Maya M. Juarez

A review of current and novel therapies for idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressively fibrotic interstitial lung disease that is associated with a median survival of 2-3 years from initial diagnosis. To date, there is no treatment approved for IPF in the United States, and only one pharmacological agent has been approved outside of the United States. Nevertheless, research over the past 10 years has provided us with a wealth of information on its histopathology, diagnostic work-up, and a greater understanding of its pathophysiology. Specifically, IPF is no longer thought to be a predominantly pro-inflammatory disorder. Rather, the fibrosis in IPF is increasingly understood to be the result of a fibroproliferative and aberrant wound healing cascade. The development of therapeutic targets has shifted in accord with this paradigm change. This review highlights the current understanding of IPF, and the recent as well as novel therapeutics being explored in clinical trials for the treatment of this devastating disease.

Novel computed tomographic chest metrics to detect pulmonary hypertension

BackgroundEarly diagnosis of pulmonary hypertension (PH) can potentially improve survival and quality of life. Detecting PH using echocardiography is often insensitive in subjects with lung fibrosis or hyperinflation. Right heart catheterization (RHC) for the diagnosis of PH adds risk and expense due to its invasive nature. Pre-defined measurements utilizing computed tomography (CT) of the chest may be an alternative non-invasive method of detecting PH.MethodsThis study retrospectively reviewed 101 acutely hospitalized inpatients with heterogeneous diagnoses, who consecutively underwent CT chest and RHC during the same admission. Two separate teams, each consisting of a radiologist and pulmonologist, blinded to clinical and RHC data, individually reviewed the chest CTs.ResultsMultiple regression analyses controlling for age, sex, ascending aortic diameter, body surface area, thoracic diameter and pulmonary wedge pressure showed that a main pulmonary artery (PA) diameter ≥29 mm (odds ratio (OR) = 4.8), right descending PA diameter ≥19 mm (OR = 7.0), true right descending PA diameter ≥ 16 mm (OR = 4.1), true left descending PA diameter ≥ 21 mm (OR = 15.5), right ventricular (RV) free wall ≥ 6 mm (OR = 30.5), RV wall/left ventricular (LV) wall ratio ≥0.32 (OR = 8.8), RV/LV lumen ratio ≥1.28 (OR = 28.8), main PA/ascending aorta ratio ≥0.84 (OR = 6.0) and main PA/descending aorta ratio ≥ 1.29 (OR = 5.7) were significant predictors of PH in this population of hospitalized patients.ConclusionThis combination of easily measured CT-based metrics may, upon confirmatory studies, aid in the non-invasive detection of PH and hence in the determination of RHC candidacy in acutely hospitalized patients.

Pharmacokinetics and clinical effects of mono-L-aspartyl chlorin e6 (NPe6) photodynamic therapy in adult patients with primary or secondary cancer of the skin and mucosal surfaces

Background/Purpose: Mono‐l‐aspartyl chlorin e6 (NPe6) is a photosensitizer that exhibits chemical purity, absorption at 664 nm wavelength and may be useful in photodynamic therapy (PDT).

Acute exacerbation of idiopathic pulmonary fibrosis-a review of current and novel pharmacotherapies.

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive form of lung disease of unknown etiology for which a paucity of therapies suggest benefit, and for which none have demonstrated improved survival. Acute exacerbation of IPF (AE-IPF) is defined as a sudden acceleration of the disease or an idiopathic acute injury superimposed on diseased lung that leads to a significant decline in lung function. An AE-IPF is associated with a mortality rate as high as 85% with mean survival periods of between 3 to 13 days. Under these circumstances, mechanical ventilation (MV) is controversial, unless used a as a bridge to lung transplantation. Judicious fluid management may be helpful. Pharmaceutical treatment regimens for AE-IPF include the use of high dose corticosteroids with or without immunosuppressive agents such as cyclosporine A (CsA), and broad spectrum antibiotics, despite the lack of convincing evidence demonstrating benefit. Newer research focuses on abnormal wound healing as a cause of fibrosis and preventing fibrosis itself through blocking growth factors and their downstream intra-cellular signaling pathways. Several novel pharmaceutical approaches are discussed.

