Assessment of Efficacy and Safety Issues of Current Biological Agents in Management of Asthma.

Perils of asthma research in vulnerable groups

Is Theophylline Obsolete?

Severe asthma is a highly heterogeneous disorder associated with significant morbidity. The management of severe asthma in children is multifaceted and complicated by psychosocial factors, difficulties and barriers to medication adherence, difficulties of medication delivery, and comorbid diseases. This article aims to review the approach to the management of childhood severe asthma and examine the recent literature in the advances in phenotype-directed management of severe asthma in children. Recently, more focus has been placed on the development of multidisciplinary clinics, school medication management programs, home management programs, and other interventions in order to optimize asthma management and care. Furthermore, there has been a shift in the paradigm of asthma management in children towards phenotype-directed management, especially in children with severe difficult-to-control or treatment-resistant asthma. Current treatment of pediatric severe asthma includes three approved targeted biologic phenotype-directed therapies. There are some targeted therapies that are approved for adults which may prove to be beneficial in children with asthma as ongoing research continues. Further investigation into identifying predictors of treatment response and biomarkers that can lead to precision and personalized management for children with severe asthma is ongoing and will be imperative in determining the optimal treatment strategies for pediatric severe asthma.

Monoclonal antibodies (mAbs) play a crucial role in the treatment of severe asthma. Physicians rely on patient-specific characteristics to determine the appropriate asthma classification for treatment. Currently, there are five biological agents designed to target the 'TH2-high' asthma phenotype, characterized by inflammation primarily driven by type 2 T-helper cells (TH2). This subtype is associated with severe eosinophilic asthma, marked by elevated levels of immunoglobulin E, fractional exhaled nitric oxide (FeNO), and eosinophils. In contrast, the ' TH2-low' asthma phenotype, characterized by increased sputum neutrophil counts and activation of the TH17-mediated interleukin-17 pathway, remains less understood. This review examines the role of mAbs in the management of severe asthma, with a focus on their efficacy in different asthma phenotypes. We analyze existing literature, clinical trials, and studies involving mAbs in severe asthma treatment, particularly those targeting thymic stromal lymphopoietin (TSLP). Biologics targeting 'TH2-high' asthma have shown promising outcomes, effectively reducing symptoms and exacerbations. However, the management of ' TH2-low' asthma remains a challenge due to limited therapeutic options. Recent medical trials have explored the use of mAbs, specifically TSLP-targeting mAbs, which have demonstrated significant efficacy in improving asthma control, even in ' TH2-low' phenotypes. Monoclonal antibodies have revolutionized the treatment of severe asthma, primarily focusing on the ' TH2-high' phenotype. While challenges persist in addressing ' TH2-low' asthma, recent developments, particularly TSLP-targeting mAbs, provide hope for more comprehensive asthma management across various phenotypes. Further research is needed to expand our understanding of ' TH2-low' asthma and explore additional biological agents that may be effective in its treatment. Clinicians should consider personalized treatment approaches, including mAbs, based on the specific asthma phenotype of each patient to optimize asthma management.

ABSTRACTIntroduction: Bronchial thermoplasty is a licensed non-pharmacological treatment for severe asthma.Area covered: This article considers evidence for the efficacy and safety of bronchial thermoplasty from clinical trials and observational studies in clinical practice. Its place in the management of severe asthma, predictors of response and mechanisms of action are reviewed.Expert commentary: Bronchial thermoplasty improves quality of life and reduces exacerbations in moderate to severe asthma. Morbidity from asthma is increased during treatment. Overall, patients treated in clinical practice have worse baseline characteristics and comparable clinical outcomes to trial data. Follow-up studies provide reassurance on long-term safety. Despite some progress, future research needs to investigate uncertainties about predictors of response, mechanism of action and place in management of asthma.

