Large-scale plasma proteomic profiling identifies a high-performance biomarker panel for Alzheimer's disease screening and staging.

INTRODUCTION: Blood proteins are emerging as candidate biomarkers for Alzheimer's disease (AD). We systematically profiled the plasma proteome to identify novel AD blood biomarkers and develop a high-performance, blood-based test for AD. METHODS: We quantified 1160 plasma proteins in a Hong Kong Chinese cohort by high-throughput proximity extension assay and validated the results in an independent cohort. In subgroup analyses, plasma biomarkers for amyloid, tau, phosphorylated tau, and neurodegeneration were used as endophenotypes of AD. RESULTS: We identified 429 proteins that were dysregulated in AD plasma. We selected 19 "hub proteins" representative of the AD plasma protein profile, which formed the basis of a scoring system that accurately classified clinical AD (area under the curve  = 0.9690-0.9816) and associated endophenotypes. Moreover, specific hub proteins exhibit disease stage-dependent dysregulation, which can delineate AD stages. DISCUSSION: This study comprehensively profiled the AD plasma proteome and serves as a foundation for a high-performance, blood-based test for clinical AD screening and staging.

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.

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.

The acute management of asthma.

Patients presenting to the emergency department (ED) or clinic with acute exacerbation of asthma (AEA) can be very challenging varying in both severity and response to therapy. High-dose, frequent or continuous nebulized short-acting beta2 agonist (SABA) therapy that can be combined with a short-acting muscarinic antagonist (SAMA) is the backbone of treatment. When patients do not rapidly clinically respond to SABA/SAMA inhalation, the early use of oral or parenteral corticosteroids should be considered and has been shown to impact the immediate need for ICU admission or even the need for hospital admission. Adjunctive therapies such as the use of intravenous magnesium and helium/oxygen combination gas for inhalation and for driving a nebulizer to deliver a SABA and or SAMA should be considered and are best used early in the treatment plan if they are likely to impact the patients' clinical course. The use of other agents such as theophylline, leukotriene modifiers, inhaled corticosteroids, long-acting beta2 agonist, and long-acting muscarinic antagonist currently does not play a major role in the immediate treatment of AEA in the clinic or the ED but is an important therapeutic option for physicians to be aware of and to consider initiating at the time of discharge from clinic, hospital, or ED to reduce later clinical worsening and readmission to the ED and hospital. A comprehensive summary is provided of the currently available respiratory pharmaceuticals approved for asthma and other airway syndromes. Clinicians must be prepared to use the entire spectrum of medications available for the treatment of acute asthma exacerbations and the agents that should be initiated to prevent worsening or additional exacerbations. They need to be familiar with the major potential drug toxicities associated with their use.

New combination treatments in the management of asthma: focus on fluticasone/vilanterol.

Despite the 2007 National Asthma Education and Prevention Program Expert Panel 3 guidelines for the treatment of uncontrolled asthma, many patients with poorly controlled asthma still continue to tax the health care system. Controlling asthma symptoms and preventing acute exacerbations have been the foundation of care. Using long-term controller treatments such as inhaled corticosteroids (ICS) and inhaled long-acting beta2-agonists (LABAs) is a common approach. While patient responses to recommended pharmacotherapy may vary, poor adherence to therapy also contributes to poor asthma control. A once-daily combination inhaler, such as fluticasone furoate, an ICS, in combination with vilanterol, a LABA, offers increased convenience and potential improved adherence, which should result in enhanced clinical outcomes and reduced exacerbations. The ICS/LABA combination inhaler of fluticasone furoate and vilanterol is currently approved in the United States for use in the maintenance of chronic obstructive pulmonary disease and to reduce exacerbations. This paper reviews the expanding literature on the efficacy of fluticasone furoate and vilanterol in treating asthma.

Pulmonary cystic disease associated with integumentary and renal manifestations.

A 69-year-old man with multiple skin lesions on his face, neck and upper torso, which first appeared in the 3rd decade of his life, was admitted to our hospital. He had cystic changes in his lungs noted on chest computed tomography (CT) scanning, as well as a left kidney mass. This patient exhibited a rare complex of renal, cutaneous and pulmonary manifestations, eponymously named Birt-Hogg-Dube syndrome, with characteristic skin features (fibrofolliculomas, trichodiscomas and acrochordons). This syndrome is due to an autosomal dominant germ-line mutation of the folliculin (FLCN) gene located at chromosome 17p11.2. Diagnosis and differentiation from other disease complexes including the skin, kidneys and lungs are important in prognostication and management of potentially life-threatening complications such as renal cell carcinoma and pneumothoraces.

