Phosphoinositide 3-kinase δ (PI3Kδ) in respiratory disease

Defining features of chronic airway diseases include abnormal and persistent inflammatory processes, impaired airway epithelial integrity and function, and increased susceptibility to recurrent respiratory infections. Phosphoinositide 3-kinases (PI3K) are lipid kinases, which contribute to multiple physiological and pathological processes within the airway, with abnormal PI3K signalling contributing to the pathogenesis of several respiratory diseases. Consequently, the potential benefit of targeting PI3K isoforms has received considerable attention, being viewed as a viable therapeutic option in inflammatory and infectious lung disorders. The class I PI3K isoform, PI3Kδ (Phosphoinositide 3-kinases δ) is of particular interest given its multiple roles in modulating innate and adaptive immune cell functions, airway inflammation and corticosteroid sensitivity. In this mini-review, we explore the role of PI3Kδ in airway inflammation and infection, focusing on oxidative stress, ER stress, histone deacetylase 2 and neutrophil function. We also describe the importance of PI3Kδ in adaptive immune cell function, as highlighted by the recently described Activated PI3K Delta Syndrome, and draw attention to some of the potential clinical applications and benefits of targeting this molecule

Role of unfolded proteins in lung disease.

The lungs are exposed to a range of environmental toxins (including cigarette smoke, air pollution, asbestos) and pathogens (bacterial, viral and fungal), and most respiratory diseases are associated with local or systemic hypoxia. All of these adverse factors can trigger endoplasmic reticulum (ER) stress. The ER is a key intracellular site for synthesis of secretory and membrane proteins, regulating their folding, assembly into complexes, transport and degradation. Accumulation of misfolded proteins within the lumen results in ER stress, which activates the unfolded protein response (UPR). Effectors of the UPR temporarily reduce protein synthesis, while enhancing degradation of misfolded proteins and increasing the folding capacity of the ER. If successful, homeostasis is restored and protein synthesis resumes, but if ER stress persists, cell death pathways are activated. ER stress and the resulting UPR occur in a range of pulmonary insults and the outcome plays an important role in many respiratory diseases. The UPR is triggered in the airway of patients with several respiratory diseases and in corresponding experimental models. ER stress has been implicated in the initiation and progression of pulmonary fibrosis, and evidence is accumulating suggesting that ER stress occurs in obstructive lung diseases (particularly in asthma), in pulmonary infections (some viral infections and in the setting of the cystic fibrosis airway) and in lung cancer. While a number of small molecule inhibitors have been used to interrogate the role of the UPR in disease models, many of these tools have complex and off-target effects, hence additional evidence (eg, from genetic manipulation) may be required to support conclusions based on the impact of such pharmacological agents. Aberrant activation of the UPR may be linked to disease pathogenesis and progression, but at present, our understanding of the context-specific and disease-specific mechanisms linking these processes is incomplete. Despite this, the ability of the UPR to defend against ER stress and influence a range of respiratory diseases is becoming increasingly evident, and the UPR is therefore attracting attention as a prospective target for therapeutic intervention strategies

Pathophysiology and diagnosis of pulmonary hypertension due to left heart disease

Pulmonary hypertension due to left heart disease (PH-LHD) is the most common type of pulmonary hypertension, although an accurate prevalence is challenging. PH-LHD includes PH due to systolic or diastolic left ventricular dysfunction, mitral or aortic valve disease and congenital left heart disease. In recent years a new and distinct phenotype of “combined post-capillary and pre-capillary PH,” based on diastolic pulmonary gradient and pulmonary vascular resistance, has been recognized. The roles of right ventricular dysfunction and pulmonary vascular compliance in PH-LHD have also been elucidated recently and they appear to have significant clinical implications. Echocardiography continues to play a seminal role in diagnosis of PH-LHD and heart failure with preserved LV ejection fraction, as it can identify valve disease and help to distinguish PH-LHD from pre-capillary PH. Right, and occasionally left heart catheterization, remains the gold-standard for diagnosis and phenotyping of PH-LHD, although Cardiac Magnetic Resonance Imaging is emerging as a useful alternative tool in non-invasive diagnostic and prognostic assessment of PH-LHD. In this review, the latest evidence for more recent advances will be discussed, including the role of fluid challenge and exercise during cardiac catheterization to unravel occult post-capillary and the role of vasoreactivity testing. The use of many or all of these diagnostic techniques will undoubtedly provide key information about sub-groups of patients with PH-LHD that might benefit from medical therapy previously considered to be only suitable for pulmonary arterial hypertension

Combining creative writing and narrative analysis to deliver new insights into the impact of pulmonary hypertension

Introduction Pulmonary hypertension is life-limiting. Delays in diagnosis are common, and even after treatment has been initiated, pulmonary hypertension has marked effects on many aspects of social and physical function. We believed that a new approach to examining disease impact could be achieved through a combination of narrative research and creative writing. Methods Detailed unstructured narrative interviews with people with pulmonary hypertension were analysed thematically. Individual moments were also summarised and studied using creative writing, in which the interviewer created microstories from narrative and interview data. Stories were shared with their subjects, and with other patients, clinicians, researchers and the wider public. The study was carried out in hospital and in patients’ homes. Results Narrative analysis generated a rich data set which highlighted profound effects of pulmonary hypertension on identity, and demonstrated how the disease results in very marked personal change with ongoing and unpredictable requirement for adaptation. The novel methodology of microstory development proved to be an effective tool to summarise, communicate, and explore the consequences of pulmonary hypertension and the clinical challenges of caring for patients with this illness. Conclusions A holistic approach to treatment of chronic respiratory diseases such as pulmonary hypertension requires and benefits from explicit exploration of the full impacts of the illness. Narrative analysis and the novel approach of targeted microstory development can form a valuable component of the repertoire of approaches to effectively comprehend chronic disease and can also facilitate patient-focused discussion and interventions