Severe asthma is the main cause of disability and death in patients with asthma, with a high risk of future disease, but also caused serious social and economic burden. The pathophysiological mechanisms such as obvious heterogeneity of airway inflammation, severe airway remodeling, influence of genetic factors, decreased glucocorticoid responsiveness, and many factors affecting asthma control make the treatment of severe asthma particularly difficult. In recent years, with the deepening of the understanding of the pathogenesis of asthma, especially the development of biologics targeting type 2 inflammation, a new approach has been opened up for the treatment of patients with severe asthma. How to correctly diagnose and evaluate severe asthma patients and how to choose treatment are still the perplexity and challenge in clinical practice. This expert consensus is based on the "Chinese Expert Consensus on the Diagnosis and Management of Severe Asthma" published in 2017 and combined with the latest research progress at home and abroad, and is updated on the definition, pathogenesis, diagnosis and evaluation, and treatment of severe asthma, especially the treatment recommendation for type 2 inflammatory biologics, so as to provide reference for the individualized diagnosis and treatment of severe asthma.

Pediatric health-care providers may be unaware of how best to partner with their patients’ schools to create asthma-friendly environments in which patients’ asthma health needs are communicated clearly, school heath staff are empowered and equipped to react to asthma exacerbations appropriately, and school personnel reinforce asthma health maintenance messages with families.After completing this article, readers should be able to: More than 5.5 million school-age children in the United States are diagnosed as having asthma. (1) This equates to almost 1 in 10 school-age children, making asthma the most common chronic childhood condition in the country. More than half of all children with a diagnosis of asthma have at least 1 asthma exacerbation each year. Particularly concerning, rates of pediatric asthma deaths have been increasing. In 2018, 156 children aged 5 to 17 years died of asthma. Non-Hispanic black children have a 6 times greater mortality rate from asthma complications than Hispanic white children and a 7 times greater rate than non-Hispanic white children. (1) Deaths that occur outside the clinical setting account for 13% of all asthma deaths in children.Asthma can affect a child’s academic attendance and education. Children with asthma miss more school than those without asthma and are at greater risk for missing more than 10 school days per year, a degree of absenteeism that may put them at risk for grade retention. (2)(3) Almost half of all students with asthma miss at least 1 day of school each year due to related symptoms, accounting for 13.8 million lost days. (4) Absences occur most frequently during colder months, among students with persistent rather than intermittent asthma, and among students attending a school with a part- versus full-time nurse on staff. (3)(5) Studies suggest that 1 of the peak times for ambulance-treated pediatric asthma exacerbations is around 1 pm (ie, in the middle of the school day), further underscoring the importance of school factors in contributing to students’ asthma outcomes. (6)A recent policy statement from the American Academy of Pediatrics highlights the importance of coordination of care between community-based pediatricians and other child health-care providers (hereafter referred to collectively as pediatricians) and school health staff. (7) This review article focuses on the role of pediatricians in supporting and contributing to high-quality school-based asthma management. By gaining an understanding of the challenges that schools face in promoting asthma wellness, and of how to partner with students, families, school nurses, and school staff to overcome these challenges, pediatricians can help ensure that their patients with asthma are safe, healthy, and primed to learn.The Centers for Disease Control and Prevention (CDC) Healthy Schools and the CDC’s National Asthma Control Program (NACP) have developed strategies to guide school personnel and other stakeholders in creating asthma-friendly schools. (8) Asthma-friendly schools are defined as environments that are safe for children with asthma and have policies and practices in place that support children and their caregivers in managing their asthma. The NACP recommends multiple evidence-based strategies to address asthma in schools, including supporting students in asthma self-management, educating school staff and caregivers, improving school air quality, linking students to medical providers for asthma health maintenance, allowing students to self-carry quick-relief medication (such as albuterol), and having schools stock a supply of albuterol for communal student use.In interventional studies, school-based asthma management programs have typically involved a combination of interventions designed to improve schools’ ability to identify students with asthma and assess their level of symptom control, educate high-risk students on disease management, link students to primary care providers, and/or develop protocols for managing asthma emergencies. (9)(10)(11)(12) School-based asthma interventional trials have achieved varying levels of success in terms of improving students’ quality of life and reducing their number of hospitalizations and emergency department visits. Results suggest that strong partnerships among schools, families, and health-care providers are key to programmatic success, and limitations in available resources for program implementation are a primary barrier. (12)Note that interventional trials are typically conducted in relatively highly resourced school settings with engaged stakeholders. Depending