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Personalized medicine in idiopathic pulmonary fibrosis: facts and promises

imagePurpose of review: In this article, we summarize and discuss the most recent literature on personalized medicine in idiopathic pulmonary fibrosis (IPF), a chronic progressive and almost invariably lethal disease of unknown cause. This review is timely as major advances in our understanding of disease pathobiology and improvements in molecular techniques have recently led to the identification of potential surrogates of diagnosis, prognosis and response to treatment.

Recent findings: The most promising and advanced candidate biomarkers are presented based on their proposed mechanistic pathways (e.g. alveolar epithelial cell dysfunction, immune dysregulation, microbiome, extracellular matrix remodeling and fibroproliferation, epigenetic markers and metabolomics). Recent data suggest that components of the immune system may contribute to the development of IPF. A potential role for infections as a cofactor in disease development and progression or as a trigger in disease exacerbation has also recently been proposed.

Summary: Clinical management of IPF is unsatisfactory because of limited availability of truly effective therapies, lack of accurate predictors of disease behavior and absence of simple short-term measures of therapeutic response. A number of putative biomarkers have been identified in patients with IPF, although none has been validated to the standard necessary for their use in either therapeutic trials or clinical practice. Currently, ongoing prospective longitudinal studies will hopefully permit such validation.

Staging systems and disease severity assessment in interstitial lung diseases

imagePurpose of review: In the evaluation of patients with interstitial lung diseases (ILD), treatment decisions made by clinicians, including referral for lung transplant, are based on disease severity assessment. It is crucial to quantify disease severity and numerous attempts were made to find a reliable prognostic assessment method.

Recent findings: Research focused on which severity thresholds should be used to identify patients at higher risk of death and, more recently, on prognostic composite physiologic indices and staging systems, which compared with single variables offer a number of advantages. Composite indices, such as the composite physiologic index, provide a more accurate overall estimate of disease severity and account for confounding coexisting disease process, such as pulmonary hypertension and emphysema. In idiopathic pulmonary fibrosis clinical measures have been integrated in the GAP model that strongly correlates with disease severity and mortality. Recently, the GAP model derived for idiopathic pulmonary fibrosis (IPF) has been successfully applied to non-IPF fibrotic ILD.

Summary: The heterogeneity in ILDs related to both disease and patient-specific factors, for many years, has impeded progress in the development of a reliable method to quantify disease severity. In the last decade, novel composite physiologic indices and staging systems have been shown to accurately reflect disease severity and reliably predict survival. Moreover, the recent finding of one informative staging system applicable to different subgroups of ILD patients has the potential to radically transform both clinical practice and research strategy in the near future of ILD.

Right ventricle dysfunction in pulmonary hypertension: mechanisms and modes of detection

imagePurpose of review: This review highlights the right ventricular (RV) involvement in pulmonary hypertension from pathophysiologic changes to current imaging tools used to screen, diagnose and follow up RV function in patients with pulmonary hypertension.

Recent findings: Although right heart catheterization is the gold standard for the diagnosis of pulmonary hypertension, other diagnostic methods such as echocardiography, magnetic resonance and nuclear imaging are of great utility in the assessment of the RV in pulmonary hypertension. Apart from its conventional use as a screening tool for pulmonary hypertension, echocardiography allows assessment of RV size and function and has prognostic value. Among the novel applications of echocardiography, exercise echocardiography and measurements of RV strain might help unveil subclinical pulmonary hypertension, whereas three-dimensional echocardiography allows more accurate measures of RV morphology and function. Cardiac magnetic resonance imaging is currently the gold standard noninvasive imaging method to assess RV volume, mass and function and has prognostic value in the assessment of pulmonary hypertension. Finally, positron emission tomography is a promising tool in the metabolic assessment of the RV and pulmonary circulation.

Summary: RV assessment is essential in the overall evaluation of pulmonary hypertension. Despite the availability of several methods and measurements for this assessment, there is, however, no standard approach or broad consensus on their application.

Practical considerations in the pharmacologic treatment of idiopathic pulmonary fibrosis

imagePurpose of review: Idiopathic pulmonary fibrosis (IPF) is a progressive and deadly disease. The US Food and Drug Administration recently approved two medications for the treatment of IPF – pirfenidone and nintedanib. Given the limited clinical experience with these agents, a number of questions remain regarding their use.

Recent findings: Both pirfenidone and nintedanib were demonstrated to reduce the rate of decline in forced vital capacity in independent large, double-blind, randomized controlled clinical trials. The successful implementation of both agents in clinical practice is dependent on many factors, including which patients to prescribe them in and managing patient expectations regarding efficacy and side effects. Pirfenidone is frequently associated with gastrointestinal upset, malaise, and rash. Nintedanib often causes diarrhea. Both drugs may cause elevations in liver-associated enzymes and require serial monitoring. Despite the side effects mentioned, these drugs are generally well tolerated in the long term. It should be emphasized to patients that these drugs do not represent a ‘cure’ for IPF and that the goal of therapy is stabilization of their disease.

Summary: Currently many questions remain regarding the use of pirfenidone and nintedanib in IPF, including which drug to prescribe, the optimal patient population to treat, the duration of therapy, and how to define treatment success or failure. It also remains to be seen whether combination therapy with both agents will result in improved outcomes. Hopefully, future randomized controlled trials will address these issues.

Balloon pulmonary angioplasty for inoperable chronic thromboembolic pulmonary hypertension

Purpose of review: Chronic thromboembolic pulmonary hypertension (CTEPH), especially when severe in patients unsuited for pulmonary endarterectomy, has a poor prognosis. Balloon pulmonary angioplasty (BPA) is a new catheter-based alternative treatment option for patients with inoperable CTEPH. BPA has not been widely accepted, however, primarily because of possible fatal complications, although effects described in 2001 were encouraging.

Recent studies about BPA from Japan and Norway are promising. However, this emerging catheter-based intervention is still considered to be experimental because of a number of concerns and unanswered questions. This review describes the recent progress in BPA at the dawn of a new CTEPH treatment era.

Recent findings: Recent studies about BPA show consistently beneficial effects in haemodynamics, symptoms, 6-minute walking distance, and biomarkers. Exercise capacity and right ventricular function are also improved by BPA. However, this new technique still has potentially fatal complications, including reperfusion oedema and pulmonary artery perforation, even in recent studies. There remain a number of concerns and unanswered questions about BPA, including indications, best procedural approach, and long-term outcomes.

Summary: Recent advances in BPA for inoperable CTEPH are promising. Further investigation by multidisciplinary CTEPH teams is mandatory before BPA's role in CTEPH treatment strategies is determined.

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