Biochemical markers in the management of pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is a severe disease usually diagnosed by echocardiography and further confirmed by right heart catheterisation. Follow-up under treatment consists in assessment of clinical signs, various types of exercise testing and repeated echocardiograms. Several molecules which can be measured in the blood or sometimes in other biological fluids are known to be elevated in PAH. The most extensively studied are members of the family of natriuretic peptides, uric acid, and products generated by nitric oxide activity. Due to the low prevalence of PAH and their suboptimal specificity, these potential markers are generally of modest positive predictive value which precludes their use as screening tools. However, some of them correlate significantly with prognosis, and thus, in conjunction with classical clinical and paraclinical parameters, they may be a further aid to clinical decision-making for the specialist dealing with PAH patients

Current management of pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a vascular disease of unknown aetiology, characterised by an abnormal thickening of the arterial wall that is responsible for an increase in pulmonary vascular resistance. The haemodynamic consequence of PAH is an increased afterload for the right ventricle and, eventually, right heart failure. When untreated, PAH has a grim prognosis with a median survival of about 2 to 4 years from diagnosis. In the last 10 years new orally administered compounds have demonstrated clinical efficacy in controlled trials using various surrogate endpoints to survival. Although the disease remains without cure until now, the available phase III trials have allowed evidence-based recommendations for the medical management of these patients to be established. It appears, however, that none of the compounds from the three main therapeutic classes, endothelin receptor antagonists, agents acting on the nitric oxide-cyclic guanosine monophosphate pathway (including phosphodiesterase type 5 inhibitors and guanylate cyclase stimulator), and prostanoid receptor agonists are able alone to control disease progression in every patient. Therefore combination therapy with two or three drugs may be necessary in a significant number of patients in order to maintain patients in, or bring them to, a low risk profile. Several recent studies have now validated this approach for specific double or triple drug regimens. It remains, however, unclear whether an upfront combination is preferable to a sequential step-up approach based on clinical response. In addition, some specific combination therapies have failed to demonstrate superiority to single drug alone in randomised controlled trials. Besides PAH-specific treatment, the place of nonspecific pharmaceutical and nonpharmaceutical treatment has been also recently clarified

Carbon Monoxide Diffusion Capacity as a Severity Marker in Pulmonary Hypertension.

Carbon monoxide diffusion capacity (DLCO) is negatively associated with patient survival in idiopathic pulmonary hypertension (PH), but is not included in the risk stratification score proposed by the 2015 European guidelines. Since 2015, several new stratification scores based on a 3- or 4-severity scale have been explored. This retrospective cohort single-center study sought to investigate the association between DLCO and PH severity and survival. We included 85 treatment-naive patients with precapillary PH and DLCO measurement at diagnosis. DLCO status, based on lower and upper quartiles ranges, was added to a 3- and a 4-strata modified-risk assessment. DLCO was strongly associated with transplant-free survival (HR 0.939, 95% CI: 0.908-0.971, p < 0.001). In the intermediate and high-risk categories, DLCO was associated with transplant-free survival, irrespective of the risk category (HR 0.934, 95% CI: 0.880-0.980, p = 0.005). The correlation between modified-risk category and transplant-free survival was significant (HR 4.60, 95% CI: 1.294-16.352, p = 0.018). Based on the Akaike information criterion (AIC) levels, the 3- and 4-strata modified-risk stratification fits our results better than the conventional stratification. Low DLCO is associated with patient transplant-free survival, independently of the risk category. Inclusion of DLCO into a PH risk stratification score seems promising and needs further investigation

Inter-observer agreement on apnoea hypopnoea index using portable monitoring of respiratory parameters.

