Comorbid “treatable traits” in difficult asthma: Current evidence and clinical evaluation

The care of patients with difficult‐to‐control asthma (“difficult asthma”) is challenging and costly. Despite high‐intensity asthma treatment, these patients experience poor asthma control and face the greatest risk of asthma morbidity and mortality. Poor asthma control is often driven by severe asthma biology, which has appropriately been the focus of intense research and phenotype‐driven therapies. However, it is increasingly apparent that extra‐pulmonary comorbidities also contribute substantially to poor asthma control and a heightened disease burden. These comorbidities have been proposed as “treatable traits” in chronic airways disease, adding impetus to their evaluation and management in difficult asthma. In this review, eight major asthma‐related comorbidities are discussed: rhinitis, chronic rhinosinusitis, gastroesophageal reflux, obstructive sleep apnoea, vocal cord dysfunction, obesity, dysfunctional breathing and anxiety/depression. We describe the prevalence, impact and treatment effects of these comorbidities in the difficult asthma population, emphasizing gaps in the current literature. We examine the associations between individual comorbidities and highlight the potential for comorbidity clusters to exert combined effects on asthma outcomes. We conclude by outlining a pragmatic clinical approach to assess comorbidities in difficult asthma.     

The burden of nonadherence among adults with asthma: a role for shared decision‐making

A shared approach to decision‐making framework has been suggested for chronic disease management especially where multiple treatment options exist. Shared decision‐making (SDM) requires that both physician and patients are actively engaged in the decision‐making process, including information exchange; expressing treatment preferences; as well as agreement over the final treatment decision. Although SDM appears well supported by patients, practitioners and policymakers alike, the current challenge is to determine how best to make SDM a reality in everyday clinical practice. Within the context of asthma, adherence rates are poor and are linked to outcomes such as reduced asthma control, increased symptoms, healthcare expenditures, and lower patient quality of life. It has been suggested that SDM can improve treatment adherence and that ignoring patients’ personal goals and preferences may result in reduced rates of adherence. Furthermore, understanding predictors of poor treatment adherence is a necessary step toward developing effective strategies to improve the patient‐reported and clinically important outcomes. Here, we describe why a shared approach to treatment decision‐making for asthma has the potential to be an effective tool for improving adherence, with associated clinical and patient‐related outcomes. In addition, we explore insights into the reasons why SDM has not been implemented into routine clinical practice.     

A potential treatment option for elderly non-Hodgkin lymphoma patients with multiple comorbidities: Two case reports and literature review

Non-Hodgkin lymphoma (NHL) is a heterogeneous lymphoproliferative malignancy. More than half of the NHL cases occur in patients over 65 years of age. As elderly patients have a poor performance status and multiple comorbidities, the use of standard chemotherapy is often limited, leading to poor clinical outcomes and an increasing need for an alternate therapeutic modalities.A 73-year-old man was diagnosed with extranodal NK/T-cell lymphoma concurrently combined with recurrent gastric adenocarcinoma and metastatic prostate cancer. A 79-year-old woman was diagnosed with T-cell and B-cell dual-phenotype NHL on the right chest wall showing tumor thrombosis and multiple enlarged lymph nodes under chronic emphysema with extensive pleural calcification. Both elderly patients had multiple comorbidities and pathologically confirmed non-Hodgkin lymphoma. Both patients achieved tumor responses following anticancer treatment with Korean medicine (KM), suggesting that the extracts of Angelica gigas Nakai and Geopungtang are potential options for treating NHL in elderly patients with multiple comorbidities.Considering the clinical outcomes of KM treatment in the two elderly patients with NHL and multiple comorbidities, this study generates a research hypothesis for future prospective clinical studies in patients with NHL who are ineligible for conventional anticancer therapy.     

