Everolimus Treatment for Chronic Lung Allograft Dysfunction in Lung Transplantation.

Our study aims to evaluate the effect of everolimus treatment on lung function in lung transplant (LT) patients with established chronic lung allograft dysfunction (CLAD). METHODS: This retrospective study included LT patients in two reference LT units who started everolimus therapy to treat CLAD from October 2008 to October 2016. We assessed the variation in the maximum forced expiratory volume in the first second (FEV1) before and after the treatment. RESULTS: Fifty-seven patients were included in this study. The variation in the FEV1 was -102.7 (149.6) mL/month before starting everolimus compared to -44.7 (109.6) mL/month within the first three months, +1.4 (63.5) mL/month until the sixth month, and -7.4 (46.2) mL/month until the twelfth month (p < 0.05). Glomerular filtrate remained unchanged after everolimus treatment [59.1 (17.5) mL/min per 1.73 m2 at baseline and 60.9 (19.6) mL/min per 1.73 m2, 57.7 (20.5) mL/min per 1.73 m2, and 57.3 (17.8) mL/min per 1.73 m2, at 1, 3, and 6 months, respectively] (p > 0.05). Everolimus was withdrawn in 22 (38.6%) patients. The median time to withdrawal was 14.1 (5.5-25.1) months. CONCLUSIONS: This study showed an improvement in FEV1 decline in patients with CLAD treated with everolimus. However, the drug was withdrawn in a high proportion of patients.

Long-Term Effect of Noninvasive Ventilation on Diaphragm in Chronic Respiratory Failure.

PURPOSE: Home non-invasive ventilation (NIV) is recommended in patients with COPD and hypercapnic chronic respiratory failure (HCRF). The mechanism by it can improve alveolar ventilation during spontaneous breathing is not yet completely explained. Our aim is to evaluate the impact of on diaphragm muscle function in a series of patients with HCRF. PATIENTS AND METHODS: Observational, longitudinal, prospective study of a series of patients with very severe chronic obstruction to airflow treated with home high imntensity NIV (HINIV). Patients underwent a baseline and after 12 months assessment including adherence to treatment, quality of life, respiratory function tests and diaphragmatic ultrasound. SPSS v.26 software was used for statistical analysis. RESULTS: We studied 30 patients, 63% male, the mean age was 60.8 (±6.4) years old. Patients had a severe obstructive ventilatory pattern [FEV1 21.8 (±6.1)%] and hypercapnia [pCO2 56.4 (±7.2) mmHg]. After 12 months of HINIV, we observed significant increases in FVC of 9.2% (p = 0.002), FEV1 of 3.5% (p = 0.04), MIP of 9.4% (p = 0.006), and 6-minute-walking test (6MWT) of 31.9 m (p = 0.001), as well as decreases in paCO2 of 12.5 mmHg (p = 0.001), HCO3 of 4.7 mmol/L (p = 0.001) and BODE index from 7 to 6. Diaphragmatic ultrasound demonstrated an increase in the thickening fraction of 14% (p = 0.002). Respiratory symptoms (p = 0.04), physical function (p = 0.03), and sleep (p = 0.04) also improved. CONCLUSION: In patients with HCRF due to very severe chronic obstruction to airflow, long-term HINIV can improve respiratory performance by improving the function of the diaphragmatic musculature. Larger multicenter clinical trials are needed to confirm the results suggested in this study.

Role of MUC1 rs4072037 polymorphism and serum KL-6 levels in patients with antisynthetase syndrome.