Although portable polygraphy or portable monitoring of respiratory parameters (PM) is commonly used to confirm obstructive sleep apnoea syndrome, agreement on apnoea hypopnoea index (AHI), the main measure of disease severity, has not been evaluated. The aim of this study was to assess the agreement on AHI among multiple observers as well as between individual observers and automated analysis. A total of 88 ambulatory sleep recordings ("Embletta") were independently scored by 8 physicians (observers). Agreement on AHI, using intraclass correlation coefficient (ICC), was measured among observers. Bland Altman plots were built to compare individual observers with PM. Among observers, ICCs were .73 for agreement on AHI, .71 for hypopnoea index and .98 for desaturation index. Compared to visual analysis, automated analysis underestimated AHI by 5.1 events on average. When comparing individual observers with automated analysis, systematic bias varied from -1. to +1 .5 events/h on AHI. Among observers who used PM in a clinical setting, agreement on AHI was limited. When automated and individual visual analyses were compared, the systematic bias varied from almost zero to values sufficient to affect clinical diagnosis. Much of the discordance was due to different counts of hypopnoea, whereas agreement on apnoea and desaturation index was better. Efforts should be directed towards standardisation of visual analysis, improvement and quality control of ambulatory sleep studies

Magnetic resonance imaging in pulmonary hypertension: an overview of current applications and future perspectives.

Pulmonary hypertension is an heterogeneous group of diseases characterised by increased pulmonary arterial pressures which impact on the upstream right ventricle. Pulmonary hypertension can be challenging to diagnose, classify and monitor when specific therapies are applicable. Cardiac magnetic resonance (CMR) imaging has greatly evolved in the last decades and is a promising tool to non-invasively follow pulmonary hypertension patients. CMR provides a comprehensive evaluation of the heart and is therefore the gold standard for quantification of right ventricular volumes, mass and function, which are critical for pulmonary hypertension prognosis. In addition, innovative MR techniques allow an increasingly precise evaluation of pulmonary haemodynamics and lung perfusion. This review highlights the main advantages offered by CMR in pulmonary hypertension and gives an overview of putative future applications. Although right heart catheterisation remains mandatory in the diagnostic algorithm, CMR could play an increasingly important role in the coming years in monitoring pulmonary hypertension patients

Fibrogenic Disorders in Human Diseases: From Inflammation to Organ Dysfunction.

Fibrosis is an inadequate response to tissue stress with very few therapeutic options to prevent its progression to organ dysfunction. There is an urgent need to identify drugs with a therapeutic potential for fibrosis, either by designing and developing new compounds or by repurposing drugs already in clinical use which were developed for other indications. In this Perspective, we summarize some pathways and biological targets involved in fibrosis development and maintenance, focusing on common mechanisms between organs and diseases. We review the therapeutic agents under experimental development, clinical trials, or in clinical use for the treatment of fibrotic disorders, evaluating the reasons for the discrepancies observed between preclinical and clinical results. We also discuss the improvement that we envision in the development of therapeutic molecules able to achieve improved potential for treatment, including indirect modulators, targeting approaches, or drug combinations

Pulmonary angioplasty: A step further in the continuously changing landscape of chronic thromboembolic pulmonary hypertension management.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a potentially fatal and frequently undiagnosed form of pulmonary hypertension (PH), classified within group 4 by the World Health Organization (WHO). It is a type of precapillary PH, which uncommonly develops as a peculiar sequel of acute pulmonary embolism due to the partial resolution of the mechanically obstructing thrombus with a coexisting inflammatory response from pulmonary vessels. CTEPH is one of the potentially treatable forms of PH whose current standard of care is surgical pulmonary endarterectomy. Medical therapy with few drugs in non-operable disease is approved and has shown improvement in patients' hemodynamic condition and functional ability. Recently, balloon pulmonary angioplasty (BPA) has shown promising results as a treatment option for technically inoperable patients, those with unacceptable risk-to-benefit ratio and in a case of residual PH after endarterectomy. Lack of meticulous CTEPH screening programs in post-pulmonary embolism patients leading to underdiagnosis of this condition, complex operability assessment, and diversity in BPA techniques among different institutions are still the issues that need to be addressed. In this paper, we review the recent achievements in the management of non-operable CTEPH, their outcome and safety, based on available data

Idiopathic desquamative interstitial pneumonia in a child: a case report.

