Lung Transplantation in Cystic Fibrosis and the Impact of Extracorporeal Circulation

Introduction

Lung disease is the major cause of death among cystic fibrosis (CF) patients, affecting 80% of the population. The impact of extracorporeal circulation (ECC) during transplantation has not been fully clarified. This study aimed to evaluate the outcomes of lung transplantation for CF in a single center, and to assess the impact of ECC on survival.

Study of a Cohort of Patients With Cystic Fibrosis and Isolation of Scedosporium spp.

IntroductionIn recent years an increase in the prevalence of colonization and infection by Scedosporium spp. in patients with cystic fibrosis (CF) has been observed. In this article, we study the frequency of isolation of Scedosporium spp. in an adult CF Unit, analyzing characteristics of the patients and predisposing factors.MethodsA retrospective observational study was conducted in 87 adult CF patients in whom the presence of positive culture for Scedosporium spp. was tested for a 5-year period (January 2012–July 2017). We recorded the following clinical variables: age, sex, body mass index, genotype, presence of pancreatic insufficiency, bacterial colonization, lung function, other complications, exacerbations and treatment, and the modified Bhalla score from the last high-resolution computed tomography. Results were analyzed with IBM SPSS Statistics Version 22.0 software.ResultsScedosporium spp. was isolated in 25.3% of patients. In the bivariate analysis, these patients showed a higher rate of Pseudomonas aeruginosa infection, worse score in the Bhalla classification (highlighting the following items: bronchiectasis, mucus plugs and bronchial generations), a slight decrease in the lung diffusion capacity and more frequently received inhaled antibiotics. In the logistic regression multivariate analysis, only the bronchial generations item was significant.ConclusionScedosporium spp. must be considered an emerging opportunistic pathogen in patients with CF whose clinical involvement, risk factors or need for treatment is unknown.     

Guidelines on the Diagnosis and Treatment of Pulmonary Hypertension: Summary of Recommendations

Pulmonary hypertension is a hemodynamic disorder defined by abnormally high pulmonary artery pressure that can occur in numerous diseases and clinical situations. The causes of pulmonary hypertension are classified into 5 major groups: arterial, due to left heart disease, due to lung disease and/or hypoxemia, chronic thromboembolic, with unclear and/or multifactorial mechanisms. This is a brief summary of the Guidelines on the Diagnostic and Treatment of Pulmonary Hypertension of the Spanish Society of Pulmonology and Thoracic Surgery. These guidelines describe the current recommendations for the diagnosis and treatment of the different pulmonary hypertension groups.     

Medical and Surgical Management for Chronic Thromboembolic Pulmonary Hypertension: A Single Center Experience

IntroductionPulmonary endarterectomy (PE) is the treatment of choice for chronic thromboembolic pulmonary hypertension (CTEPH). The aim of this study was to analyze our experience in the medical and surgical management of CTEPH.MethodsWe included 80 patients diagnosed with CTEPH between January 2000 and July 2012. Thirty-two patients underwent PE and 48 received medical treatment (MT). We analyzed functional class (FC), 6-min walking distance (6MWD), and pulmonary hemodynamics. Mortality in both groups and periods were analyzed.ResultsPatients who underwent PE were younger, mostly men, and had longer 6MWD. No differences were observed in pulmonary hemodynamics or FC at diagnosis. One year after treatment, all PE patients versus 41% in MT group were at FC I–II. At follow-up, the PE group showed greater increase in 6MWD, and greater reduction in mean pulmonary arterial pressure and pulmonary vascular resistance than the MT group (P<.05). Overall survival in the MT group at 1 and 5 years was 83% and 69%, respectively. Conditional survival in patients alive 100 days post-PE at 1 and 5 years was 95% and 88%, respectively. Surgical mortality in operated patients in the first period (2000–2006) was 31.3%, and 6.3% in the second (2007–2012).ConclusionsPE provides good clinical results, and improves pulmonary hemodynamics in patients who successfully overcome the immediate postoperative period. After a learning period, the current operatory mortality in our center is similar to international standards.     

Compassionate Use of Lumacaftor/Ivacaftor in Cystic Fibrosis: Spanish Experience

Background

The most common cystic fibrosis (CF)-causing mutation is deltaF508 (F508del), which is present in 28% of CF Spanish patients. While the literature based on real-life studies on CF patients homozygous F508del treated with lumacaftor/ivacaftor is limited, it demonstrates the need for better strategies to prevent related adverse events (AEs) as well as the development of newer drugs.