Mucin 1/Krebs von den Lungen-6 (KL-6) is proposed as a serum biomarker of several interstitial lung diseases (ILDs), including connective tissue disorders associated with ILD. However, it has not been studied in a large cohort of Caucasian antisynthetase syndrome (ASSD) patients. Consequently, we assessed the role of MUC1 rs4072037 and serum KL-6 levels as a potential biomarker of ASSD susceptibility and for the differential diagnosis between patients with ILD associated with ASSD (ASSD-ILD +) and idiopathic pulmonary fibrosis (IPF). 168 ASSD patients (149 ASSD-ILD +), 174 IPF patients and 523 healthy controls were genotyped for MUC1 rs4072037 T > C. Serum KL-6 levels were determined in a subgroup of individuals. A significant increase of MUC1 rs4072037 CC genotype and C allele frequencies was observed in ASSD patients compared to healthy controls. Likewise, MUC1 rs4072037 TC and CC genotypes and C allele frequencies were significantly different between ASSD-ILD+ and IPF patients. Additionally, serum KL-6 levels were significantly higher in ASSD patients compared to healthy controls. Nevertheless, no differences in serum KL-6 levels were found between ASSD-ILD+ and IPF patients. Our results suggest that the presence of MUC1 rs4072037 C allele increases the risk of ASSD and it could be a useful genetic biomarker for the differential diagnosis between ASSD-ILD+ and IPF patients.

Influence of Cytomegalovirus on the Survival of Cytomegalovirus-Seropositive Lung Transplant.

BACKGROUND: The primary aim of this study was to analyze the survival of patients undergoing lung transplant (LT) with cytomegalovirus (CMV)-positive serologies at the time of transplantation, according to the presence of CMV events and according to the severity of these events. The secondary objective was to assess whether there are differences in the incidence of chronic lung allograft dysfunction (CLAD) according to the presence of these events. METHODS: This was an observational, single-center, retrospective study. The inclusion criterion for the study was having undergone LT at the Hospital Universitario 12 de Octubre from October 2008 to February 2019. Survival was calculated using the Kaplan-Meier method and compared using the log-rank test. The incidence of CLAD was compared using the χ2 test. RESULTS: Inclusion criteria were met by 239 LTs. In terms of survival, no difference was found between patients with and without CMV events (log-rank P = .52), with mean survival of 3223 ± 164 days and 3024 ± 146 days, respectively. Nor did we find a difference when stratifying patients according to no CMV events, infection, syndrome, and disease (log-rank P = .6). There was also no difference in the incidence of CLAD between patients with and without CMV events (P > .178). CONCLUSION: In patients with positive CMV serology, the development of CMV events, including severe disease, does not seem to influence survival. The incidence of CLAD also is not increased by the presence of CMV events.

Antithymocyte Globulin Treatment for Chronic Lung Allograft Dysfunction in Lung Transplant Recipients: Experience From a National Reference Transplant Center.

BACKGROUND: Chronic lung allograft dysfunction (CLAD) is the leading cause of mortality after the first year of transplantation and treatments can have little impact on CLAD progression in some cases. The objective of this study was to evaluate the effectiveness and safety of antithymocyte globulin (ATG) in lung transplant recipients with CLAD. METHODS: We reviewed all patients from our center that had undergone a lung transplant between 2008 and 2019 and selected those with CLAD who were treated with ATG. The closest lung function (forced expiratory volume in the first second) to the ATG administration was recorded, as well as the values 3, 6, and 12 months before and after treatment. We followed and recorded survival during the 12 months after treatment. RESULTS: A total of 13 patients with CLAD received ATG treatment. A favorable positive response to treatment (improvement or stabilization on lung function) was achieved in half of the patients. Most patients (71%) who responded well to ATG were in CLAD stage 1 to 2. The fall slope of forced expiratory volume in the first second is better after treatment. The median survival was 27 months, and we found a trend toward better survival in early CLAD stages 1 to 2. There were also differences in survival between rapid decliners and nonrapid decliners. CONCLUSIONS: ATG treatment could play a role in patient with CLAD who do not respond to conventional therapies. The effect of cytolytic therapy with ATG is clearly better in those patients in early stages, with little effect in those in CLAD stage 3.

Morbidity and mortality of serious gastrointestinal complications after lung transplantation.