on local context, the level of medical support that can be provided to students at any given school may be very different. Although US federal laws mandate that all children have access to health services at school, individual states determine the minimum qualifications for school nurses, which may or may not include a baccalaureate degree, nursing certification, registered nursing license, and minimum amount of experience. (13) States also regulate which activities, such as administering medications, can be performed only by a registered nurse versus a licensed practical nurse. Although the American Academy of Pediatrics strongly endorses a minimum of 1 full-time registered nurse in every school, this standard is not always met. (14) Access to school nurses has been associated with improvements in chronic disease management, including reduced frequency of asthma exacerbations and absenteeism due to asthma. (14) Nonetheless, only 63% of schools have full-time nursing coverage, 19% have part-time coverage, and 18% have no nursing coverage. (15) Approximately 80% of public schools have support from a registered nurse, either full- or part-time, whereas among private schools the percentage is much lower at 35%. In addition to nurses, nearly 1 in 5 schools use volunteers, and nearly 3 of 4 schools use teachers or school staff to supplement nursing activities, including performing health promotion education.Most assessments of barriers to asthma care management at school have exclusively included schools with nurses on staff. Presumably schools without nursing staff experience even greater obstacles to the provision of quality care to students. In a survey of school nurses that sampled from a national database, 78% of respondents reported that albuterol was available at their school. (16) However, because most schools do not stock albuterol for communal student use, it is unclear how many of the respondents were simply reporting that at least 1 student at their school had access to a personal supply of albuterol brought from home. (17) In another survey of nurses from 36 predominantly urban schools in Alabama, respondents collectively reported that only 14% of students with asthma had an albuterol inhaler at school. (18) Another survey of 126 nurses from a different urban school district found that nearly three-quarters of the respondents agreed that “asthma is one of the biggest health problems I deal with among students in my school,” and “most of the kids who have to be dismissed early because of asthma symptoms could go back to class if they had an inhaler at school.” (19) These results underscore the perceived impact of asthma on student health and suggest that some asthmatic children with mild symptoms and no inhaler are being sent home, leading to higher rates of absenteeism.Beyond limited access to albuterol, school nurses have also reported that their efforts to manage students’ asthma are hampered by inadequate nurse staffing and time, limited support from school administrators, and challenges in communicating with parents and pediatricians. Other barriers cited by school nurses include a lack of knowledge about asthma management guidelines among students, parents, teachers, school personnel, pediatricians, and school nurses, as well as a lack of appreciation for school nurses’ expertise. (20)Pediatricians’ efforts to partner with schools on asthma management should begin with self-evaluation to determine whether personal clinical practice adheres to guidelines for asthma diagnosis and management. In 2007, the National Heart, Lung and Blood Institute’s National Asthma Education and Prevention Program (NAEPP) established age-based criteria for the classification of asthma based on patients’ level of risk for severe exacerbation and degree of daily impairment. (21) In 2020, the NAEPP published focused updates across 6 topic areas to the original guidelines. (22).Assessing asthma risk involves considering all of a child’s significant asthma exacerbations in the preceding year, and assessing asthma impairment involves considering all of the child’s daily symptoms in the past 2 to 4 weeks. Risk and impairment are used to classify a child’s asthma severity (intermittent, mild persistent, moderate persistent, and severe persistent) and control (well controlled, not well controlled, or very poorly controlled). The NAEPP guidelines provide standardized recommendations for therapy initiation, escalation, and de-escalation based on the child’s risk and impairment classification at the time of the assessment. For more details on asthma diagnosis and management, see the article “Asthma” in the November 2019 issue of Pediatrics in Review and the 2007 and 2020 NAEPP recommendations. (21)(22)(23)NAEPP guidelines emphasize the importance of patient and family education regarding asthma diagnosis, symptom recognition, and management. Pediatricians should provide families with asthma self-management education at the time of diagnosis and reinforce key messages routinely at follow-up visits. Messages should be tailored to a child’s level of comprehension and developmental stage to encourage engagement. Proper use of inhalers should be repeatedly reviewed using the teach-back method, with parents and older children demonstrating their ability to administer medication. Asthma education initiated in the medical home should establish concepts and language that transcend care setting.Beyond following evidence-based guidelines in caring for individual patients with asthma, pediatricians can also leverage the functionality of their electronic medical record system to optimize asthma management on a practice or population level. Specifically, pediatricians can use medical record search tools to identify their at-risk patients and patients with asthma who have had gaps in care (eg, missed appointments or lack of prescription for an indicated controller