Jules Hernández-Sánchez

Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension

Background: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. Methods: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource–Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of <1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. Results: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (KCO; 33% [interquartile range, 30%–35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23–38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. Conclusions: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low KCO and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation.

Vaccination of koalas with a prototype chlamydial vaccine is safe, does not increase the incidence of lymphoma-related disease and maybe associated with increased lifespan in captive koalas

OBJECTIVES To assess the impact of Chlamydia vaccination on survival of captive koalas, and to compare the incidence of lymphomas and neoplasias between vaccinated and unvaccinated koalas. METHODS Survival analysis using Cox and Weibull regressions on 54 vaccinated and 52 matched unvaccinated koalas, and chi-square contingency table for incidence of lymphomas/neoplasias. RESULTS Vaccination was found to have a significant positive effect on koala lifespan (P=0.03), with vaccinated koalas having a median lifespan of 12.25 years compared to 8.8 years for unvaccinated ones. The effect of sex on lifespan was not significant (P=0.31). The risk ratio of unvaccinated over vaccinated koalas was 2.2 with both Cox and Weibull regressions. There was no association between the incidence of lymphoma/neoplasias and vaccination status (P=0.33). CONCLUSIONS Koalas vaccinated with a prototype Chlamydia vaccine may live longer than unvaccinated ones. There was no known Chlamydia infection among koalas, so our interpretation is that vaccination may have boosted the innate and adaptive immune systems to protect against a wide spectrum of bacteria, fungi and parasites. Vaccinated koalas did not show negative physiological effects of the vaccine, for example, the frequency of deaths due to lymphomas/neoplasias was the same in both vaccinated and unvaccinated animals.

Clinical trial protocol for TRANSFORM-UK: A therapeutic open-label study of tocilizumab in the treatment of pulmonary arterial hypertension:

Our aim is to assess the safety and potential efficacy of a novel treatment paradigm in pulmonary arterial hypertension (PAH), immunomodulation by blocking interleukin-6 (IL6) signaling with the IL6 receptor antagonist, tocilizumab. Inflammation and autoimmunity are established as important in PAH pathophysiology. One of the most robust observations across multiple cohorts in PAH has been an increase in IL6, both in the lung and systemically. Tocilizumab is an IL-6 receptor antagonist established as safe and effective, primarily in rheumatoid arthritis, and has shown promise in scleroderma. In case reports where the underlying cause of PAH is an inflammatory process such as systemic lupus erythematosus, mixed connective tissue disease (MCTD), and Castleman’s disease, there have been case reports of regression of PAH with tocilizumab. TRANSFORM-UK is an open-label study of intravenous (IV) tocilizumab in patients with group 1 PAH. The co-primary outcome measures will be safety and the change in resting pulmonary vascular resistance (PVR). Clinically relevant secondary outcome measurements include 6-minute walk distance, WHO functional class, quality of life score, and N-terminal pro-brain natriuretic peptide (NT-proBNP). If the data support a potentially useful therapeutic effect with an acceptable risk profile, the study will be used to power a Phase III study to properly address efficacy.

Medication and patient factors associated with adherence to pulmonary hypertension targeted therapies

The aims of this study were to investigate the medication adherence of patients on pulmonary hypertension (PH)-targeted therapies and uncover factors that might influence adherence values. Patients taking at least one specialist medicine (sildenafil, tadalafil, bosentan, ambrisentan, iloprost, epoprostenol, treprostinil) completed a Morisky Medication Adherence Scale-8 (MMAS-8) questionnaire. Participants’ MMAS-8 scores were used to estimate overall medicine adherence. Potential adherence co-factor data were collected from patient databases and hospital discharge summaries. The MMAS-8 questionnaire was completed by 263 patients (mean age = 61.6 ± 14.8 years, 70.6% women). Data from MMAS-8 showed that 47.9% reported high adherence, 40.3% moderate adherence, and 11.8% low adherence. Factors associated with adherence as measured by the MMAS-8 included: older age; taking monotherapy; and having a higher number of co-morbidities or concurrent medicines. Higher administration frequency, greater length of time on targeted therapy, and use of a compliance aid had a negative association with adherence. Overall adherence to PH specialist medicines is relatively high but a proportion of patients report sub-optimal adherence behavior. A number of factors may help to recognize susceptible patients.