The pharmacological approach to the elderly COPD patient.

The elderly patient (65 years and older) with chronic obstructive pulmonary disease (COPD) can be a challenge to the clinician. This begins with the correct and early diagnosis, the assessment of disease severity, recognizing complicating comorbidities, determining the burden of symptoms, and monitoring the frequency of acute exacerbations. Comprehensive management of COPD in the elderly patient should improve health-related quality of life, lung function, reduce exacerbations, and promote patient compliance with treatment plans. Only smoking cessation and oxygen therapy in COPD patients with hypoxemia reduce mortality. Bronchodilators, corticosteroids, methylxanthines, phosphodiesterase-4 inhibitors, macrolide antibiotics, mucolytics, and pulmonary rehabilitation improve some outcome measures such as spirometry measures and the frequency of COPD exacerbations without improving mortality. International treatment guidelines to reduce symptoms and reduce the risk of acute exacerbations exist. Relief of dyspnea and control of anxiety are important. The approach to each patient is best individualized. Earlier use of palliative care should be considered when traditional pharmacotherapy fails to achieve outcome measures and before consideration of end-of-life issues.

The asthma-chronic obstructive pulmonary disease overlap syndrome: pharmacotherapeutic considerations.

Asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) is a commonly encountered yet loosely defined clinical entity. ACOS accounts for approximately 15-25% of the obstructive airway diseases and patients experience worse outcomes compared with asthma or COPD alone. Patients with ACOS have the combined risk factors of smoking and atopy, are generally younger than patients with COPD and experience acute exacerbations with higher frequency and greater severity than lone COPD. Pharmacotherapeutic considerations require an integrated approach, first to identify the relevant clinical phenotype(s), then to determine the best available therapy. The authors discuss the array of existing and emerging classes of drugs that could benefit those with ACOS and share their therapeutic approach. A consensus international definition of ACOS is needed to design prospective, randomized clinical trials to evaluate specific drug interventions on important outcomes such as lung function, acute exacerbations, quality of life and mortality.

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.

Therapeutic update in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a disease of the elderly with a mean age at presentation of 66 years. It is the most common type of idiopathic lung fibrosis, and the most lethal, with a median survival of 3 to 5 years after diagnosis. Abnormalities in fibroblast and humoral response mechanisms may play a role in the pathogenesis of fibrosis in IPF. Clinical trials suggest that pirfenidone, an oral antifibrotic agent, N-acetylcysteine, an antioxidant and perhaps anticoagulation, may have some beneficial effect; however, large-scale studies are necessary for confirmation. Immunosuppression with corticosteroids likely does not confer benefit. Lung transplantation has been shown to improve survival in selected IPF patients. Comorbidities accompanying IPF include gastroesophageal reflux, sleep disturbance, pulmonary arterial hypertension, and coronary artery disease amongst others, and ought to be promptly recognized and managed appropriately. While the US Food and Drug Administration has not currently approved any treatments for IPF, patients with IPF should continue to be strongly encouraged to enroll in ongoing clinical trials for this devastating disease.

Are fluoroquinolones superior antibiotics for the treatment of community-acquired pneumonia?

Various guidelines for the antibiotic treatment of community-acquired pneumonia (CAP) are presented that include fluoroquinolone antibiotics. The efficacy of current fluoroquinolone antibiotics in the treatment of CAP is summarized. Healthcare resource utilization and shortened duration of clinical symptoms have been shown in some, but not all of CAP trials utilizing fluoroquinolone antibiotics. Although evidence for both the clinical and microbiological efficacy of fluoroquinolone antibiotics is abundant, no convincing data demonstrates that they are superior to other standard antibiotics included in CAP guidelines.

Bird fancier's lung: a state-of-the-art review.

