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 Everolimus was withdrawn in 22 (38.6%) patients.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 However, the drug was withdrawn in a high proportion of patients.

Antifibrotics and lung transplantation: A Spanish multicentre case-controlled study.

BACKGROUND AND OBJECTIVE: Antifibrotic drugs are the standard treatments for patients with idiopathic pulmonary fibrosis (IPF). This study aims to assess the safety of antifibrotic treatment in IPF patients undergoing lung transplantation. METHODS: Patients with a diagnosis of IPF who received a lung transplant between January 2015 and June 2019 at four Spanish hospitals specialized in lung transplantation were retrospectively recruited. Cases were defined as patients receiving antifibrotic treatments at time of transplant. Each case was matched with a control who did not receive antifibrotic treatment. RESULTS: A total of 164 patients were included in the study cohort (103 cases and 61 controls). There were no statistically significant differences between the cases and controls in any of the items studied related to transplantation except the time until the appearance of chest wall dehiscence: although there were no differences in the incidence of wall dehiscence in either group (12.3% vs. 13.7%; p = 0.318), the patients on antifibrotic drugs experienced it earlier (21 days [IQR = 12.5-41.5] vs. 63 days [IQR = 46.75-152.25]; p = 0.012). There were no differences in overall post-transplant survival between the two groups (p = 0.698) or in conditional survival at 30 days, 90 days, 3 years or 5 years. However, 1 year survival was significantly greater among controls (80.6% vs. 93.3%; p = 0.028). CONCLUSION: There was evidence that chest wall dehiscences appeared earlier post-transplant in patients using antifibrotics, even though this factor did not significantly impact survival.

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.

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.

Role of VEGF Polymorphisms in the Susceptibility and Severity of Interstitial Lung Disease.

The search for biomarkers that can help to establish an early diagnosis and prognosis of interstitial lung disease (ILD) is of potential interest. VEGF polymorphisms have been implicated in the development of several lung disorders. Consequently, we assessed, for the first time, the role of VEGF polymorphisms in the susceptibility and severity of ILD. A total of 436 Caucasian ILD patients (244 with idiopathic interstitial pneumonias (IIPs) and 192 with non-IIP) and 536 ethnically-matched healthy controls were genotyped for VEGF rs833061, rs1570360, rs2010963, rs3025020, and rs3025039 polymorphisms by TaqMan assays. Pulmonary function tests were collected from all the patients. VEGF serum levels were determined by ELISA in a subgroup of patients. No VEGF genotype, allele, carrier, or haplotype differences were found between ILD patients and controls as well as between IIP and non-IIP patients. However, an association of rs1570360 with IIP in women and also with lung function in IIP patients was found. None of the VEGF polymorphisms were associated with VEGF levels. In conclusion, our results suggest that VEGF does not seem to play a relevant role in ILD, although rs1570360 may influence the severity of ILD in women and a worse outcome in IIP patients.

Radiological Findings in Multidetector Computed Tomography (MDCT) of Hereditary and Sporadic Pulmonary Veno-Occlusive Disease: Certainties and Uncertainties.

Pulmonary veno-occlusive disease (PVOD) is a very infrequent form of pulmonary arterial hypertension with an aggressive clinical course, poor response to specific vasodilator treatment, and low survival. Confirming a definitive diagnosis is essential to guide treatment and assess lung transplantation. However, in the absence of histological or genetic confirmation, the diagnosis is complex, requiring a clinical suspicion. Multidetector computed tomography (MDCT) is an essential part of the non-invasive diagnostic tools of PVOD. We retrospectively reviewed the MDCT findings from a consecutive series of 25 patients diagnosed with PVOD, 9 with the sporadic form and 16 with the hereditary form of the disease. The presence and extent of typical findings of the diagnostic triad were assessed in all patients (ground glass parenchymal involvement, septal lines, and lymphadenopathy). In our series, 92% of patients showed at least two of the radiological findings described as typical of the disease. All patients presented at least one typical radiological characteristic. The incidence of radiological findings considered typical is very high, however was not associated with greater hemodynamic severity nor to the development of acute lung edema. No significant differences were found between the two groups. A poorly expressive MDCT does not exclude the disease.

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.

Esophageal motor disorders are frequent during pre and post lung transplantation. Can they influence lung rejection?

BACKGROUND: lung transplantation (LTx) is a viable option for most patients with end-stage lung diseases. Esophageal motor disorders (EMD) are frequent in candidates for LTx, but there is very little data about changes in esophageal motility post-LTx. AIM: the aim of our study was to assess esophageal motor disorders by high resolution manometry (HRM) both pre-LTx and six months post-LTx in patients with and without organ rejection. STUDY: HRM (Manoscan®) was performed in 57 patients both pre-LTx and six months post-LTx. HRM plots were analyzed according to the Chicago classification 3.0. RESULTS: EMD were found in 33.3% and in 49.1% of patients pre-LTx and post-LTx, respectively, and abnormal peristalsis was more frequently found post-LTx (p = 0.018). Hypercontractile esophagus was frequently found post-LTx (1.8% and 19.3% pre-LTx and post-LTx, respectively). Esophagogastric junction (EGJ) morphology changed significantly pre-LTx and post-LTx; type I (normal) was more frequent post-LTx (63-2% and 82.5% respectively, p = 0.007). EMD were more frequent post-LTx in both the non-rejection and rejection group, although particularly in the rejection group (43.2% and 69.2% respectively, p = 0.09). EMD such as distal spasm, hypercontractile esophagus and EGJ outflow obstruction were also observed more frequently post-LTx in the rejection group. CONCLUSION: significant changes in esophageal motility were observed pre-LTx and particularly post-LTx; hypercontractile esophagus was a frequent EMD found post-LTx. EMD were more frequent in the group of patients that experienced organ rejection compared to the non-rejection group. EMD leading to an impaired esophageal clearance should be considered as an additional factor that contributes to LTx failure.