Desquamative interstitial pneumonia is a rare form of interstitial lung disease in children. Respiratory symptoms appear progressively, are often subtle, and diagnosis is often delayed by a mean of 6 months after onset. High resolution chest computed tomography is the most sensitive imaging technique for demonstrating and identifying interstitial pneumonia. The typical histologic pattern of desquamative interstitial pneumonia, with prominent clustered alveolar macrophages, diffuse reactive alveolar epithelial hyperplasia and globular proteinaceous material, is diagnostic. Desquamative interstitial pneumonia in children can be idiopathic, though it is mostly related to an inborn error of surfactant metabolism. We present the complex clinical course and pathologic findings of a 30-months-old Mauritian and Senegalese girl with idiopathic desquamative interstitial pneumonia and multiple extrapulmonary manifestations. To our knowledge, this is the first case report of desquamative interstitial pneumonia to occur as part of a syndrome with multiple organ involvement. We believe that desquamative interstitial pneumonia is not always associated with mutations of the surfactant proteins, and can still be idiopathic, especially when occurring as part of a syndrome with multiple organ involvement, as described in other interstitial lung diseases

Secondary pulmonary alveolar proteinosis treated by lung transplant: A case report.

Pulmonary alveolar proteinosis (PAP) is a pulmonary disease characterized by disruption of surfactant homeostasis resulting in its accumulation in the alveoli. PAP is classically classified into three categories (Table 1): 1/primary (or autoimmune) with antibodies targeting the GM-CSF pathway, 2/secondary to another disease, typically a hematologic malignancy, and 3/genetic. A 30 year-old woman received an allogenic hematopoietic stem cell transplantation (HSCT) after treatment for acute myeloid leukemia (AML). Within the first 6 months post HSCT, she developed an ocular, oral, digestive and hepatic graft-versus-host disease associated with a mixed ventilatory defect with a very severe obstructive syndrome and a severe CO diffusion impairment. High resolution computed tomography showed a classical "crazy paving" pattern. Aspect and differential cell count of BAL were normal. All microbiological samples remained culture negative. Histo-pathological analysis of transbronchial biopsies was unremarkable. Because of the severity of the respiratory insufficiency, open-lung biopsy (OBL) could not be performed. Despite multiple immunosuppressive therapies, lung function deteriorated rapidly; the patient also developed an excavated fungal lesion unresponsive to treatment. She underwent a bilateral lung transplant 48 months after HSCT. Histo-pathological analysis of explanted lungs showed obliterative bronchiolitis (OB), diffuse PAP and invasive cavitary pulmonary aspergillosis. This case illustrates the simultaneous occurrence of OB, PAP and a fungal infection in a 30-year old female patient who underwent HSCT for acute myeloid leukemia (AML). To our knowledge this is the only documented case of PAP associated with OB treated by lung transplantation

Pulmonary Hypertension and Indicators of Right Ventricular Function.

Pulmonary hypertension (PH) is a rare disease, whose underlying mechanisms are not fully understood. It is characterized by pulmonary arterial vasoconstriction and vessels wall thickening, mainly intimal and medial layers. Several molecular pathways have been studied, but their respective roles remain unknown. Cardiac repercussions of PH are hypertrophy, dilation, and progressive right ventricular dysfunction. Multiple echocardiographic parameters are being used, in order to assess anatomy and cardiac function, but there are no guidelines edited about their usefulness. Thus, it is now recommended to associate the best-known parameters, such as atrial and ventricular diameters or tricuspid annular plane systolic excursion. Cardiac catheterization remains necessary to establish the diagnosis of PH and to assess pulmonary hemodynamic state. Concerning energetic metabolism, free fatty acids, normally used to provide energy for myocardial contraction, are replaced by glucose uptake. These abnormalities are illustrated by increased (18)F-fluorodeoxyglucose ((18)F-FDG) uptake on positron emission tomography/computed tomography, which seems to be correlated with echocardiographic and hemodynamic parameters