Age of asthma onset does not impact the response to omalizumab.

TRIAL REGISTRATION: These studies were conducted before clinical trial registration was required; therefore, clinical trial registration numbers are not available.

Asthma Care in the Elderly: Practical Guidance and Challenges for Clinical Management - A Framework of 5 "Ps".

Uncontrolled asthma in the elderly is a public health issue recognized in developed countries such as the United States and among the European Union, both from patient safety and economic perspectives. Variations in the cutoff, which defines elderly age, contribute to epidemiological study difficulties. Nonetheless, the relevance of elderly asthma from a socioeconomic perspective is inarguable. The projected growth of the enlarging geriatric population in the United States portends an impending national health burden that may or may not be preventable with pharmacologic and non-pharmacologic treatments. Asthma in the elderly might be a consequence of uncontrolled disease that is carried throughout a lifetime. Or elderly asthmatics could suffer from uncontrolled asthma, which overlaps with other ailments common with advancing ages that merit consideration, eg, COPD, heart disease, OSA, diabetes mellitus, and other comorbidities. Because of the heterogeneity of asthma phenotypes and other conditions that could mimic the symptoms of elderly asthma, further cohort studies are needed to elucidate the elderly asthmatic pathophysiology and management. More studies to characterize elderly asthma can help address these patients' unmet need for evidence-based guidelines. We introduce the 5 "Ps" (phenotypes, partnership, pharmacology, practice in acute exacerbations, and problems or barriers for the elderly asthmatics) that establish a framework approach for clinical practice.

Geoepidemiology of COPD and idiopathic pulmonary fibrosis.

Progress in improving patient outcomes and advancing therapeutics in chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) is hampered by phenotypic heterogeneity and variable responsiveness to clinical interventions that are not fully explained by currently held disease paradigms for COPD and IPF. Although these chronic lung diseases differ in their geoepidemiology and immunopathogenesis, emerging evidence suggest that organ-specific autoimmunity may underlie subphenotypes of COPD and IPF. In particular, the links to tobacco smoking, diet, gender, and environment are explored in this review. We also highlight potential mechanisms that could guide future investigations in both laboratory and clinical settings. A paradigm shift is needed in how we think about COPD and IPF, based on geoepidemiology and a broader understanding of disease pathogenesis that may ultimately lead to new therapies and improved patient outcomes.

Self-Administered Mepolizumab in the Management of Severe Asthma: Usability and Patient Acceptance.

The increasing use of advanced biologic therapies for patients with severe asthma is transforming the standard of care, clinic workflow, and the clinic business model. Expanded patient access to at-home injection treatment possibilities with some biologics has the potential to improve patient adherence and outcomes. Simultaneously, transition to the home setting can address the escalating costs that limit access for certain patients and healthcare facilities. Such moves come with recognized risks. Garnering input from physicians and other healthcare specialists as well as scrutinizing best practice position statements are vital to implementing truly patient-safe and cost-effective strategies in medicine. Mepolizumab is the first anti-IL-5 inhibitor to receive FDA approval in late 2015. We focus on this injectable medication and discuss the specific indications and contraindications for transitioning patients to at-home injection with mepolizumab. In doing so, we review our recent real-world experiences in the University of California, Davis and Loma Linda University severe asthma clinics, which can provide the foundation for building a comprehensive clinic and home-based biologics asthma program. In addition, we offer insight into the barriers to implementing a successful program and strategies for overcoming them.

Bronchial Thermoplasty: A Decade of Experience: State of the Art.

Bronchial thermoplasty (BT) delivers targeted radiofrequency energy to bronchial airway walls and results in the partial ablation of the airway smooth muscle that is responsible for bronchoconstriction. It is approved for the treatment of severe persistent asthma. Multiple, large clinical trials including a recent "real-world" study demonstrate significant improvements in asthma-related quality of life, reduction in asthma exacerbations, emergency department visits, and hospitalizations after BT that is sustained out to 5 years. In this article, we review the state of the art of BT treatment in severe persistent asthma and share a decade of BT research and clinical experience. We share our personal experience and introduce the three "I"s (identification, implementation, and intense follow-up) that we believe promote successful patient outcomes and help build a successful BT program.

Viruses and non-allergen environmental triggers in asthma.