Adherence in severe asthma

Adherence in asthma is an important cause for concern. Although nearly 50% of asthma patients are considered poorly adherent to therapeutic advices, adherence is still difficult to assess, understand and improve despite major medical consequences. In this review, we revisited the literature of the last 10 years related to adherence in severe asthma. The concepts have changed and “compliance” is usually replaced by “adherence”. Assessment of adherence is addressing ethical issues, but provides important insight into difficult‐to‐treat asthma. Different tools have been used but none is routinely recommended. Health‐related outcomes (poor control, exacerbations, hospitalizations, lung function decline), which are clearly associated with severe asthma, are often worsened by non‐adherence with consequences also on patient related outcomes (quality of life). The potential behaviour associated with non‐adherence and all other related factors including easy‐to‐recognize psychological traits can help for patient's future management. Therapeutic educational interventions have been recognized with a scientifically proven efficiency even though evolution and improvements are needed. A multidisciplinary approach is required in severe asthma. Therapeutic adherence for a given patient is always a prerequisite to any other aspects when addressing severe asthma phenotypes. Severe asthma should be considered only in those who still experienced poor asthma outcomes despite optimal adherence. At a glance, poor adherence and severe asthma should be considered antinomic. Better understanding of the causes and customised management are potential future directions.     

Allergen immunotherapy in the prevention of asthma

PURPOSE OF REVIEW: Asthma is a disease causing significant morbidity and mortality. In the recent past, there has been an explosion of pharmacotherapeutic options attempting to control the disease. Unfortunately, none of the current options offers the promise of prevention or a permanent cure. However, there appear to be exciting, new data emerging to support the hypothesis that the prevention or early treatment of allergic rhinitis, such as with the use of allergen immunotherapy, may help mitigate the severity of bronchial symptoms and even prevent the development of asthma. In this paper, we review recent research published proposing immunotherapy as a means of preventing the development of, or at least ameliorating, allergic asthma. RECENT FINDINGS: There is evidence that the upper and lower airways may be considered a single unit, with the nasal and bronchial mucosa having features in common. Epidemiological, pathophysiological and clinical studies have shown that they can be affected by similar inflammatory triggers, with interconnected mechanisms amplifying the inflammatory cascade. Allergic rhinitis is interrelated to, and is a risk factor for, the development of asthma. An evidence-based review validates the successful use of allergen immunotherapy in treating allergic rhinitis and asthma. There is promising evidence advocating its use in the prevention of clinical asthma. SUMMARY: This article explores current research pertaining to the use of immunomodulation, such as by using allergen immunotherapy, to ameliorate and prevent the development of allergic asthma.     

Angiotensin II type I receptor antibodies in pediatric solid organ transplant

Minimizing immunologic complications is critical for long-term patient survival in pediatric solid organ transplant recipients. Multiple factors distinguish pediatric from adult organ transplant recipients which may influence the risk and manifestations of immunologic responses. Angiotensin II type 1 receptor antibody (AT1R-Ab) is a non-HLA antibody that has been has been associated with poor clinical outcomes in adult kidney transplant recipients. There is now limited evidence available to suggest that AT1R-Ab may be an important part of the immunologic milieu impacting pediatric organ transplant outcomes and that differences in this phenomenon may exist between pediatric and adult patients. The mechanisms by which autoimmunity is provoked and mediates organ dysfunction in childhood and effective treatment options require further research.     

Small Airways Dysfunction in Asthma: Evaluation and Management to Improve Asthma Control

The small airways have been neglected for many years, but interest in the topic has been rekindled with recent advances in measurement techniques to assess this region and also the ability to deliver therapeutics to the distal airways. Current levels of disease control in asthmatic patients remain poor and there are several contributory factors including; poor treatment compliance, heterogeneity of asthma phenotypes and associated comorbidities. However, the proposition that we may not be targeting all the inflammation that is present throughout the whole respiratory tree may also be an important factor. Indeed decades ago, pathologists and physiologists clearly identified the importance of small airways dysfunction in asthmatic patients. With improved inhaler technology to deliver drug to target the whole respiratory tree and more sensitive measures to assess the distal airways, we should certainly give greater consideration to treating the small airway region when seeing our asthmatic patients in clinic. The aim of this review is to address the relevance of small airways dysfunction in the daily clinical management of patients with asthma. In particular the role of small particle aerosols in the management of patients with asthma will be explored.     