Bird fancier's lung (BFL) resulting from avian antigen exposure is a very common form of hypersensitivity pneumonitis. Its pathogenesis is modified by genetic polymorphisms located within the major histocompatibility complex, and also by smoking, which may decrease serum antibody response to inhaled antigen. Acute, subacute, and chronic presentations of BFL are recognized, but often overlap clinically. Continued antigen exposure in the chronic phase portends a worse prognosis. Chronic bronchitis symptoms may be part of the BFL clinical spectrum, and rhinitis may suggest an allergic component. The diagnosis of BFL is enhanced by a high index of suspicion of exposure to avian antigen, recurrent symptomatic episodes occurring 4-8 h after exposure, inspiratory "velcro" crackles on auscultation, weight loss, and positive IgG precipitins to the antigen. Characteristic findings on high-resolution computed tomography of the chest include centrilobular nodules, ground-glass opacification, and mosaicism due to air trapping. Bronchoalveolar lavage will classically show >25% lymphocytosis, a CD4/CD8 ratio of <1.0 and >1% mast cells in the acute phase. Lung biopsies, if obtained in the subacute phase of the disease, typically show loosely formed granulomas, giant cells, a lymphoplasmacytic interstitial infiltrate, and possibly some degree of fibrosis. In some patients, usual interstitial pneumonia or fibrotic non-specific interstitial pneumonia patterns may be seen on surgical biopsy. Skin testing, serological testing, and bronchial provocation tests for BFL frequently suffer from a lack of standardization. Effective treatment for BFL consists mainly of antigen avoidance, as corticosteroids likely do not alter long-term prognosis. Lung transplantation can be considered for progressive chronic disease refractory to medical measures.

Cerebral gas embolism from bronchoscopic argon plasma coagulation: a case report.

Argon plasma coagulation (APC) is a common and safe bronchoscopic technique used in the management of obstructing lesions and hemorrhage in the central airways. Complications of bronchoscopic APC are uncommon and include hemorrhage, perforation and fire in the airways. While bronchoscopic APC has been reported to cause systemic gas embolization and associated cardiovascular collapse, we report a case of cerebral gas embolization that occurred during bronchoscopic APC and highlight underappreciated potential risk factors for its occurrence.

Bronchial thermoplasty: a new treatment paradigm for severe persistent asthma.

Patients with severe asthma represent only a minority of the total asthma population; however, they account for the majority of the mortality, morbidity, and health care-related cost of this chronic illness. Bronchial thermoplasty is a novel treatment modality that employs radiofrequency energy to alter the smooth muscles of the airways. This therapy represents a radical change in our treatment paradigm from daily repetitive dosing of medications to a truly long-term and potentially permanent attenuation of perhaps the most feared component of asthma--smooth muscle-induced bronchospasm. A large, multicentered, double-blinded, randomized controlled trial employed the unprecedented (but now industry standard for bronchoscopic studies) approach of using sham bronchoscopy as a control. It demonstrated that bronchial thermoplasty is safe, improved quality of life, and decreased frequency of severe exacerbations in the treatment group compared to the control group. Although the mechanism of action of bronchial thermoplasty is not currently completely understood, it should be considered as a valid and potentially valuable option for patients who have severe persistent asthma and who remain symptomatic despite inhaled corticosteroids and long-acting beta-2 agonists. Such patients should however be carefully evaluated at centers with expertise in managing severe asthma patients and with physicians who have experience with this promising new treatment modality.

Gastrointestinal decontamination in the acutely poisoned patient.

OBJECTIVE: To define the role of gastrointestinal (GI) decontamination of the poisoned patient. DATA SOURCES: A computer-based PubMed/MEDLINE search of the literature on GI decontamination in the poisoned patient with cross referencing of sources. STUDY SELECTION AND DATA EXTRACTION: Clinical, animal and in vitro studies were reviewed for clinical relevance to GI decontamination of the poisoned patient. DATA SYNTHESIS: The literature suggests that previously, widely used, aggressive approaches including the use of ipecac syrup, gastric lavage, and cathartics are now rarely recommended. Whole bowel irrigation is still often recommended for slow-release drugs, metals, and patients who "pack" or "stuff" foreign bodies filled with drugs of abuse, but with little quality data to support it. Activated charcoal (AC), single or multiple doses, was also a previous mainstay of GI decontamination, but the utility of AC is now recognized to be limited and more time dependent than previously practiced. These recommendations have resulted in several treatment guidelines that are mostly based on retrospective analysis, animal studies or small case series, and rarely based on randomized clinical trials. CONCLUSIONS: The current literature supports limited use of GI decontamination of the poisoned patient.