Relationship Among Radiological Measurements of Anterior Mediastinal Fat and Outcomes of Lung Transplantation in Fibrotic Patients

ObjectiveLung transplantation (LT) for pulmonary fibrosis is related to higher mortality than other transplant indications. We aim to assess whether the amount of anterior mediastinal fat (AMF) was associated to early and long-term outcomes in fibrotic patients undergoing LT.MethodsRetrospective analysis of 92 consecutive single lung transplants (SLT) for pulmonary fibrosis over a 10-year period. AMF dimensions were measured on preoperative CT-scan: anteroposterior axis (AP), transverse axis (T), and height (H). AMF volumes (V) were calculated by the formula: AP × T × H × 3.14/6.According to the radiological AMF dimensions, patients were distributed into two groups: low-AMF (V < 20 cm³) and high-AMF (V > 20 cm³), and early and long-term outcomes were compared by univariable and multivariable analyses.ResultsThere were 92 SLT: 73M/19F, 53 ± 11 [14–68] years old. 30-Day mortality (low-AMF vs. high-AMF): 5 (5.4%) vs. 15 (16.3%), p = 0.014. Patients developing primary graft dysfunction within 72 h post-transplant, and those dying within 30 days post-transplant presented higher AMF volumes: 21.1 ± 19.8 vs. 43.3 ± 24.7 cm³ (p = 0.03) and 24.4 ± 24.2 vs. 56.9 ± 63.6 cm³ (p < 0.01) respectively. Overall survival (low-AMF vs. high-AMF) (1, 3, and 5 years): 85%, 81%, 78% vs. 55%, 40%, 33% (p < 0.001).Factors predicting 30-day mortality were: BMI (HR = 0.77, p = 0.011), AMF volume (HR = 1.04, p = 0.018), CPB (HR = 1.42, p = 0.002), ischaemic time (HR = 1.01, p = 0.009).Factors predicting survival were: AMF volume (HR = 1.02, p < 0.001), CPB (HR = 3.17, p = 0.003), ischaemic time (HR = 1.01, p = 0.001).ConclusionPreoperative radiological assessment of mediastinal fat dimensions and volumes may be a useful tool to identify fibrotic patients at higher risk of mortality after single lung transplantation.     

Tuberculosis Following Lung Transplantation. A 27-Year Spanish Multicenter Experience. Incidence,Presentation, Prevention and Treatment with Rifampicin

BackgroundTuberculosis (TB) represents a diagnostic and therapeutic challenge for solid organ transplant recipients, particularly after lung transplant (LT). Our aim was to determine the impact of TB in LT patients in Spain, considering prevalence, clinical presentation, prevention and therapeutic management. In addition, differences in outcome between rifampicin (RIF) versus non-RIF containing regimens were analyzed.MethodsMulticenter, observational retrospective study, including all cases of TB diagnosed in recipients after LT, in five pulmonary transplant units in Spain, between January 1990 and December 2017.ResultsAmong 2962 LT recipients, 45 cases of TB were diagnosed, resulting in a prevalence of 1.52%. Most of them (88.89%) were diagnosed during the first year posttransplantation, 86.67% with pulmonary presentation. Screening for latent TB infection (LTBI) was done in 36 of the 45 patients and LTBI was detected pretransplant in 12 (33.33%). Less than half of the patients with disease (42.22%) received rifampicin (RIF). Lower probability of TB worsening was found in RIF-containing regimens (p = 0.049), as well as longer survival (p = 0.001). RIF use was not associated with an increased risk in rejection (p = 0.99), but doses of calcineurin inhibitors (CNI) had to be raised an average of 215%.ConclusionsRisk of TB after LT was lower in our series than previously reported. TB should be searched during the first year posttransplant in patients with TB risk factors. Pulmonary presentation was predominant. More sensitive algorithms for detecting LTBI before LT are crucial. It is reasonable to use RIF-containing regimens over non-RIF regimens based on the tendency toward better outcome in our series. RIF regimen requires close monitoring of CNI trough level for 2–3 weeks, until stability is achieved.     