Do airway metallic stents for benign lesions confer too costly a benefit

BackgroundThe use of self-expanding metallic stents (SEMAS) in the treatment benign airway obstruction is controversial.MethodsTo evaluate the safety and efficacy of SEMAS for this indication, we conducted a 10-year retrospective review at our tertiary medical centre.ResultsUsing flexible bronchoscopy, 82 SEMAS (67% Ultraflex, 33% Wallstent) were placed in 35 patients with inoperable lesions, many with significant medical comorbidities (88%). 68% of stents were tracheal, and 83% of patients showed immediate symptomatic improvement. Reversible complications developed in 9% of patients within 24 hrs of stent placement. Late complications (>24 hrs) occurred in 77% of patients, of which 37% were clinically significant or required an interventional procedure. These were mainly due to stent migration (12.2%), fracture (19.5%), or obstructive granulomas (24.4%). The overall granuloma rate of 57% was higher at tracheal sites (59%) than bronchial ones (34%), but not significantly different between Ultraflex and Wallstents. Nevertheless, Wallstents were associated with higher rates of bleeding (5% vs. 30%, p = 0.005) and migration (7% vs. 26%, p = 0.026). Of 10 SEMAS removed using flexible bronchoscopy, only one was associated with incomplete removal of fractured stent wire. Median survival was 3.6 ± 2.7 years.ConclusionIll patients with inoperable lesions may be considered for treatment with SEMAS.

Myeloperoxidase-dependent oxidative metabolism of nitric oxide in the cystic fibrosis airway.

BACKGROUND Decreased expired nitric oxide (eNO) is commonly observed in cystic fibrosis (CF) patients and is usually explained by dysregulation of NO synthase (NOS) isoforms in respiratory tract epithelium. Later stages of this disease are accompanied by intense airway infiltration of phagocytes with high NOS activity, abundant levels of the hemoprotein myeloperoxidase (MPO) and significant production of significant reactive oxygen species. METHODS This study characterizes the contribution of the high airway levels of MPO to decreased eNO levels in adult CF patients. NO metabolites (NO(x)) and MPO levels in fresh sputum of control and adult CF patients were determined and related to measurements of eNO and to in vitro consumption of NO in CF sputum. RESULTS Despite essentially equal levels of NO(x) in sputum, eNO was 2- to 3-fold lower in CF patients compared to healthy controls. In CF patients, eNO levels were negatively associated with sputum peroxidase activity. In vivo correlations were confirmed by ex vivo studies of NO consumption by MPO in CF sputum. Immunodepletion studies confirmed MPO as the major heme peroxidase in CF sputum contributing to the hydrogen peroxide (H(2)O(2))-dependent consumption of NO. CONCLUSIONS In CF airways MPO acts as a phagocyte-derived NO oxidase that diminishes NO bioavailability at airway surfaces, possibly identifying this peroxidase as a potential target for therapeutic intervention.

Management of critical asthma syndrome during pregnancy.

One-third of pregnant asthmatics experience a worsening of their asthma that may progress to a critical asthma syndrome (CAS) that includes status asthmaticus (SA) and near-fatal asthma (NFA). Patients with severe asthma before pregnancy may experience more exacerbations, especially during late pregnancy. Prevention of the CAS includes excellent asthma control involving targeted early and regular medical care of the pregnant asthmatic, together with medication compliance. Spontaneous abortion risk is higher in pregnant women with uncontrolled asthma than in non-asthmatics. Should CAS occur during pregnancy, aggressive bronchodilator therapy, montelukast, and systemic corticosteroids can be used in the context of respiratory monitoring, preferably in an Intensive Care Unit (ICU). Systemic epinephrine should be avoided due to potential teratogenic side-effects and placental/uterine vasoconstriction. Non-invasive ventilation has been used in some cases. Intratracheal intubation can be hazardous and rapid-sequence intubation by an experienced physician is recommended. Mechanical ventilation parameters are adjusted based on changes to respiratory mechanics in the pregnant patient. An inhaled helium–oxygen gas admixture may promote laminar airflow and improve gas exchange. Permissive hypercapnea is controversial, but may be unavoidable. Sedation with propofol which itself has bronchodilating properties is preferred to benzodiazepines. Case reports delineating good outcomes for both mother and fetus despite intubation for SA suggest that multidisciplinary ICU care of the pregnant asthmatic with critical asthma are feasible especially if hypoxemia is avoided.