medication).Guidelines dictate that all patients with asthma have an asthma action plan that is individualized. The written asthma action plan provides individualized instructions and a roadmap for education at school to reinforce appropriate medication use by families. The treatment plan should be developed through a joint decision-making process among the pediatrician, the patient, and the patient’s family. Input from a child’s school nurse may also be helpful for proper execution of the plan at school. Coordinating educational messages via the asthma action plan and other health records shared with school health staff allows the pediatrician to be sure that families receive consistent advice across care settings.Key elements of the asthma action plan include the following (24): Many pediatricians and school systems have adopted asthma action plans with these important components. These plans often use a stoplight format designating green, yellow, and red zones to indicate the actions needed when a child is doing well, should be monitored for worsening symptoms, or requires emergency medical intervention, respectively. Helpful asthma action plan examples in English and Spanish are available for download from the American Lung Association website. (25) Of note, some schools and school districts only accept their own, approved asthma action plan as the official form authorizing school health staff to administer asthma medication to students.A 2012 survey of 1,412 health-care providers (including adult-focused health-care providers and mid-level providers) found that only 16.4% of primary care providers “almost always” gave asthma action plans to patients, and 17.6% “never” gave them to patients. (26) A 2013 CDC survey found that only half (50.8%) of parents of a child aged 0 to 17 years with asthma recalled ever having received an asthma action plan. (27)Giving an asthma action plan to a family at medical visits does not guarantee that the form reaches school health staff. Manual delivery of asthma action plans to the school nurse by families has not been found to be reliable. (28) Faxing or mailing forms to the school are other options but require accurate school information and appropriate labeling of documents because they contain protected health information that should not be shared with non–health personnel at the school. Sharing of medical forms using electronic medical record interfaces, portals, and direct secure messaging should be explored as options for communicating with schools as these tools become more widely available.Communication between pediatricians and school health staff must comply with federal privacy laws governing the exchange of protected health information. Local school districts and health organizations may have additional regulations. Misconceptions regarding the requirements of these laws and regulations pose a barrier to effective care coordination across sectors.The Health Insurance Portability and Accountability Act (HIPAA) is a US federal law that protects the privacy of patient health information held by “covered entities.” (29) Pediatricians are considered covered entities, and thus, signed parental consent for the disclosure of a child’s protected health information by the pediatrician is required; however, there are exceptions. The exchange of protected health information with other health-care providers for treatment purposes is one of those exceptions permitting pediatricians to discuss a student’s medications and plan for the provision of care with the student’s school health staff without the written authorization of the student’s parent. (30)The Family Educational Rights and Privacy Act (FERPA) is a US federal law that protects the privacy of students’ personal records held by educational agencies or institutions that receive federal funds under programs administered by the US Secretary of Education. (31) School health records are maintained as part of the students’ educational records and are, therefore, governed by FERPA, not HIPAA. Under FERPA, school health staff is not allowed to disclose information in a student’s educational record to any party outside the school without written consent from parents. As such, school health staff can request documents and forms from the pediatrician but may not share information about asthma symptoms and medication use at school, absenteeism, or school performance without parental authorization. (32) In other words, HIPAA allows the pediatrician to communicate with the school nurse regarding the child’s health without written consent. However, FERPA requires parental consent for the school nurse to share any educational record information, including student health data, with the pediatrician.Bidirectional health information exchange between pediatricians and school health staff is a key component of creating an asthma-friendly school. Obtaining parental consent for this exchange needs to be standard procedure and, ideally, should be documented in the asthma action plan. Supplementary consent documents or treatment orders can also be used. Beyond the asthma action plan, standardized forms or documents to facilitate communication between school health staff and pediatricians can be used to streamline information exchange, particularly for children with poorly controlled asthma and/or chronic absenteeism due to asthma. Such a form may include space to document details about a student’s hospital admissions, emergency department visits, urgent care visits, school health suite visits, school days missed, whether the student has an asthma action plan and medication at school, and how both health-care parties prefer to exchange documents in the future. A standardized form may also include a place to document parental consent to permit bidirectional communication between the school and the pediatrician if consent is not already captured in the asthma