Diagnosis of asthma - a new approach

Current definition of asthma involves four cornerstones: inflammation, hyperresponsiveness, bronchoconstriction, and symptoms. In research, the symptoms have had the slightest attention. According to international guidelines, the asthma symptoms are episodic breathlessness, wheeze, cough, tightness of the chest, and shortness of breath. As there are several symptoms, a primary question is how they are related to bronchoconstriction, the main clinical feature of asthma. Symptoms and lung function tests are regularly used for the evaluation of clinical health status and effect of treatment. However, there is no or poor correlation between these two variables, which means that they represent different mechanisms. Reduced lung function, such as a low FEV(1) , represents bronchial constriction, what do the symptoms represent? Some symptoms such as breathlessness and shortness of breath seem not to be evidence-based asthma symptoms. Focusing on bronchial obstruction is important in view of the potential risk of asthma attacks, but nonobstructive symptoms occur frequently and may also cause severe discomfort and poor quality of life. Interpreting all symptoms as signs of bronchoconstriction (asthma) may lead to misinterpretation when assessing health status and effect of treatment. Although a 'soft' variable, the strength of symptoms is that they are representing various mechanisms. The physiological preconditions for control and defense of respiration must be considered in the diagnostic process, regardless of inflammation, allergy, psychology, or other etiological factors. Based on studies on dyspnea in cardiopulmonary diseases, including asthma and asthma-like disorders, there seems to be a continuous spectrum of symptoms and mechanisms integrated in a single asthma syndrome.     

EUFOREA consensus on biologics for CRSwNP with or without asthma

Novel therapies such as type 2 targeting biologics are emerging treatment options for patients with chronic inflammatory respiratory diseases, fulfilling the needs of severely uncontrolled patients. The majority of patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and over half of patients with asthma show a type 2 inflammatory signature in sinonasal mucosa and/or lungs. Importantly, both chronic respiratory diseases are frequent comorbidities, ensuring alleviation of both upper and lower airway pathology by systemic biological therapy. Type 2‐targeting biologics such as anti‐IgE, anti‐IL4Rα, anti‐IL5, and anti‐IL5Rα have entered the market for selected pheno/endotypes of asthma patients and may soon also become available for CRSwNP patients. Given the high prevalence of chronic respiratory diseases and the high cost associated with biologics, patient selection is crucial in order to implement such therapies into chronic respiratory disease care pathways. The European Forum for Research and Education in Allergy and Airway Diseases (EUFOREA) organized a multidisciplinary Expert Board Meeting to discuss the positioning of biologics into the care pathways for CRSwNP patients with and without comorbid asthma.     

Health literacy and asthma

The report "Healthy people" from the US Department of Health and Human Services defines health literacy (HL) as follows: "The degree to which individuals have the capacity to obtain, process, and understand basic health information and services needed to make appropriate health decisions." The same report identifies asthma as a public health problem of high priority. Unfortunately, impaired HL is prevalent in our society, and patients with low HL and asthma face multiple challenges as they attempt to manage their disease. Indeed, the National Asthma Education and Prevention Program's current guidelines require patients to have considerable HL and self-management skills. Numerous studies have linked inadequate literacy with poor health outcomes. Unlike many sociodemographic variables, HL can potentially be addressed in the health care setting. The purpose of this review is to raise awareness of the problem, summarize the current evidence linking HL and asthma, and offer strategies to strengthen the communication between patients and health care providers to decrease asthma health disparities. In addition, we discuss potential future directions for research in this field.     

National Asthma Education and Prevention Program guidelines: what is new?

New guidelines for the diagnosis and management of asthma were released in 2007. Separate recommendations are presented for three separate age groups (ages 0–4, 5–11 and ≥ 12). Six pharmacologic steps of therapy are defined for each age group. Severity is assessed in patients not on long-term control medication as a guide to initiating therapy. Control is assessed in patients on long-term control therapy to determine whether a step up, no change or a step down in therapy is indicated. Before increasing pharmacologic therapy in patients with uncontrolled asthma, adverse environmental exposure, poor adherence and inadequately treated comorbidities should be considered as targets of therapy. Guidelines for the management of asthma exacerbations are also presented.     