Interventional bronchoscopy for obstructing benign airway tumors: which modality is ideal?

In the early 19th century, rigid illuminating tubes were used to visualize the tracheobronchial tree (1). Since that time, bronchoscopic diagnostic and treatment modalities including interventional bronchoscopic techniques now encompass a myriad of indications. Despite the many options, the management of airway obstruction from both malignant or nonmalignant causes is a complex problem that requires thorough evaluation by a multidisciplinary team including interventional bronchologists, thoracic surgeons and chest radiologists (2). In the case of nonmalignant airway obstructing lesions, the choice of therapy, whether surgically curative or minimally-invasive endoscopic-based, very much depends on tumor pathology, size, wall invasion depth, anatomical location, the acuity and degree of symptoms from airway compromise, patient co-morbidities, and also operator experience and expertise (1,3).

Interstitial lung abnormality is prevalent and associated with worse outcome in patients undergoing transcatheter aortic valve replacement

BACKGROUND Interstitial lung abnormality (ILA) is found in 5-10% of the general population and is associated with increased mortality risk. Risk factors for ILA, including advanced age and smoking history also increase the risk for aortic stenosis (AS). Transcatheter aortic valve replacement (TAVR) has become an increasingly utilized intervention for patients with severe AS, and requires a high-resolution computed tomography (HRCT) of the chest to assess aortic valve dimensions. OBJECTIVES To determine the prevalence and clinical significance of ILA on HRCT performed in patients referred for TAVR. METHODS Consecutive pre-TAVR HRCTs performed over a 5-year period were reviewed. ILA was defined as bilateral, nondependent reticular opacities. All-cause mortality among TAVR recipients was compared between ILA cases and non-ILA controls matched 2:1 by age and gender using Cox proportional hazards regression and the Kaplan Meier estimator. RESULTS Of 623 HRCTs screened, ILA was detected in 92 (14.7%), including 62 patients that underwent TAVR. Among ILA cases, 17 (27.4%) had a typical or probable usual interstitial pneumonia pattern, suggesting a diagnosis of idiopathic pulmonary fibrosis. Survival was worse in ILA cases compared to non-ILA controls (p = 0.008) and ILA was an independent predictor of mortality after multivariable adjustment (HR 3.29, 95% CI 1.34-8.08; p = 0.009). CONCLUSIONS ILA is a common finding among patients with severe AS and is associated with increased mortality in those undergoing TAVR. Further research is needed to elucidate the biology underpinning this observation and determine whether ILA evaluation and risk stratification modulates this mortality risk.

Weight loss as a predictor of mortality in patients with interstitial lung disease

The interstitial lung diseases (ILDs) are a diverse group of diffuse parenchymal lung disorders that commonly result in pulmonary fibrosis. ILDs are broadly classified according to known and unknown aetiologies. Connective tissue disease-associated ILD (CTD-ILD) and chronic hypersensitivity pneumonitis (CHP) are among the most common ILDs of known aetiology, while idiopathic pulmonary fibrosis (IPF) and unclassifiable ILD (U-ILD) are among the most common of unknown aetiology [1–4]. Weight loss in patients with ILD was associated with increased mortality risk in those with IPF and U-ILD http://ow.ly/Nk0D30l2Apm