action plan.In 2004, the US Congress passed the Asthmatic Schoolchildren’s Treatment and Health Management Act, which gives states preference for certain sources of federal funding if they enact local laws requiring schools to permit students to access their asthma medications during the school day. (33) Complying states must require public schools to authorize students to self-carry and self-administer asthma medication if 1) a health-care provider prescribed the medication for use during school hours; 2) the student demonstrates to the health-care provider and school nurse (if available) the skill level necessary to use the medication; 3) the health-care provider has written a treatment plan guiding medication use and asthma management (ie, an asthma action plan); and 4) the student’s parent or guardian has submitted to the school the asthma action plan and any other documents required by the school related to liability. Per the Act, students must have immediate access to their asthma medication while 1) at school; 2) at school-sponsored activities, including sporting events; and 3) traveling to or from school or school-sponsored activities. The asthma action plan, any other related documents, and backup medication, if provided to the school, must all be kept in a location at school to which the student and staff have immediate access in case of emergency. The medication authorization can apply only to the school for which it was granted, and it must be renewed by the parent each school year.All states and the District of Columbia now have albuterol self-carry laws for students. Nonetheless, states differ in the amount of detail included in their local laws. Those with less-detailed legislation rely on individual schools and school systems to determine the specific policies used to implement the mandate. It has been found that schools and school systems often create policies that add restrictions beyond what is minimally required. (34) For example, school systems may require the submission of extra forms beyond the asthma action plan. They may dictate that backup medication must be new and unopened, or accompanied by the asthma action plan at the time it is received rather than working with families to collect all the necessary items piecemeal. These policies effectively limit the number of asthmatic students with access to lifesaving treatment at school. Local variation in medication access rules can also cause confusion for parents and pediatricians in terms of knowing what items need to be submitted for which school.There are multiple prerequisite steps for a student to have access to a personal supply of quick-relief medication at school: Depending on when parents initiate the process and the time it takes for all the steps to be completed, a student may not gain access to albuterol at school until the winter or spring. In such cases, it is helpful for the pediatrician to alert the family that the process will need to be repeated again in the fall for the new school year.Access to albuterol remains low despite every state passing laws allowing students access to their self-supplied asthma medications at school. (18)(19) As a result, the NACP, professional organizations such as the National Association of School Nurses, and advocacy groups such as the American Lung Association all maintain the position that schools should stock albuterol inhalers for students who experience asthma symptoms or emergencies at school and lack access to their own medication. (8)(35)(36) In addition to the inhalers, schools need spacers to ensure effective delivery of medication. School policies and procedures need to minimize any contagion risk related to the use of medications and delivery devices.Most successful legislative efforts to enact so-called stock albuterol policies for schools have been modeled on existing stock epinephrine laws. (37) Currently, all states and the District of Columbia allow or require schools to stock epinephrine. In contrast, fewer than 20 states have passed laws or provided guidelines for stock albuterol in schools, and legislative efforts at the federal level have not been successful thus far. Important considerations for creating and implementing stock albuterol policies include the following: Toolkits and recommendations are available to help guide efforts to enact stock albuterol policies and programs, including from the American Lung Association (https://www.lung.org/), the National Association of School Nurses (https://www.nasn.org/home), and state agencies that have succeeded in such efforts. (35)(38)(39)(40)Some early adopters of stock albuterol policies have found promising results. For example, the state of Missouri enacted its stock albuterol legislation in 2012. Data collected in the 2013–2014 school year revealed that 981 students received stock albuterol, with 86% of those students returning to the classroom. (41) A low-income urban district in Arizona saw a 20% reduction in 911 calls and a 40% reduction in medical transports to the emergency department after implementing a stock albuterol policy that delivered 222 albuterol doses to 55 children at 22 schools. (42)Importantly, establishing a stock albuterol program does not replace the necessary components for the appropriate clinical diagnosis and management of asthma, such as effective communication between pediatricians and school health staff, use of an asthma action plan, and ongoing asthma self-management education for patients and families. Rather, stock albuterol should be viewed as 1 important tool among many in the toolbox for creating asthma-friendly school settings.Daily use of inhaled corticosteroids, with or without concomitant long-acting beta2-agonist (LABA) therapy depending on age and asthma severity, is recommended for many children who meet the NAEPP’s definition of having persistent asthma. (21) add Ref: National Asthma Education and Prevention Program Expert Panel. 