What are the Alternatives to Increasing Inhaled Corticosteroids for the Long Term Control of Asthma?

The Global Initiative for Asthma (GINA) guidelines stated the therapeutic goals for the management of asthma and, through a stepwise approach to treatment, defined the various grades of asthma severity and the therapeutic options available to the clinician at each step. This article considers the options at step 3; the management of a patient with poorly controlled asthma who is already taking low-dose inhaled corticosteroids. Before considering a change in therapy, the clinician should rule out alternative diagnoses, confirm compliance with treatment, explore potential exacerbants in the patient’s environment and, where possible, remove them. If a change in medication is necessary, the choice of drug will depend on the therapeutic goal that needs to be achieved. If the most important goal is the control of symptoms and optimisation of lung function, most studies support the addition of a long-acting β2-agonist to low dose inhaled corticosteroids. If recurrent severe exacerbations are a major feature of the poor control, increasing the dosage of inhaled corticosteroids may be most effective. The addition of a leukotriene antagonist may be the best choice if exercise-induced symptoms are prominent or in the setting of aspirin-sensitive asthma. General recommendations supported by the findings of large therapeutic trials do not allow for significant variability in the individual response to a particular drug. Receptor polymorphisms have recently been discovered that may account for variability in the response to β2-agonists and leukotriene receptor antagonists. However, until more is known about the reasons behind this variability, a therapeutic trial may be the most effective way of determining the best drug for an individual patient. One of the key developments in asthma over the past decade has been the acceptance of the concept of asthma as a chronic inflammatory disorder of the airways. However, the long term significance of this inflammation is not clear and the importance of control of inflammation beyond the suppression of symptoms, reduction of exacerbation frequency and the optimisation of lung function has not been established.     

Long-Acting β- Agonist Treatment in Patients with Persistent Asthma Already Receiving Inhaled Corticosteroids

International guidelines recommend that long-acting β-agonists should be considered in patients who are symptomatic despite moderate doses of inhaled corticosteroids. When combined with inhaled corticosteroids they improve asthma symptoms and lung function and reduce exacerbations. The evidence suggests that they are well tolerated. However, they are less effective than inhaled corticosteroids as monotherapy and should not be used alone, although the addition of a long-acting β-agonist may permit a small reduction in the corticosteroid dose. Both salmeterol and formoterol appear equally effective in improving asthma control. Formoterol, however, has a rapid onset of action and is now being promoted for the relief of acute asthma symptoms. Both drugs provide prolonged protection against exercise-induced bronchospasm. However, this effect rapidly diminishes with continuous therapy and if this is the main aim of treatment, intermittent use may be preferable. When compared with alternative treatments, inhaled long-acting β-agonists are more effective in controlling asthma symptoms than either theophylline or antileukotriene agents. Bambuterol, an oral prodrug of terbutaline, appears to be as effective as the inhaled long-acting β-agonists and has the advantage of once daily oral administration. However, the inhaled long-acting β-agonists are less likely to have systemic adverse effects. There are theoretical concerns that regular β-agonist treatment may lead to tolerance and a failure to respond to emergency asthma treatment. While there is no doubt that tolerance occurs, there is currently little evidence that this is a clinical problem. Insights into pharmacological as well as therapeutic interactions between inhaled corticosteroids and β-agonists are providing justification for their use in combination. Guidelines for the management of patients with chronic persistent asthma are likely to require modification to reflect these developments.     

Infectious triggers of asthma

There is abundant evidence that asthma is frequently exacerbated by infectious agents. Several viruses have been implicated in the inception and exacerbation of asthma. Recent attention has been directed at the role of infections with the atypical bacteria Mycoplasma pneumoniae and Chlamydia pneumoniae as agents capable of triggering asthma exacerbations and potentially as inciting agents for asthma. This article examines the evidence for interaction between specific infectious agents and exacerbations of asthma, including the immunopathology of infection-triggered asthma, and the current therapeutic options for management.     