Asthma is a complex inflammatory disease with many triggers. The best understood asthma inflammatory pathways involve signals characterized by peripheral eosinophilia and elevated immunoglobulin E levels (called T2-high or allergic asthma), though other asthma phenotypes exist (eg, T2-low or non-allergic asthma, eosinophilic or neutrophilic-predominant). Common triggers that lead to poor asthma control and exacerbations include respiratory viruses, aeroallergens, house dust, molds, and other organic and inorganic substances. Increasingly recognized non-allergen triggers include tobacco smoke, small particulate matter (eg, PM2.5), and volatile organic compounds. The interaction between respiratory viruses and non-allergen asthma triggers is not well understood, though it is likely a connection exists which may lead to asthma development and/or exacerbations. In this paper we describe common respiratory viruses and non-allergen triggers associated with asthma. In addition, we aim to show the possible interactions, and potential synergy, between viruses and non-allergen triggers. Finally, we introduce a new clinical approach that collects exhaled breath condensates to identify metabolomics associated with viruses and non-allergen triggers that may promote the early management of asthma symptoms.

Tyrosine sulfation is prevalent in human chemokine receptors important in lung disease.

Post-translational sulfation of tyrosines affects the affinity and binding of at least some chemokine receptors to their ligand(s) and has been hypothesized to be a feature in all chemokine receptors. This binding initiates downstream signaling cascades. By this mechanism, tyrosine sulfation can influence the cells involved in acute and chronic events of cellular immunity. These events include leukocyte trafficking and airway inflammation important in asthma and chronic obstructive pulmonary disease (COPD). We are using computational methods to convert the poorly defined hypothesis of more widespread sulfation of chemokine receptors to more specific assessments of how closely the sequence environment of each tyrosine residue resembles the sequence environment of tyrosine residues proven to be sulfated. Thus, we provide specific and readily tested hypotheses about the tyrosine residues in all of the chemokine receptors. Tyrosine sulfation was predicted with high scores in the N-terminus domain of 13 out of 18 human chemokine receptor proteins using a position-specific scoring matrix, which was determined to be 94.2% accurate based on Receiver Operating Characteristic analysis. The remaining chemokine receptors have sites exhibiting features of tyrosine sulfation. These putative sites demonstrate clustering in a manner consistent with known tyrosine sulfation sites and conservation both within the chemokine receptor family and across mammalian species. Human chemokine receptors important in asthma and COPD, such as CXCR1, CXCR2, CXCR3, CXCR4, CCR1, CCR2, CCR3, CCR4, CCR5, and CCR8, contain at least one known or predicted tyrosine sulfation site. Recognition that tyrosine sulfation is found in most clinically relevant chemokine receptors could help the development of specific receptor-ligand antagonists to modulate events important in airway diseases.

Integrating palliative care in severe chronic obstructive lung disease.

Palliative care services for patients with chronic obstructive pulmonary disease (COPD) have been limited in most health care schemes despite the significant impact its symptoms can have on quality of life (QOL). Palliative care must be integrated to address physical and emotional distress and QOL deterioration more effectively. Multi-factorial barriers in current health care systems impede the provision of palliative care, including the lack of familiarity among health care professionals. There are sparse evidence-based studies and guidelines for clinicians to better recognize the need for palliative care in COPD patients compared to the large experience and resources available to cancer patients and hospice care. The multidisciplinary approach of palliative care should help COPD patients navigate through the continuum of chronic disease management. Highest QOL, not necessarily the highest physiologic goals, with relief of physical and emotional suffering, are most important to patients. Hospice care, the last phase of palliative care, can be offered to COPD patients when their goal of care has changed from life-prolonging therapies to comfort treatment. We suggest a scheme for identifying COPD patients for palliative care and for delivering simultaneous disease-directed care to help patients live life to the fullest. Pulmonary rehabilitation offers the best venue for incorporating palliative care. We review the need for, barriers to, and key activities for integrating palliative care into the current health care management of patients living with COPD.

Bronchial thermoplasty: implementing best practice in the era of cost containment.

Increasing dependence on advanced technologies in the 21st century has created a dilemma between the practice and business of medicine. From information technology to robotic surgery, new technologies have expanded treatment possibilities and have potentially improved patient outcomes and safety. Simultaneously, their escalating costs limit access for certain patients and health care facilities. Nevertheless, medical decisions should not simply be based on cost. Input from physicians and other health care specialists as well as adherence to best practice position statements, are vital to implementing truly cost-effective strategies in medicine. Bronchial thermoplasty (BT), a US Food and Drug Administration approved bronchoscopy procedure in difficult-to-control persistent asthma, is a prime example of a new technology facing cost and implementation challenges. We discuss the specific indications and contraindications for BT and review recent real-world experiences that can provide the foundation for building a comprehensive asthma program that provides BT for difficult-to-control asthma patients who fail national guideline treatment recommendations after an adequate clinical trial of one. We also offer insight into the barriers to implementing a successful BT program and strategies for overcoming them.

Paradigms in chronic obstructive pulmonary disease: phenotypes, immunobiology, and therapy with a focus on vascular disease.