Pilot Trial of Extended Hypothermic Lung Preservation to Analyze Ischemia-reperfusion Injury in Pigs

BackgroundIn lung transplantation (LT), the length of ischemia time is controversial as it was arbitrarily stablished. We ought to explore the impact of extended cold-ischemia time (CIT) on ischemia-reperfusion injury in an experimental model.MethodsExperimental, randomized pilot trial of parallel groups and final blind analysis using a swine model of LT. Donor animals (n = 8) were submitted to organ procurement. Lungs were subjected to 6 h (n = 4) or 12 h (n = 4) aerobic hypothermic preservation. The left lung was transplanted and re-perfused for 4 h. Lung biopsies were obtained at (i) the beginning of CIT, (ii) the end of CIT, (iii) 30 min after reperfusion, and (iv) 4 h after reperfusion. Lung-grafts were histologically assessed by microscopic lung injury score and wet-to-dry ratio. Inflammatory response was measured by determination of inflammatory cytokines. Caspase-3 activity was determined as apoptosis marker.ResultsWe observed no differences on lung injury score or wet-to-dry ratio any given time between lungs subjected to 6 h-CIT or 12h-CIT. IL-1β and IL6 showed an upward trend during reperfusion in both groups. TNF-α was peaked within 30 min of reperfusion. IFN-γ was hardly detected. Caspase-3 immunoexpression was graded semiquantitatively by the percentage of stained cells. Twenty percent of apoptotic cells were observed 30 min after reperfusion.ConclusionsWe observed that 6 and 12 h of CIT were equivalent in terms of microscopic lung injury, inflammatory profile and apoptosis in a LT swine model. The extent of lung injury measured by microscopic lung injury score, proinflammatory cytokines and caspase-3 determination was mild.     

Effect of Sex Differences on Computed Tomography Findings in Adults With Cystic Fibrosis: A Multicenter Study

BackgroundThe survival of women with cystic fibrosis (CF) is lower than that of men by approximately 5 years. While various factors have been put forward to account for this discrepancy, no specific reasons have been established. Our hypothesis was that anatomical-structural involvement is more pronounced in women with CF than in men and that this is reflected in thoracic HRCT findings.Material and methodsWe performed a prospective multicentre study, in which adult patients were consecutively included over 18 months. Chest HRCT was performed, and findings were scored by 2 thoracic radiologists using the modified Bhalla system. We also studied respiratory function, applied the CFQR 14+ questionnaire, and collected clinical variables.ResultsOf the 360 patients followed up in the participating units, 160 were eventually included. Mean age was 28 years, and 47.5% were women. The mean ± SD global score on the modified Bhalla score was 13.7 ± 3.8 in women and 15.2 ± 3.8 in men (p = 0.024). The highest scores were observed for sacculations, bronchial generations, and air trapping in women. Women had lower BMI, %FEV₁, %FVC, and %DLCO. Similarly, the results for the respiratory domain in CFQR 14+ were worse in women, who also had more annual exacerbations.ConclusionsThis is the first study to provide evidence of the implication of sex differences in HRCT findings in patients with CF. Women with CF present a more severe form of the disease that results in more frequent exacerbations, poorer functional and nutritional outcomes, deterioration of quality of life, and greater structural damage.     

Pulmonary Veno-Occlusive Disease in a Female Gardener

Pulmonary veno-occlusive disease (PVOD) is a subgroup of pulmonary arterial hypertension with a poor prognosis. The diagnosis is usually delayed and treatment options other than lung transplantation are unfortunately limited. We report the case of a 51-year-old female gardener diagnosed with PVOD by open lung biopsy before her death. Although there are many reported cases of hepatic veno-occlusive disease due to toxic agents present in nature, such as pyrrolizidine alkaloid exposure, to date this has not been linked to PVOD.     

Quality of Pulmonary Function Tests in Participants with Down Syndrome

IntroductionPeople with Down syndrome (DS) have high respiratory morbidity, evaluating their respiratory health with standardized, objective tests is desirable. Thus, the objective of this study was to evaluate the technical quality of Pulmonary Function Tests (PFTs) to determine which ones are most suitable for this population.MethodsParticipants included children, teenagers and adults with DS, 5 years of age or older (n = 302). The technical quality of the impulse oscillometry system (IOS), forced spirometry, lung-diffusing capacity for carbon monoxide (DL_CO), and 6-min walk test (6MWT) were analyzed by age group. Capnography and pulse oximetry were included in the study. Technical quality was determined on the basis of current international PFTs standards.ResultsFifty-one percent of participants were males. A total of 184 participants (71%) who completed the IOS fulfilled the quality criteria, while 210 (70%) completed the 6MWT. Performance on forced spirometry and DL_CO was poor. All pulse oximetries and 96% percent heart rates obtained had good quality, but exhaled carbon dioxide (PetCO₂) and respiratory rate (RR) showed deficient repeatability.ConclusionsIOS appears to be the most reliable instrument for evaluating lung mechanics in individuals with DS.     