Usefulness of the STOP-Bang Questionnaire in a Cardiac Surgical Population

OBJECTIVE The aim of this study was to assess the predictive accuracy of the STOP-Bang questionnaire in relation to obstructive sleep apnea (OSA) detected by nocturnal oximetry, as well as postoperative outcomes, in a population undergoing cardiac surgery. DESIGN A prospective observational cohort study. SETTING The specialist cardiothoracic center at the Royal Papworth Hospital, Cambridge University Health Partners, United Kingdom. PARTICIPANTS All adult patients, undergoing elective coronary artery bypass grafting with or without cardiac valve surgery between March 2013 and July 2014 were included. The authors excluded patients participating in other interventional studies, those who had a tracheostomy before surgery, and those who required emergency surgery or were due to be admitted on the day of surgery. INTERVENTIONS None. MEASUREMENTS AND RESULTS Cardiac surgical patients were screened for the risk of OSA with the use of STOP-Bang questionnaire. The presence of OSA prior to surgery was assessed with overnight oximetry. The predictive performance of the STOP-Bang questionnaire was assessed by calculating sensitivity, specificity, positive predictive value, negative predictive value, and area under the curve (AUC)-receiver operating characteristic curve (ROC). Multiple-logistic regression models were used to assess for associations between the STOP-Bang scores and postoperative outcomes. The STOP-Bang questionnaire discriminated poorly between mild OSA (AUC-ROC 0.57 [95% confidence interval (CI) 0.47-0.67]) and moderate/severe OSA (AUC-ROC 0.82 (95% CI 0.69-0.95)]. Accuracy was increased by modifying the cut-off value to 6 or greater, with sensitivity and specificity of 75% and 77%, respectively. A STOP-Bang score indicating the possibility of OSA was not significantly associated with prolonged intensive care unit lengths of stay (hazard ratio [HR] 1.1; 95% CI 0.99-1.19; p = 0.08) or postoperative complications (odds ratio [OR] 1.0; 95% CI 0.59-1.72; p = 0.98). CONCLUSIONS In the study population, a STOP-Bang questionnaire score of 3 or greater had limited predictive value for identifying cardiac surgical patients at high risk of OSA. STOP-Bang scores were not significantly associated with worse postoperative outcomes. A STOP-Bang score of 6 or greater could help identify patients in need of a sleep study to confirm the presence of OSA as such patients may be at increased risk of postoperative complications.

Age should not be a barrier for pulmonary endarterectomy in carefully selected patients

Pulmonary endarterectomy (PEA) is the treatment of choice in operable chronic thromboembolic pulmonary hypertension (CTEPH) with excellent long-term outcomes [1]. It is a complex surgical procedure requiring cardiopulmonary bypass and removal of obstructive thromboembolic material during periods of deep hypothermic circulatory arrest [1]. We have observed an increase in the number of older CTEPH patients referred for consideration of PEA, which is consistent with other cardiothoracic surgeries. The UK population is ageing with a projected 3% increase in subjects aged >85 years in the next 20 years [2]. This may be mirrored by patients with CTEPH getting older, as the incidence of pulmonary embolism, which frequently precedes CTEPH, markedly increases with age [3, 4]. Furthermore, an epidemiological analysis by Gall et al. [5] has projected that the annual incidence of CTEPH will increase over the next 10 years. Therefore, the management of CTEPH in older patients is a pertinent topic for investigation. CTEPH patients over 80 years old undergoing pulmonary endarterectomy have similar outcomes to those under 80 years http://ow.ly/MlCj30guFPu

S27 Predictive performance of STOPBANG questionnaire for diagnosis of sleep apnoea in a cardiac surgical cohort

