screening for latent tuberculosis infection in patients who are to receive these therapies has reduced this risk. In 2016, the consensus document on the prevention and treatment of tuberculosis in patients who are candidates for biological treatment was published in Spain. The main objective of this study was to evaluate adherence to these guidelines. METHODS: Multicenter, descriptive, observational study via an anonymous online survey sent to medical societies involved in biologics. RESULTS: We received 747 responses. Most respondents performed screening at the right time in the right patients (93.7%). Only 36.6% of respondents requested the appropriate diagnostic test, while 56.3% correctly recommended chemoprophylaxis. Up to 96% were familiar with the recommended chemoprophylaxis regimens, while only 63.9% initiated them at the right time. The specialist area that participated most and screened most patients for latent tuberculosis infection was rheumatology (54%). In most cases, pulmonologists were involved in an advisory capacity. CONCLUSIONS: This study shows poor overall adherence to recommendations, with only 56% of respondents reporting appropriate compliance. The incidence of tuberculous disease in patients who are to receive biological therapies could be reduced further by emphasizing the importance of the right diagnostic test and use of the diagnostic algorithm for latent tuberculosis infection.

Outcomes in systemic sclerosis-related lung disease after lung transplantation.

BACKGROUND: Lung disease is the leading cause of death in systemic sclerosis (SSc). The diagnosis of SSc-related lung disease (SSc-LD) is often a contraindication to lung transplantation (LT) due to concerns that extrapulmonary involvement will yield worse outcomes. We sought to evaluate posttransplantation outcomes in persons with SSc-LD with esophageal involvement compared with persons with nonconnective tissue disease-related interstitial lung disease (nCTD-ILD). METHODS: From 1998 to 2012, persons undergoing LT for SSc-LD were age and gender matched in a 2:1 fashion to controls undergoing LT for nCTD-ILD. Esophageal function was assessed by pH testing and manometry. We defined esophageal dysfunction as the presence of a DeMeester score >14 or dysmotility more severe than "mild nonspecific disorder". The primary outcome was posttransplantation survival. Secondary outcomes included freedom from bronchiolitis obliterans syndrome (fBOS) and rates of acute rejection. Survival and fBOS were estimated with Kaplan-Meier methods. Acute rejection was compared with Student's t test. RESULTS: Survival was similar in 23 persons with SSc-LD and 46 controls who underwent LT (P = 0.47). For the SSc-LD group, 1- and 5-year survival was 83% and 76% compared with 91% and 64% in the nCTD-ILD group, respectively. There were no differences in fBOS (P = 0.83). Rates of acute rejection were less in SSc-ILD (P = 0.05). Esophageal dysfunction was not associated with worse outcomes (P>0.55). CONCLUSIONS: Persons with SSc-LD appear to have similar survival and fBOS as persons transplanted for nCTD-ILD. The risk of acute rejection after transplantation may be reduced in persons with SSc-LD. Esophageal involvement does not appear to impact outcomes.