2020 Focused Updates to the Asthma Management Guidelines. National Heart Lung and Blood Institute; December 2020. Poor adherence to prescribed use of a daily inhaled corticosteroid as a controller medication among children with persistent asthma is associated with lower quality of life and increased frequency of asthma exacerbation, sleep disruption, and school absence. (21)(43) Nonetheless, mean adherence among children with their prescribed inhaled corticosteroid regimen is likely less than 50%. (44)(45)(46) The school nurse may be an underused resource for achieving asthma control for students with persistent asthma, poor adherence to an inhaled corticosteroid regimen, and high asthma morbidity. In addition to providing outreach to families to educate them about the need for improved asthma control, school nurses may administer daily inhaled corticosteroid medication to students.To implement school-based asthma controller therapy, the pediatrician prepares an asthma action plan with separate for inhaled corticosteroid use or without on school days versus to be shared with the student’s family and school nurse. school the student to the health suite on that typically be daily is administered all at by the school nurse. and on other days that school is not in students or parents administer and doses of the controller medication at to of school-based asthma controller therapy are School-based asthma controller therapy is only at schools with an nurse to administer In plans must be to the of 2 controller medication at a Although most will only 1 per without some will authorize the of a for school use for children with a of high health-care for asthma school nurses and parents must be able to maintain an of communication because the parent must supply the school nurse with a new controller medication each Pediatricians can parents that the US delivery of medications, and parents can for to go to the school. delivery to the school needs to be and with school staff. all the school-based asthma controller therapy is most for students with very poor asthma control who are at high risk for morbidity. In such cases, it can be well the necessary to for school-based asthma controller therapy because multiple trials have it to be associated with fewer and symptoms, a greater number of days without any symptoms, and albuterol use and frequency of urgent care visits.

This study provides an overview of the consequence of the use of oral corticosteroid in the treatment of severe asthma in adults; it also identified recent evidence based alternative drug regimen for asthma management to prevent long term negative effect of oral corticosteroids. Asthma is a chronic inflammatory airway disease affecting about 300 million people globally. Approximately 4% to 8% of asthma patient’s symptoms remain uncontrolled and exacerbations occur frequently despite high-intensity treatment, hence the need for corticosteroid treatment for sustain symptom control and to prevent flare-ups. Oral corticosteroids are powerful anti-inflammatory medicine which helps by quickly reducing the swelling in the lungs. There is no doubt that the use of oral corticosteroids (OCS) plays a vital role in the management of asthma, particularly in the management of acute exacerbations and severe asthma. However, there is clinical evidence that both long- and short-term use of corticosteroids in asthma has complicated relationship with some referring to them as a ‘frenemy, as side effect of oral corticosteroids has detrimental effect on quality of life of asthma patients. The study utilized literature review of web-based articles and journals using multiple databases. Studies both on short term and long- term use of OCS was reviewed to have better understanding of the subject matter. Studies in children populations were excluded as the focus of this study is on adult patients living with asthma. Following the literature search, ten articles met the inclusion criteria and were selected. The study concluded that due to widely acknowledged side effects, and advances in care, there is clinical support for a shift away from a reliance on OCS in the treatment of severe asthma to other alternative management.

Update on the NAEPPCC Asthma Guidelines: The wait is over, or is it?

Severe therapy-resistant asthma has been defined as "asthma which requires treatment with high dose inhaled corticosteroids (ICSs) plus a second controller (and/or systemic corticosteroids) to prevent it from becoming 'uncontrolled' or which remains 'uncontrolled' despite this therapy". Patients who usually present with 'difficult-to-treat asthma' should first be assessed to determine whether he/she has asthma with the exclusion of other diagnoses and if so, whether the asthma can be classified as severe therapy-resistant. This necessitates an assessment of adherence to medications, confounding factors, and comorbidities. Increasingly, management of severe therapy-resistant asthma will be helped by the determination of phenotypes to optimize responses to existing and new therapies. Severe asthma patients are usually on a combination of high dose ICS and long-acting β-agonist (LABA) and, in addition, are often on a maintenance dose of oral corticosteroids. Phenotyping can be informed by measuring blood eosinophil counts and the level of nitric oxide in exhaled breath, and the use of sputum granulocytic counts. Severe allergic asthma and severe eosinophilic asthma are two defined phenotypes for which there are efficacious targeted biologic therapies currently available, namely anti-immunoglobulin E (IgE) and anti-interleukin (IL)-5 antibodies, respectively. Further progress will be realized with the definition of noneosinophilic or non-T2 phenotypes. It will be important for patients with severe asthma to be ultimately investigated and managed in specialized severe asthma centers.