Early treatment of asthma

The early treatment of asthma was not greatly studied before the 1990s. Subjects included in intervention trials have usually had persistent asthma with a long duration of symptoms. Only a few studies have been done on early intervention. It has also become obvious that eosinophilic airway inflammation is common and does not always significantly affect lung function. If patients do not fulfill the functional criteria for asthma, they may not receive specific diagnosis and effective treatment. I have suggested the term "asthma-like inflammation" to describe the disorder of such patients. Bronchial obstruction and increased bronchial responsiveness are outcomes of the inflammatory process, and it may be argued that detection of eosinophilic inflammation is always late at the time asthma is diagnosed. The diagnosis of asthma is often severely delayed, a fact which influences the prognosis and efficacy of therapeutic interventions. The benefits of early treatment of symptomatic asthma have been shown, and several international guidelines recommend anti-inflammatory medication, preferably with inhaled steroids as first-line treatment to gain control of the disease as fast as possible. Very few studies, however, have addressed the long-term influence of various therapeutic approaches. Usually, the beneficial effects gradually disappear when treatment is withdrawn. There is no convincing evidence that any of the current pharmacologic therapies can change the natural course of asthma. Nevertheless, inhaled steroids seem to have a disease-modifying effect if started early enough, and there is a consensus that steroids abolish symptoms, improve lung function, and decrease the need for hospitalization and probably the mortality rate. In future, various combinations of immunologic and pharmacologic treatments may offer more permanent results in asthma therapy.     

Discovery of genetic difference between asthmatic children with high IgE level and normal IgE level by whole genome linkage disequilibrium mapping using 763 autosomal STR markers

The genome-wide linkage disequilibrium screen for loci associated with genetic difference between allergic and nonallergic asthma was conducted with 763 autosomal STR markers and included 190 asthmatic children. Evidence for association with differences between the two forms of asthma was observed for 36 STR markers. Marker-to-marker synergetic effect and by simulation resampling tests revealed D5S2011, D6S305, and D9S286 were important loci in allergic asthma while D6S1574, D8S1769, and D19S226 were important in nonallergic asthma. Our results show strong genetic evidence that these markers play an important role in defining allergic and nonallergic asthma and provides important candidates of susceptible genes in these two categories of asthma. This study further shows that asthma is, indeed, a heterogeneous group of underlying diseases and, although with similar clinical phenotypes, may have different clinical severities, outcomes, and need more tailor-made management.     

Relations among asthma knowledge,treatment adherence,and outcome

BACKGROUND: Asthma knowledge is frequently assumed to be a prerequisite for optimal asthma treatment. However, the validity of existing asthma knowledge questionnaires has not been rigorously examined, and no contemporary measure of asthma knowledge has received widespread acceptance. OBJECTIVE: To construct and examine the psychometric properties of an asthma knowledge instrument, and its association with demographic and psychosocial variables, asthma medication adherence, and treatment outcome. METHODS: A 25-item Asthma Knowledge Questionnaire was developed with input from national pediatric asthma experts. Parents of 155 children with asthma completed the Asthma Knowledge Questionnaire as well as demographic, family functioning, and home environment measures. Asthma outcomes and adherence with inhaled medication was measured across 12 months. RESULTS: Despite the many steps taken to develop a strong measure of asthma knowledge, reliability was relatively poor. There was also no association between asthma knowledge and treatment adherence or outcomes. Furthermore, asthma knowledge was not a unidimensional construct and was not a simple function of education. CONCLUSIONS: Findings from this study, in combination with previous studies of asthma knowledge questionnaires, suggest that the construction of a simple self-report asthma knowledge instrument for use as a primary outcome measure demonstrating mastery of asthma self-management skills may not be achievable.     