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.

Trends in Pulmonary Hypertension Over a Period of 30 Years: Experience From a Single Referral Centre.

INTRODUCTION AND OBJECTIVES: Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary vascular resistance, right ventricular dysfunction and death. Despite scientific advances, is still associated with high morbidity and mortality. The aim is to describe the clinical approach and determine the prognostic factors of patients with PAH treated in a national reference center over 30 years. METHODS: Three hundred and seventy nine consecutive patients with PAH (January 1984 to December 2014) were studied. Were divided into 3 periods of time: before 2004, 2004-2009 and 2010-2014. Prognostic factors (multivariate analysis) were analyzed for clinical deterioration. RESULTS: Median age was 44 years (68.6% women), functional class III-IV: 72%. An increase was observed in more complex etiologies in the last period of time: Pulmonary venooclusive disease and portopulmonary hypertension. Upfront combination therapy significantly increased (5% before 2004 vs 27% after 2010; P < .05). Multivariate analysis showed prognostic significance in age, sex, etiology and combined clinical variables as they are independent predictors of clinical deterioration (P < .05). Survival free from death or transplantation for the 1st, 3rd and 5th year was 92.2%, 80.6% and 68.5% respectively. The median survival was 9 years (95% confidence interval, 7.532-11.959) CONCLUSIONS: The PAH is a heterogeneous and complex disease, the median survival free from death or transplantation in our series is 9 years after diagnosis. The structure of a multidisciplinary unit PAH must adapt quickly to changes that occur over time incorporating new diagnostic and therapeutic techniques.

Obstructive sleep apnea-hypopnea syndrome in patients with severe chronic respiratory insufficiency. / Síndrome de apnea-hipopnea durante el sueño en pacientes con insuficiencia respiratoria crónica grave.

INTRODUCTION AND OBJECTIVE: Although sleep disordered breathing is common in patients with a severe chronic respiratory insufficiency (SCRI), there is few information on its prevalence. Our aim was to describe the prevalence and characteristics of the obstructive sleep apnea-hypopnea syndrome (OSAHS) in these patients. MATERIAL AND METHODS: Prospective and observational study carried out on patients with a SCRI included in a waiting list for a lung transplantation and who had undergone a standard polysomnography. RESULTS: A total of 105 patients were examined, of which 85 met the study's inclusion criteria. The prevalence of the OSAHS was 24.7%, with 19% of cases being severe. The most common underlying respiratory condition was COPD (62%). The OSAHS was linked to the male gender (P=.002), weight (P=.013), BMI (P=.034) and neck circumference (P=.01). Although most patients experienced symptoms suggestive of an OSAHS, the average score obtained in the Epworth Sleepiness Scale was low. CONCLUSIONS: We observed a high prevalence of OSAHS in patients with a SCRI but without clinical data suggestive of its diagnosis; hence, we believe that sleep studies should be carried out in these patients given the low pre-test clinical suspicion of the disease.

Sleep-Related Breathing Disorders and Lung Transplantation.

AIM: Sleep-related breathing disorders (SRBD) are common in patients with lung transplantation (LT); however, there are few data about its prevalence, and none about its pathogenesis or evolution. The SRBD events consist mainly obstructive, central, and mixed apnea, as well as hypopneas. The aim of this study was to describe the prevalence of SRBD before the LT, and its evolution after a period of 1 year follow-up. METHODS: Prospective, observational, descriptive, and analytical study of the SRBD and its evolution in 20 LT patients. The group was studied before and at 6 and 12 months after the LT; in each phase, standard polysomnography was performed, and anthropometric, pathologic, clinical, and pharmacological data were collected. RESULTS: Prevalence of obstructive sleep apnea syndrome was 38% before the LT, 86% at 6 months, and 76% at 12 months after LT. There was a significant increase of weight, body mass index, neck circumference, blood pressure during the first year of follow-up, especially at 6 months after LT. We also observed an increase in the number of central and mixed apneas during the follow-up, although not as remarkable as obstructive apneas. There was no correlation between immunosuppressant studied drugs and any of the studied variables. CONCLUSIONS: We have observed a significant prevalence of obstructive sleep apnea syndrome in patients in waiting list for LT, and LT has an important influence in the evolution of the disorder. In our series, LT has somehow affected the stability of upper airway and ventilatory mechanics.

Treatment of bronchus intermedius stenosis in lung transplantation with Montgomery T-tube stent. A novel technique.

Airway complications after lung transplant are relatively common although the rates vary according to the different studies. Pathogenesis is diverse but the principal mechanism is usually bronchus intermedius ischemia in the post-transplant period. One major complication is bronchial stenosis, with relatively frequent involvement of the bronchus intermedius in the case of right lung transplantation. Various treatments have been proposed for bronchus intermedius stenosis, such as endobronchial balloon dilation, laser, cryosurgery and bronchial stents. We present two cases of lung transplant recipients with bronchus intermedius stenosis treated with a Montgomery stent or T-stent, commonly used for tracheal stenosis, who showed positive clinical and functional response.

Recommendations of diagnosis and treatment of pleural effusion. Update.

Although during the last few years there have been several important changes in the diagnostic or therapeutic methods, pleural effusion is still one of the diseases that the respiratory specialist have to evaluate frequently. The aim of this paper is to update the knowledge about pleural effusions, rather than to review the causes of pleural diseases exhaustively. These recommendations have a longer extension for the subjects with a direct clinical usefulness, but a slight update of other pleural diseases has been also included. Among the main scientific advantages are included the thoracic ultrasonography, the intrapleural fibrinolytics, the pleurodesis agents, or the new pleural drainages techniques.