We studied the usefulness of 18 weeks of therapy with two high doses of inhaled beclomethasone dipropionate (BDP) in the management of severe asthma in adults. The patients had asthma symptoms that had not been controlled by combination therapy with BDP (800 micrograms/day) and bronchodilators. They were divided into two groups. Patients in group A (n = 16) were treated with 1800 micrograms/day of BDP and bronchodilators. Patients in group B (n = 10) were treated with 1400 micrograms/day of BDP and bronchodilators. BDP was inhaled via a large spacer (Volumatic). Eleven patients in group A and 6 patients in group B had been given an oral steroid regularly before the study. Asthma symptom scores, peak expiratory flow (PEF), pulmonary function, bronchial reactivity to methacholine, the total amount of oral steroid, and adrenocortical function were recorded. Results. 1) Clinical characteristics before the start of the study did not differ between groups. 2) Asthma symptom scores decreased to a greater extent in patients who received the higher dose of BDP than in those who received the lower dose. 3) Only the higher dose of BDP significantly increased evening and morning % PEF, as measured 6 weeks and 8 weeks after the start of the treatment. 4) Only the higher dose of BDP significantly increased the FEV1 and the PC20 for methacholine. FVC did not increase. 5) Only the higher dose of BDP significantly decreased the total amount of oral steroid needed to control asthma. 6) Results of the rapid ACTH test indicated that neither dose of BDP suppressed adrenocoritical function. Furthermore, the serum cortisol level measured early in the morning increased to within the normal range in the three patients in whom oral steroid therapy could be reduced or stopped after treatment. These data indicate that 1800 micrograms of BDP per day is more effective than 1400 micrograms/day at the beginning of long-term management of severe chronic asthma in adults whose symptoms are not controlled with the combination of 800 micrograms/day BDP and bronchodilators. Therapy with a higher dose (at least 1600 micrograms/day) of an inhaled steroid is more useful and should be promptly begun to treat severe asthma.

PurposeBronchial thermoplasty is approved in many countries worldwide as a non-pharmacological treatment for severe asthma. This review summarizes recent publications on the selection of patients with severe asthma for bronchial thermoplasty, predictors of a beneficial response and developments in the procedure and discusses specific issues about bronchial thermoplasty including effectiveness in clinical practice, mechanism of action, cost-effectiveness, and place in management.ResultsBronchial thermoplasty is a treatment option for patients with severe asthma after assessment and management of causes of difficult-to-control asthma, such as nonadherence, poor inhaler technique, comorbidities, under treatment, and other behavioral factors. Patients treated with bronchial thermoplasty in clinical practice have worse baseline characteristics and comparable clinical outcomes to clinical trial data. Bronchial thermoplasty causes a reduction in airway smooth muscle mass although it is uncertain whether this effect explains its efficacy since other mechanisms of action may be relevant, such as alterations in airway epithelial, gland, and/or nerve function; improvements in small airway function; or a placebo effect. The cost-effectiveness of bronchial thermoplasty is greater in countries where the costs of hospitalization and emergency department are high. The place of bronchial thermoplasty in the management of severe asthma is not certain, although some experts propose that bronchial thermoplasty should be considered for patients with severe asthma associated with non-type 2 inflammation or who fail to respond favorably to biologic therapies targeting type 2 inflammation.ConclusionBronchial thermoplasty is a modestly effective treatment for severe asthma after assessment and management of causes of difficult-to-control asthma. Asthma morbidity increases during and shortly after treatment. Follow-up studies provide reassurance on the long-term safety of the procedure. Uncertainties remain about predictors of response, mechanism(s) of action, and place in management of severe asthma.