BACKGROUND: Gastrointestinal complications after lung transplatation are associated with an increased risk of morbidity and mortality. This study aims to describe severe gastrointestinal complications (SGC) after lung transplantation. METHODS: We performed a prospective, observational study that included 136 lung transplant patients during a seven year period in a tertiary care universitary hospital. SGC were defined as any diagnosis related to the gastrointestinal or biliary tract leading to lower survival rates or an invasive therapeutic procedure. Early and late complications were defined as those occurring < 30 days and ≥ 30 days post-transplant. The survival function was calculated through the Kaplan-Meier estimator. Variables were analyzed using univariate and multivariate analysis. Statistical significance was defined as p < 0.05. RESULTS: There were 17 (12.5%) SGC in 17 patients. Five were defined as early. Twelve patients (70.6%) required surgical treatment. Mortality was 52.9% (n = 9). Patients with SGC had a lower overall survival rate compared to those who did not (14 vs 28 months, p = 0.0099). The development of arrhythmias in the first 48 h of transplantation was a risk factor for gastrointestinal complications (p = 0.0326). CONCLUSIONS: SGC are common after lung transplantation and are associated with a considerable increase in morbidity-mortality. Early recognition is necessary to avoid delays in treatment, since a clear predictor has not been found in order to forecast this relevant comorbidity.

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.

Experience with leflunomide as treatment and as secondary prophylaxis for cytomegalovirus infection in lung transplant recipients: A case series and review of the literature.

BACKGROUND: Data concerning the use of leflunomide-a drug approved for rheumatoid arthritis with in vitro anticytomegalovirus (CMV) activity-in lung transplant (LT) recipients are scarce. AIMS: To report the use of leflunomide in LT recipients diagnosed with CMV infection/disease. MATERIAL AND METHODS: We performed a single-center retrospective study including LT recipients who received leflunomide for CMV infection or as secondary prophylaxis after viremia clearance. We also conducted a full systematic PubMed search until June 30, 2017. RESULTS: We identified 5 LT recipients in our center plus 7 patients reported in the literature. All patients had previously received ganciclovir (GCV) and foscarnet (FOS), with drug-induced adverse effects described in 6 recipients (50%). Antiviral resistance mutations were observed in 8 patients (66.7%). Leflunomide was prescribed for CMV infection in 9 of 12 patients (75%) and as secondary prophylaxis in 3 patients (25%). Initial decrease of CMV viremia after starting leflunomide was observed in 7 of 9 recipients (77.7%), although this response was only transient in 2 patients. Long-term suppression of CMV viremia was reported in 7 of 12 patients (58.3%). In 3 recipients (25%), leflunomide was discontinued due to adverse effects. DISCUSSION: Our study has some limitations, such as the small number of patients included, its retrospective nature, and absence of leflunomide drug monitoring in serum. Notwithstanding, in our experience, leflunomide proved to be particularly effective as an anti-CMV secondary prophylaxis treatment and for clearing low-grade viremia. Moreover, leflunomide combined with a short course of GCV or intravitreal FOS also proved to be very effective in some patients. CONCLUSION: Leflunomide, alone or in combination, could be an effective treatment in selected LT recipients with GCV-resistant CMV infection and as secondary prophylaxis. Further studies are necessary.

Experience with miltefosine for persistent or relapsing visceral leishmaniasis in solid organ transplant recipients: A case series from Spain.

The incidence of visceral leishmaniasis (VL) after solid organ transplantation (SOT) is increasing. The optimal therapy for post-transplant VL remains unclear, as relapses after liposomal amphotericin B (L-AmB) are common. Miltefosine has been shown to be effective for treating VL in immunocompetent patients, although data in the specific population of SOT recipients are lacking. In the setting of an outbreak of leishmaniasis occurring in Southwest Madrid, we reviewed our experience in 6 SOT recipients with persistent or relapsing VL who received a 28-day course of miltefosine (2.5 mg/kg/day) as salvage therapy. All patients had been treated previously with L-AmB as first-line therapy. The incident episode of VL occurred at a median of 14 months after transplantation. Two patients experienced persistent infection and the remaining 4 had a relapse after a median interval of 168 days since the completion of the course of L-AmB. All the patients had an apparent initial clinical improvement with miltefosine. However, VL relapsed in 3 of them (after a median interval of 46 days), which required retreatment with L-AmB-based regimens. Miltefosine therapy was followed by a prolonged secondary prophylaxis with L-AmB in the only 2 cases with sustained clinical response and ongoing immunosuppression. No adverse effects associated with miltefosine were observed. Albeit limited, our experience suggests that miltefosine monotherapy likely has a limited utility to obtain a long-lasting clinical response in complicated (persistent or relapsing) forms of post-transplant VL, although its role in association with L-AmB-based secondary prophylaxis may merit further investigation.