Introduction and objectives Questionnaires to assess the risk of obstructive sleep apnoea (OSA) prior to surgery could reduce the need for screening sleep studies. STOPBANG questionnaire is user friendly and was previously validated in a general surgical population. A high risk of OSA has been defined as a score of ≥3 and low risk as a score 0–2. We aimed to validate the STOPBANG against nocturnal oximetry in a population undergoing major cardiac surgery and assessed its prognostic value for postoperative outcomes. Methods Patients were screened for high risk of OSA with the STOPBANG questionnaire. The presence of sleep apnoea (SA), prior to surgery, was assessed with overnight oximetry. SA was defined as mild with a 4% oxygen desaturation index (ODI) of 5–14/hr, moderate with ODI of 15–29/hr and severe ODI ≥30/hr. Predictive performance of STOPBANG against nocturnal oximetry was assessed for diagnosis of mild and moderate SA by assessing the area under curve receiver operating characteristic (AUC-ROC) and sensitivity and specificity were calculated. A multiple-logistic regression model was used to assess association of STOPBANG and post-operative outcomes. Results The AUC-ROC for mild SA was low 0.57 (95% CI = 0.47–0.67). Good performance was observed for moderate SA with AUC-ROC 0.82 (95% CI = 0.69–0.95) (Figure 1) but specificity of STOPBANG at the conventional cut of value of ≥3 for moderate SA was very low at 5% whilst sensitivity was 100%. The best predictive STOPBANG cut-off value for moderate SA was ≥6 with sensitivity and specificity of 75% and 77% respectively. Assessing predictive value for severe SA was not possible due to the lack of severe SA cases in our cohort. STOPBANG was not found to be an independent predictor of worse post-operative outcomes.Abstract S27 Figure 1 ROC curves for STOPBANG to predict ODI ≥5 and ODI ≥15 Conclusion Predictive performance of STOPBANG in our patient cohort at the conventional cut off value was poor. The probable explanation is that the cardiac surgical population is preselected as male, older and most suffer with hypertension. Thus the majority will score as high risk for OSA. STOPBANG had no prognostic value on worse postoperative outcomes in our study, which again contrasts with the findings in general surgical cohorts.

S28 Effect of sleep apnoea on post-operative outcomes in cardiac surgery

Introduction and objectives Obstructive sleep apnoea (OSA) is common and can be associated with adverse health outcomes. There are conflicting data for the impact of undiagnosed OSA on the outcome of surgical procedures but at least some results suggest an association with worse outcomes. EuroSCORE risk model was developed to calculate the risk of mortality after cardiac surgery. We evaluated the prevalence and impact of undiagnosed sleep apnoea (SA) on postoperative outcomes in cardiac surgery. Methods Patients undergoing coronary artery bypass grafting with or without cardiac valve surgery were screened for the presence of SA, prior to surgery, with the STOPBANG questionnaire and overnight oximetry. SA was defined as a 4% oxygen desaturation index (ODI) of ≥5/hr. A Weibull model was used to analyse lengths of stay (LoS) in intensive care unit (ICU). Complications in ICU were dichotomised and analysed with binary logistic regressions. Parsimonious models were obtained using a combination of step-wise regression and manually removing predictors that did not reach the 5% significance level. Results 122 subjects were included in final analysis of which 57 (47%) had a new diagnosis of SA. Of those, 45 (79%) had mild SA and 12 (21%) had moderate/severe SA. There was no simple relationship between OSA as measured by ODI and LoS in ICU. The most significant predictor for ICU LoS was developing complications at ICU (p < 0.001). The independent predictors associated with increasing likelihood of developing major organ complications following cardiac surgery were EuroSCORE, ODI and intravenous opioid analgesia (IOA). When patients with mild and moderate SA received IOA, predicted probability of complications rose 2.4 and 1.4 times respectively (Figure 1).Abstract S28 Figure 1 Predicted probabilities and 95% CI of suffering a complication at ICU as ODI increases for individuals with average EuroSCORE (5) and with or without IOA Conclusion We found a high prevalence of undiagnosed sleep apnoea in our cohort. EuroSCORE, SA and the administration of intravenous morphine were found to be independent risk factors for developing post-operative complications. This risk has increased when patients with SA received intravenous morphine.

Mismatching of population groups in thoracic surgery case control studies

Thoracic surgery is a rapidly evolving field, in continuous need of high quality clinical evidence. Case control studies are a type of observational study in which two existing groups differing in outcome are identified and compared on the basis of some supposed causal attribute. Case-control studies are often used to identify factors that may/may not contribute to a medical condition by comparing subjects who have that condition/disease (cases) with patients who do not have the condition/disease but are otherwise similar (controls). They require fewer resources but provide less evidence than a randomized controlled trial. As analytical observational studies, control studies are analytical observational studies that represent level II-2 clinical evidence (1).