Chronic obstructive pulmonary disease (COPD) is a complex and heterogeneous syndrome that represents a major global health burden. COPD phenotypes have recently emerged based on large cohort studies addressing the need to better characterize the syndrome. Though comprehensive phenotyping is still at an early stage, factors such as ethnicity and radiographic, serum, and exhaled breath biomarkers have shown promise. COPD is also an immunological disease where innate and adaptive immune responses to the environment and tobacco smoke are altered. The frequent overlap between COPD and other systemic diseases, such as cardiovascular disease, has influenced COPD therapy, and treatments for both conditions may lead to improved patient outcomes. Here, we discuss current paradigms that center on improving the definition of COPD, understanding the immunological overlap between COPD and vascular inflammation, and the treatment of COPD-with a focus on comorbid cardiovascular disease.

Benralizumab: a unique IL-5 inhibitor for severe asthma.

The presence of eosinophilic inflammation is a characteristic feature of chronic and acute inflammation in asthma. An estimated 5%-10% of the 300 million people worldwide who suffer from asthma have a severe form. Patients with eosinophilic airway inflammation represent approximately 40%-60% of this severe asthmatic population. This form of asthma is often uncontrolled, marked by refractoriness to standard therapy, and shows persistent airway eosinophilia despite glucocorticoid therapy. This paper reviews personalized novel therapies, more specifically benralizumab, a humanized anti-IL-5Rα antibody, while also being the first to provide an algorithm for potential candidates who may benefit from anti-IL-5Rα therapy.

LINX®, a novel treatment for patients with refractory asthma complicated by gastroesophageal reflux disease: a case report.

BACKGROUND: Gastroesophageal reflux disease is one of the most common comorbidities in patients with asthma. Gastroesophageal reflux disease can be linked to difficult-to-control asthma. Current management includes gastric acid suppression therapy and surgical antireflux procedures. The LINX® procedure is a novel surgical treatment for patients with gastroesophageal reflux disease refractory to medical therapy. To the best of our knowledge, we report the first case of successful treatment of refractory asthma secondary to gastroesophageal reflux disease using the LINX® procedure. CASE PRESENTATION: Our patient was a 22-year-old white woman who met the American Thoracic Society criteria for refractory asthma that had remained poorly controlled for 5 years despite progressive escalation to step 6 treatment as recommended by National Institutes of Health-National Asthma Education and Prevention Program guidelines, including high-dose oral corticosteroids, high-dose inhaled corticosteroid plus long-acting ß2-agonist, leukotriene receptor antagonist, and monthly omalizumab. Separate trials with azithromycin therapy and roflumilast did not improve her asthma control, nor did bronchial thermoplasty help. Additional consultations with two other university health systems left the patient with few treatment options for asthma, which included cyclophosphamide. Instead, the patient underwent a LINX® procedure after failure of maximal medical therapy for gastroesophageal reflux disease with the additional aim of improving asthma control. After she underwent LINX® treatment, her asthma improved dramatically and was no longer refractory. She had normal exhaled nitric oxide levels and loss of peripheral eosinophilia after LINX® treatment. Prednisone was discontinued without loss of asthma control. The only immediate adverse effects due to the LINX® procedure were bloating, nausea, and vomiting. CONCLUSIONS: LINX® is a viable alternative to the Nissen fundoplication procedure for the treatment of patients with gastroesophageal reflux disease and poorly controlled concomitant refractory asthma.

Definition of critical asthma syndromes.

Urgent visits to the clinic and emergency department for acute severe asthma exacerbations are all too frequent. Existing national guidelines do not present consistent or specific recommendations for the evaluation and treatment of individual asthma patients in respiratory distress. In this vein, we propose the term "critical asthma syndrome" (CAS) to describe any child or adult who is at high risk for fatal asthma. Acute severe asthma, refractory asthma, status asthmaticus, and near-fatal asthma all describe CAS where physical exhaustion from the overwhelming work of breathing leads to respiratory arrest and death from hypoxia or related complications. The authors of this supplement seek to emphasize the importance of early recognition, prompt and coordinated evaluation, and treatment of CAS in the emergency department, hospital, and intensive care units by experienced healthcare provider teams. CAS is not severe persistent asthma where control of symptoms and prevention of exacerbations are targets of chronic disease management in the outpatient setting. The authors address the distinctions between the two entities throughout the supplement, and elaborate on the considerations important in the care of a critically ill patient, including the common errors to avoid. In addition, gaps in knowledge and clinical experience in regards to critical asthma are highlighted. Knowledge gaps include a lack of understanding of how to recognize CAS, how to coordinate and integrate hospital and outpatient resources, when to further phenotype patients with critical asthma in order to facilitate effective treatment, and how to prevent future acute exacerbations. Lastly, CAS is complicated by the fact that asthma care in diverse healthcare settings is haphazard. We recommend that primary care physicians refer patients promptly to an asthma specialist for consultation to reduce the frequency of acute exacerbations and prevent the development of CAS.