Continuous positive airway pressure and survival of very elderly persons with moderate to severe obstructive sleep apnea.

OBJECTIVE: There is evidence of a beneficial effect of long-term continuous positive airway pressure (CPAP) on survival in elderly persons with obstructive sleep apnea (OSA), although the usual age cut off is between 60 and 70 years of age. Our objective was to determine this effect in very elderly patients (ie, those ≥80 years of age). METHODS: An observational study of a historic cohort of very elderly persons with moderate to severe OSA (apnea-hypopnea index ≥20) and the effect of long-term CPAP on their survival was performed. Two groups were formed: one prescribed CPAP treatment (≥4 hours per night), and one without CPAP treatment. Survival analyses, including Kaplan-Meier curves and Cox models, were carried out to determine the association of long-term CPAP with longer survival, RESULTS: A total of 155 very elderly persons (84 men and 71 women, mean age 81.5 ± 1.5 years) were followed up for 53 months (interquartile range, 41-77 months); 83 deaths occurred. CPAP was prescribed to 132 patients, and adherence was observed in 79 (60%). Kaplan-Meier curves showed longer survival in the treated OSA group (91 months, 95% confidence interval [CI] = 76-106) than in the untreated OSA group (52 months, 95% CI 41-64), which was statistically significant (log-rank 16.9, p < 0.0001). Although history of stroke was significantly associated with higher mortality (hazard ratio [HR] = 2.18, 95% CI = 1.14-4.17, p = 0.02), CPAP treatment was associated with higher survival rates (HR = 0.46, 95% CI = 0.27-0.78, p = 0.004) in an adjusted Cox analysis. CONCLUSIONS: CPAP treatment might be associated with a longer survival in very elderly persons with moderate to severe OSA.

[Use of positron emission tomography in assessing hidden extrathoracic metastasis in non small cell lung cancer]. / Utilidad de la tomografía por emisión de positrones en la detección de metástasis ocultas extratorácicas en el carcinoma broncogénico no células pequeñas.

INTRODUCTION: Positron emission tomography combined with computed axial tomography (PET/CT) is used for staging non small cell lung cancer (NSCLC). This study aims to describe PET/CT findings of unsuspected extrathoracic metastasis when used in mediastinal evaluation of patients with apparently resectable NSCLC. PATIENTS AND METHOD: Prospective and concurrent study including all NSCLC patients between June 2004 and November 2006 who underwent PET/CT after considering them as candidates for surgery, with resectable disease after bronchoscopy, thorax and abdominal CT, brain CT and bone gammagraphy evaluation, if metastasis at these locations were suspected. Metastasis were confirmed histopathologically or assumed when they had a compatible evolution. RESULTS: A total of 91 patients with NSCLC underwent PET/CT. In 24 of them (26%) at least one suspicious extrathoracic uptake was seen. In 7 patients (7.7%) those uptakes were NSCLC extrathoracic metastasis hidden from conventional staging. In 3 of these cases (13.1%) extrathoracic uptakes corresponded to metacrhonous tumours or pre-malignant conditions. Benign lesions were found in 12 patients (13.1%), and in 2 cases (2.2%) the uptake origins were undetermined. CONCLUSIONS: PET/CT is a complementary diagnosis method for assessing hidden metastases which could modify the therapeutical approach in patients otherwise suitable for surgery.