Integrating Evidence for Managing Asthma in Patients Who Smoke

Cigarette smoking among asthma patients is associated with worsening symptoms and accelerated decline in lung function. Smoking asthma is also characterized by increased levels of neutrophils and macrophages, and greater small airway remodeling, resulting in increased airflow obstruction and impaired response to corticosteroid therapy. As a result, smokers are typically excluded from asthma randomized controlled trials (RCTs). The strict inclusion/exclusion criteria used by asthma RCTs limits the extent to which their findings can be extrapolated to the routine care asthma population and to reflect the likely effectiveness of therapies in subgroups of particular clinical interest, such as smoking asthmatics. The inclusion of smokers in observational asthma studies and pragmatic trials in asthma provides a way of assessing the relative effectiveness of different treatment options for the management of this interesting clinical subgroup. Exploratory studies of possible treatment options for smoking asthma suggest potential utility in: prescribing higher-dose ICS; targeting the small airways of the lungs with extra-fine particle ICS formulations; targeting leukotreines, and possibly also combinations of these options. However, further studies are required. With the paucity of RCT data available, complementary streams of evidence (those from RCTs, pragmatic trials and observational studies) need to be combined to help guide judicious prescribing decisions in smokers with asthma.     

Asthma and academic performance in urban children

BackgroundUrban minority children experience high levels of asthma morbidity. Poor school performance can be an indicator that asthma is in poor control. Little attention has been paid to examining real-time links between asthma and academic performance, particularly in high-risk groups.ObjectiveExamine 1) academic performance across a range of indicators in a group of urban children with asthma and urban children without chronic illness and ethnic differences in these associations, and 2) associations between asthma and academic performance in the group of urban children with asthma and ethnic differences in these associations.MethodsTwo hundred sixteen black/African American (33%), Latino (46%), and non-Latino white (21%) urban children, ages 7 to 9 years completed a clinic- and home-based protocol that assessed asthma and allergy status, objective measurements of lung function, and academic functioning.ResultsAnalyses revealed that children with asthma experienced a higher number of school absences when compared with healthy controls. Greater disparities in academic outcomes emerged when examining ethnic differences within the groups of children with and without asthma. Poor academic outcomes were observed in Latino children with asthma. Furthermore, a strong correspondence of poor asthma outcomes and decrements in academic performance were seen in the full sample, and these associations emerged across ethnic groups.ConclusionAsthma activity contributes to poorer academic outcomes across a range of indicators, and urban minority children with asthma, particularly Latino children, may be at heightened risk for poorer academic performance. School management guidelines for asthma need to be consistently implemented and tailored for school staff, caregivers, and students with asthma to address challenges of managing asthma within the urban school setting.     

Asthma: individual patient perspective and current unmet needs

Today there is an array of medication options to treat asthma and state-of-the-art guidelines to help diagnose and manage this chronic disease. Despite this, asthma morbidity and mortality rates are rising. There is an urgent need to direct educational programmes and health resources to address this disparity. A recent US survey of asthma patients and health-care providers disclosed that a large number of asthma patients do not fully understand what control of asthma really means and what treatments are available. They underestimate the severity of their condition and over-estimate how well their asthma is being controlled. More treatment choices provide the opportunity for better asthma control for more patients. However, more choices also mean an increased need for education so that the practitioners can determine the best treatment plan for each patient. Provider/patient communication must be enhanced to address patient cultural and lifestyle practices, including environmental exposures. These factors are as important as medication options for successful patient compliance in asthma control. This will require a change in clinician educator skills or more extensive use of ancillary asthma education in clinics. An interactive seminar for physicians on how to communicate better led to patient–physician encounters that were of shorter duration, had significant impact on the prescribing and communication behaviour of physicians, led to more favourable patient responses to physicians' actions, and led to reductions in health care services use. Not all patient educational needs can be met in brief medical visits. Patient education and patient advocate organizations are essential to supplement education given by the physician. Patient organizations help develop culturally and linguistically appropriate educational materials and they organize patient assist systems that help patients exchange information, practice advice and emotional support.