Critical asthma syndrome in the ICU.

Critical asthma syndrome represents the most severe subset of asthma exacerbations, and the critical asthma syndrome is an umbrella term for life-threatening asthma, status asthmaticus, and near-fatal asthma. According to the 2007 National Asthma Education and Prevention Program guidelines, a life-threatening asthma exacerbation is marked by an inability to speak, a reduced peak expiratory flow rate of <25 % of a patient's personal best, and a failed response to frequent bronchodilator administration and intravenous steroids. Almost all critical asthma syndrome cases require emergency care, and most cases require hospitalization, often in an intensive care unit. Among asthmatics, those with the critical asthma syndrome are difficult to manage and there is little room for error. Patients with the critical asthma syndrome are prone to complications, they utilize immense resources, and they incite anxiety in many care providers. Managing this syndrome is anything but routine, and it requires attention, alacrity, and accuracy. The specific management strategies of adults with the critical asthma syndrome in the hospital with a focus on intensive care are discussed. Topics include the initial assessment for critical illness, initial ventilation management, hemodynamic issues, novel diagnostic tools and interventions, and common pitfalls. We highlight the use of critical care ultrasound, and we provide practical guidelines on how to manage deteriorating patients such as those with pneumothoraces. When standard asthma management fails, we provide experience-driven recommendations coupled with available evidence to guide the care team through advanced treatment. Though we do not discuss medications in detail, we highlight recent advances.

Severe obstructive airway disorders and diseases: vocal fold dysfunction.

Vocal Fold Dysfunction is a syndrome characterized by abnormal adduction of the focal folds during inspiration and is the cause of a wide spectrum of clinical manifestations ranging from mild inspiratory stridor to an inability to move any air. Patients present with varying degrees of intermittent respiratory difficulty, the most severe caused by intense laryngospasm. Distinguishing Vocal Fold Dysfunction from Refractory Asthma is important to avoid unnecessary pharmacotherapy and intubation. The diagnosis of Vocal Fold Dysfunction can only be made with certainty by flexible fiberoptic laryngoscopy while the patient is symptomatic. Pulmonary function studies and a lack of response to bronchodilators may provide clues to the diagnosis. Most patients with the condition can be managed by speech therapy and the use of breathing strategies that eliminate the abnormal vocal fold movement. Chronic laryngeal irritation may be a trigger for Vocal Fold Dysfunction and conditions such as laryngopharyngeal reflux disease should be aggressively managed in this patient population.

Severe chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) exacts a heavy toll on society, yet its prevention, diagnosis and treatment receives inadequate attention from both the medical community and from society at large. Guidelines released in 2001 from the Global Initiative for Chronic Obstructive Lung Disease (GOLD) are aimed at redressing this inequity. In this review, we integrate information from the GOLD guidelines with recent updates on the prevention, treatment and management as related specifically to the most severe form of this disease. In order to help distinguish COPD from other disorders that may mimic or confound its treatment, we place particular emphasis on the definition, underlying pathophysiology and diagnosis of COPD. In addition, we discuss future directions in pharmacotherapy.

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.

Critical Asthma Syndrome in the ICU.

Critical asthma syndrome represents the most severe subset of asthma exacerbations, and the critical asthma syndrome is an umbrella term for life-threatening asthma, status asthmaticus, and near-fatal asthma. According to the 2007 National Asthma Education and Prevention Program guidelines, a life-threatening asthma exacerbation is marked by an inability to speak, a reduced peak expiratory flow rate of <25 % of a patient's personal best, and a failed response to frequent bronchodilator administration and intravenous steroids. Almost all critical asthma syndrome cases require emergency care, and most cases require hospitalization, often in an intensive care unit. Among asthmatics, those with the critical asthma syndrome are difficult to manage and there is little room for error. Patients with the critical asthma syndrome are prone to complications, they utilize immense resources, and they incite anxiety in many care providers. Managing this syndrome is anything but routine, and it requires attention, alacrity, and accuracy. The specific management strategies of adults with the critical asthma syndrome in the hospital with a focus on intensive care are discussed. Topics include the initial assessment for critical illness, initial ventilation management, hemodynamic issues, novel diagnostic tools and interventions, and common pitfalls. We highlight the use of critical care ultrasound, and we provide practical guidelines on how to manage deteriorating patients such as those with pneumothoraces. When standard asthma management fails, we provide experience-driven recommendations coupled with available evidence to guide the care team through advanced treatment. Though we do not discuss medications in detail, we highlight recent advances.

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.