Update on pharmaceutical and minimally invasive management strategies for chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a debilitating pulmonary disorder with systemic effects, and it is the fourth leading cause of death in the United States. COPD patients not only develop respiratory limitations, but can also demonstrate systemic wasting, features of depression, and can succumb to social isolation. Smoking cessation is crucial, and pharmacotherapy with bronchodilators is helpful in symptom management. Inhaled corticosteroids may be beneficial in some patients. In addition, pulmonary rehabilitation and palliative care are important components under the right clinical circumstance. This review highlights current guidelines and management strategies for COPD and emphasizes novel pharmacotherapy and minimally invasive (nonsurgical) lung-volume reduction interventions that may prove to be of significant benefit in the future.

Novel computed tomographic chest metrics to detect pulmonary hypertension.

BACKGROUND: Early 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. METHODS: This 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 CT's. RESULTS: Multiple 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. CONCLUSION: This 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.

Cutting edge issues in Goodpasture's disease.

Goodpasture's disease, or anti-glomerular basement membrane (anti-GBM) disease, is a systemic autoimmune disorder defined by anti-GBM antibody-mediated damage (mainly immunoglobulin G-1) resulting in progressive crescentic glomerulonephritis and, frequently, diffuse pulmonary alveolar hemorrhage. It may be regarded as a "conformeropathy" where the quaternary structure of the α345NC1 hexamer that constitutes GBM undergoes a conformational change, exposing pathogenic epitopes on the α3 and α5 chains, eliciting a pathogenic autoantibody anti-GBM response. Goodpasture's disease accounts for 20% of all patients presenting with a pulmonary-renal syndrome and may be associated with detectable perinuclear antineutrophil cytoplasmic autoantibody positivity in up to a third of patients. Associated triggers may include tobacco smoking, hydrocarbon solvent exposure, and cocaine abuse. Cough, hemoptysis, and dyspnea with fatigue are the commonest presenting features. It is critical to rapidly distinguish Goodpasture's disease from other causes of pulmonary-renal syndromes such as Wegener's granulomatosis. Early and intensive treatment with plasmapheresis and immunosuppression with systemic corticosteroids pending results of diagnostic testing, and later cyclophosphamide, is often beneficial, with 90% of patients surviving the acute presentation of Goodpasture's disease. The need for hemodialysis on initial presentation, a serum creatinine >5 mg/dL, and 50% to 100% crescents on renal biopsy, portend the necessity of long-term hemodialysis. Further elucidation of the molecular pathobiology of Goodpasture's disease, particularly the regulation of involved antigen-specific T cells, may improve early diagnosis, treatment, and outcomes in this rare but potentially lethal autoimmune disorder.

The diagnosis and treatment of elderly patients with acute exacerbation of chronic obstructive pulmonary disease and chronic bronchitis.

The syndrome of chronic obstructive pulmonary disease (COPD) consists of chronic bronchitis (CB), bronchiectasis, emphysema, and reversible airway disease that combine uniquely in an individual patient. Older patients are at risk for COPD and its components--emphysema, CB, and bronchiectasis. Bacterial and viral infections play a role in acute exacerbations of COPD (AECOPD) and in acute exacerbations of CB (AECB) without features of COPD. Older patients are at risk for resistant bacterial organisms during their episodes of AECOPD and AECB. Organisms include the more-common bacteria implicated in AECOPD/AECB such as Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae. Less-common nonenteric, gram-negative organisms including Pseudomonas aeruginosa, gram-positive organisms including Staphylococcus aureus, and strains of nontuberculosis Mycobacteria are more often seen in AECOPD/AECB episodes involving elderly patients with frequent episodes of CB or those with bronchiectasis. Risk-stratified antibiotic treatment guidelines appear useful for purulent episodes of AECOPD and episodes of AECB. These guidelines have not been prospectively validated for the general population and especially not for the elderly population. Using a risk-stratification approach for elderly patients, first-line antibiotics (e.g., amoxicillin, ampicillin, pivampicillin, trimethoprim/sulfamethoxazole, and doxycycline), with a more-limited spectrum of antibacterial coverage, are used in patients who are likely to have a low probability of resistant organisms during AECOPD/AECB. Second-line antibiotics (e.g., amoxicillin/clavulanic acid, second- or third-generation cephalosporins, and respiratory fluoroquinolones) with a broader spectrum of coverage are reserved for patients with significant risk factors for resistant organisms and those who have failed initial antibiotic treatment.