Non-invasive methods for the estimation of mPAP in COPD using Cardiovascular Magnetic Resonance Imaging

Purpose Pulmonary hypertension (PH) is associated with a poor outcome in chronic obstructive pulmonary disease (COPD) and is diagnosed invasively. We aimed to assess the diagnostic accuracy and prognostic value of non-invasive cardiovascular magnetic resonance (CMR) models. Methods Patients with COPD and suspected PH, who underwent CMR and right heart catheter (RHC) were identified. Three candidate models were assessed: 1, CMR-RV model, based on right ventricular (RV) mass and interventricular septal angle; 2, CMR PA/RV includes RV mass, septal angle and pulmonary artery (PA) measurements; 3, the Alpha index, based on RV ejection fraction and PA size. Results Of 102 COPD patients, 87 had PH. The CMR-PA/RV model had the strongest diagnostic accuracy (sensitivity 92%, specificity 80%, positive predictive value 96% and negative predictive value 63%, AUC 0.93, p<0.0001). Splitting RHCmPAP, CMR-RV and CMR-PA/RV models by 35mmHg gave a significant difference in survival, with log-rank chi-squared 5.03, 5.47 and 7.10. RV mass and PA relative area change were the independent predictors of mortality at multivariate Cox regression (p=0.002 and 0.030). Conclusion CMR provides diagnostic and prognostic information in PH-COPD. The CMR-PA/RV model is useful for diagnosis, the RV mass index and PA relative area change are useful to assess prognosis. Key Points • Pulmonary hypertension is a marker of poor outcome in COPD. • MRI can predict invasively measured mean pulmonary artery pressure. • Cardiac MRI allows for estimation of survival in COPD. • Cardiac MRI may be useful for follow up or future trials. • MRI is potentially useful to assess pulmonary hypertension in patients with COPD

More Than Just Adolescence: Differences in Fatigue Between Youth With Cerebral Palsy and Typically Developing Peers

Objective To quantify differences in fatigue and disordered sleep between adolescents with cerebral palsy (CP) and their typically developing peers. A secondary aim was to investigate the association between fatigue and disordered sleep in adolescents with CP. Methods A convenience sample of 36 youth with CP aged 10-18 years was matched for age and sex with 36 typically developing peers. The Fatigue Impact and Severity Self-Assessment (FISSA), the Patient-Reported Outcome Measurement Information System (PROMIS) fatigue profile, and the Sleep Disturbance Scale for Children (SDSC) were collected. Results Higher fatigue was reported in participants with CP than in their typically developing peers based on the FISSA total score (mean paired difference=19.06; 99% confidence interval [CI], 6.06-32.1), the FISSA impact subscale (mean paired difference=11.19; 99% CI, 3.96-18.4), and the FISSA Management and Activity Modification subscale (mean paired difference=7.86; 99% CI, 1.1-14.6). There were no differences between groups in the PROMIS fatigue profile (mean paired difference=1.63; 99% CI, -1.57-4.83) or the SDSC total score (mean paired difference=2.71; 99% CI, -2.93-8.35). Conclusion Youth with CP experienced significantly more fatigue than their peers as assessed by a comprehensive measure that considered both general and diagnosis-specific concerns. Sleep did not differ between youth with CP and their typically developing peers. These findings underscore the need to consider the clinical management of fatigue across the lifespan of individuals with CP to prevent the associated deterioration of functional abilities

Dynamic contrast-enhanced magnetic resonance imaging in patients with pulmonary arterial hypertension.

Dynamic contrast-enhanced (DCE) time-resolved magnetic resonance (MR) imaging is a technique whereby the passage of an intravenous contrast bolus can be tracked through the pulmonary vascular system. The aim of this study was to investigate the prognostic significance of DCE-MR pulmonary blood transit times in patients with pulmonary arterial hypertension (PAH). Seventy-nine patients diagnosed with PAH underwent pulmonary DCE imaging at 1.5 T using a time-resolved three-dimensional spoiled gradient echo sequence. The prognostic significance of two DCE parameters, full width at half maximum (FWHM) of the first-pass clearance curve and pulmonary transit time (PTT), along with demographic and invasive catheter measurements, was evaluated by univariate and bivariate Cox proportional hazards regression and Kaplan-Meier analysis. DCE-MR transit times were most closely correlated with cardiac index (CI) and pulmonary vascular resistance index (PVRI) and were both found to be accurate for detecting reduced CI (FWHM area under the curve [AUC] at receiver operating characteristic analysis = 0.91 and PTT AUC = 0.92, respectively) and for detecting elevated PVRI (FWHM AUC = 0.88 and PTT AUC = 0.84, respectively). During the follow-up period, 25 patients died. Patients with longer measurements of FWHM (P = 0.0014) and PTT (P = 0.004) were associated with poor outcome at Kaplan-Meier analysis, and both parameters were strong predictors of adverse outcome from Cox proportional hazards analysis (P = 0.013 and 0.010, respectively). At bivariate analysis, DCE measurements predicted mortality independent of age, gender, and World Health Organization functional class; however, invasive hemodynamic indexes CI, PVRI, and DCE measurements were not independent of one another. In conclusion, DCE-MR transit times predict mortality in patients with PAH and are closely associated with clinical gold standards CI and PVRI