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

IntroductionImmune 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.MethodsA 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.ResultsTwenty-three patients (25%) developed 29 non-CMV infections between 6 and 12 months post-transplant. At 6 months, the immune response was moderate (ATP 225–525 ng/mL) in 14 (15.2%) patients and low (ATP < 225 ng/mL) in 78 (84.8%); no patients had a strong response (ATP ≥ 525 ng/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. <225 ng/mL during the study period (7.1% vs. 9.1%, p = 0.81).ConclusionAlthough 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.     

Perioperative management of pulmonary hypertension during lung transplantation (a lesson for other anaesthesia settings)

Patients with pulmonary hypertension are some of the most challenging for an anaesthesiologist to manage. Pulmonary hypertension in patients undergoing surgical procedures is associated with high morbidity and mortality due to right ventricular failure, arrhythmias and ischaemia leading to haemodynamic instability. Lung transplantation is the only therapeutic option for end-stage lung disease. Patients undergoing lung transplantation present a variety of challenges for anaesthesia team, but pulmonary hypertension remains the most important. The purpose of this article is to review the anaesthetic management of pulmonary hypertension during lung transplantation, with particular emphasis on the choice of anaesthesia, pulmonary vasodilator therapy, inotropic and vasopressor therapy, and the most recent intraoperative monitoring recommendations to optimize patient care.     

Validation of Global Lung Function Initiative and All Ages Reference Equations for Forced Spirometry in Healthy Spanish Preschoolers

Introduction

Recent publication of multi-ethnic spirometry reference equations for subjects aged from 3 to 95 years aim to avoid age-related discontinuities and provide a worldwide standard for interpreting spirometric test results.

Reference Ranges for Mexican Preschool-Aged Children Using the Forced Oscillation Technique

IntroductionRecently, multi-ethnic reference ranges for spirometry have been created for use worldwide. In comparison, forced oscillation technique (FOT) reference values are limited to specific equipment and study populations, with current FOT reference ranges created in a Caucasian population. We aimed to develop FOT reference ranges for preschool-aged Mexican children and to compare these with current FOT reference ranges.Patients and methodsRespiratory resistance (Rrs) and reactance (Xrs) were measured in healthy Mexican children three to five years of age using commercial FOT equipment. The relationship between height and Rrs and Xrs was determined using regression analyses, taking into account age, weight, sex, and exposure to tobacco smoke. Reference equations were calculated for the Mexican children and Z-scores determined for Rrs and Xrs at 6 and 8 Hz. A paired t-test assessed the difference in Z-scores between the Australian reference values and those created for the Mexican cohort.ResultsFOT was successfully measured in 584 children. Height was a significant predictor of Rrs and Xrs at 6 and 8 Hz (P<.05). Z-scores calculated using the Australian reference equations overestimated lung function in Mexican children for both Rrs and Xrs at 6 and 8 Hz (P<.001).ConclusionThe development of FOT reference ranges specific to Mexican preschool-aged children will allow for the correct interpretation of FOT measurements. This study also showed that current FOT reference ranges overestimate lung function in Mexican children. The importance of using ethnic appropriate reference ranges for interpreting lung function is highlighted.     

Presence of Anxiety and Depression in Patients With Bronchiectasis Unrelated to Cystic Fibrosis

IntroductionPatients with chronic bronchiectasis (BQ) may suffer from psychological disorders. The objective of this study was to assess the presence of anxiety and depression in patients from a specialised BQ Unit, using validated questionnaires.Patients and methodsWe included patients consecutively diagnosed with BQ (unrelated to cystic fibrosis) by high resolution computed tomography in the study. Patients were clinically stable in the previous three weeks and voluntarily completed the Beck Depression Inventory, State-Trait Anxiety Inventory and St. George's Respiratory Questionnaire, after signing the informed consent. They were classified according to their scores on the psychological screening questionnaires, and their results were compared with the clinical, radiological and functional parameters and Quality of Life.Results70 patients were included, 48 women and 22 men, with a mean age of 64.19 years. Thirty-four percent (34%) of patients showed symptoms of depression, and around 55% had scores above the 50th percentile in trait and state anxiety. The amount of sputum was associated with trait anxiety. Bacterial colonisation was related to anxiety (trait and state), especially Pseudomonas aeruginosa colonisation. Female patients showed a higher risk of depression. There was no relationship between the Quality of Life scores and the established classifications of anxiety and depression.ConclusionsA high percentage of patients with BQ presented anxiety (trait and state) and depression. The daily sputum production and bacterial colonisation (especially with P. aeruginosa) were the variables most related to anxiety; depression was more common in women. We believe that the presence of psychological disorders should be evaluated, especially in patients with this profile.     

Frequency of Polymorphism -262 C/T in Catalase Gene and Oxidative Damage in Slovak Children With Bronchial Asthma

IntroductionBronchial asthma is a complex disease in which genetic factors, environmental factors and oxidative damage are responsible for the initiation and modulation of disease progression. If antioxidant mechanisms fail, reactive oxygen species damage the biomolecules followed by progression of the disease. Catalase is one of the most important endogenous enzymatic antioxidants. In the present study, we examined the hypothesis that increased oxidative damage and polymorphism in the CAT gene (-262 promoter region, C/T) are associated with childhood bronchial asthma.Patients and methodsGenotyping of the polymorphisms in the CAT gene in healthy (249) and asthmatic children (248) was performed using polymerase chain reaction – restriction fragment length polymorphism. Markers of oxidative damage: content of sulfhydryl groups and thiobarbituric acid-reactive substances were determined by spectrophotometry in children.ResultsThe TT genotype of catalase was more frequent among the asthmatic patients (22.6%) than in healthy children (4.8%) (odds ratio=5.63; 95% confidence interval=2.93–10.81, P<.001). The amount of sulfhydryl groups decreased significantly and conversely, the content of thiobarbituric acid-reactive substances increased significantly in bronchial asthma and in catalase TT genotype compared to other catalase genotypes of this gene.ConclusionsThese results suggest that catalase polymorphism might participate in development of bronchial asthma and in enhanced oxidative damage in asthmatic children. Genetic variation of enzymatic antioxidants may modulate disease risk.     

CCTTT Pentanucleotide Repeats in Inducible Nitric Oxide Synthase Gene Expression in Patients With Pulmonary Arterial Hypertension

IntroductionOne of the pathways involved in pulmonary arterial hypertension (PAH) is the nitric oxide (NO) pathway. A polymorphism in the inducible NO synthase (NOS2) gene has been described, consisting of the CCTTT pentanucleotide repeat, which causes a reduction in NO production. The aim of this study was to determine if this polymorphism increases susceptibility to developing PAH.MethodsSixty-four patients with a diagnosis of PAH groups i and iv and 50 healthy controls were compared. DNA genotyping of the samples for this polymorphism was performed using PCR. The distribution between both groups was compared and correlated with clinical and hemodynamic parameters and therapeutic response.ResultsA significantly different distribution was observed in the number of repeats between patients and controls (P<.0001). When the samples were categorized by short forms (both alleles with less than 12 repeats) and long forms (≥12 repeats), it was observed that the former had an almost 4-fold risk of developing PAH (odds ratio: 3.83; 95% CI: 1.19–12.32, P=.024). There were no differences between the most common types of PAH, either in therapeutic response or survival. There was no correlation between hemodynamic parameters and the number of repeats in the patients, and only a weak correlation with systolic PAH.ConclusionsThere are significant differences in the distribution of the NOS2 promotor CCTTT polymorphism between patients with PAH and the healthy population. A minor CCTTT pentanucleotide repeat in the NOS2 gene may increase the risk of developing PAH.     

Rationale and Methodology of the SARAH Trial: Long-Term Cardiovascular Outcomes in Patients With Resistant Hypertension and Obstructive Sleep Apnea

Introduction

Patients with resistant hypertension (RH) have a high risk of developing cardiovascular events; therefore, new therapeutic approaches to better control blood pressure may be useful in improving cardiovascular outcomes. The prevalence of obstructive sleep apnea (OSA) is very high among patients with RH. Continuous positive airway pressure (CPAP) has been shown to be an effective treatment for reducing blood pressure in patients with RH. Nevertheless, the long-term effect of CPAP treatment on cardiovascular outcomes has not been explored.The main objective of the SARAH study is to assess the impact of OSA and its treatment on cardiovascular outcomes (morbidity and mortality) in patients with RH.