The era of multiple biologics: Is combination and switching an option in the management of severe asthma?

For decades, a small proportion of individuals with asthma, the 3–10% with severe disease, have suffered the consequences of treatment refractoriness, toxicity from add-on therapies and misdiagnosis. This has resulted in severe quality of life impairment,1 unacceptable asthma mortality2 and major economic costs to patients and their families, the health care system and society.3 Clinicians and patients have been left unarmed in the battle to achieve the therapeutic goals of management. However, with an era of precision-based medicine, now comes renewed hope for severe asthma management, for patients and clinicians alike. This review series 'Seeking Innovative Solutions in Severe Asthma' is therefore timely. There is a need to prioritize severe asthma research and we hope that this review series has promoted ideas and challenged thinking. For the series, we set the goal of highlighting important and contemporary issues such as the complexity of severe asthma disease mechanisms, considerations for management and gaps for knowledge transfer and implementation.4 Global leaders were invited to contribute to the series. We take the opportunity to thank all of the authors and acknowledge their outstanding contributions, which have made this series a valuable resource to guide and inform the clinical and research community. What were the common themes that emerged during this review series? It is clear that in both paediatric and adult populations, assessment and diagnosis of severe asthma are difficult. Effective management requires systematic, multidimensional, multidisciplinary and targeted approaches. There have been many notable advances in targeted therapies, supported by an improved understanding of disease mechanisms in clinical population and animal models. However, knowledge gaps remain in relation to disease pathophysiology, approaches to assess inflammatory phenotypes, mechanisms and what components are required for multidisciplinary assessment (MDA). Furthermore, implementation gaps exist on how to integrate new knowledge into the clinic and how to address disease complexity. The first manuscript of the review series reported the proceedings of roundtable discussions that were hosted by the Centre of Excellence in Severe Asthma and focused on two key areas: models of care for severe asthma and targeted therapies.5 The discussions of multidisciplinary experts from around Australia noted the variability in severe asthma definitions used and in approaches to clinical practice. McDonald et al. highlighted proposed recommendations to improve the quality and consistency of care and areas for future research. The need to identify and address access barriers to new targeted therapies and to develop better ways of determining treatment response were acknowledged as priority areas. The Centre of Excellence in Severe Asthma is progressing this area and has developed and made available clinical recommendations for the use of biological agents in practice, which is available at http://www.severeasthma.org.au/tools-resources/toolkits/. Improving asthma treatment and reducing disease burden requires an understanding of disease pathophysiology. King et al. discuss the structural, mechanical and inflammatory abnormalities relevant to severe asthma.6 King et al. eloquently describe how our understanding of the pathogenesis of severe asthma has been limited by the heterogeneity and complexity of disease processes and the difficulty performing studies in relevant clinical populations.6 Biomarkers are key to phenotyping patients and selecting those most likely to respond to individualized therapies. Fricker et al. painted an insightful view of the use of biomarkers, as an approach to assess and characterize underlying disease mechanisms.7 Novel ways to use existing biomarkers to objectively assess adherence to corticosteroids and to identify patients likely to respond to targeted therapies were described. They also recognized that limited biomarkers are available for other disease subsets, such as non-type-2 inflammation, and that future research needs to be focused here. As more biomarkers are reported, consensus is required on which to measure and how to use test results to inform clinical decision-making. Dynamic model systems are essential tools to characterize disease mechanisms and for preclinical studies of novel therapeutics. Maltby et al. provide an update on mouse models relevant to severe asthma.8 New approaches are providing insight into mechanisms underlying steroid resistance, tissue remodelling and disease exacerbations. Translation of findings from these models will require further careful characterization in clinical population. Bush et al. provide insight into severe asthma in children, highlighting the differences between paediatric and adult diseases.9 They discuss the difficulty in differentiating between 'difficult asthma', 'asthma plus comorbidities' and 'severe treatment-refractory asthma'. Similar to the approaches proposed in the management of adult severe asthma, management in the paediatric population requires approaches that recognize and address multiple factors that affect asthma disease outcomes, through multidisciplinary team input. Novel mechanistic insights in the paediatric population implicate interleukin 33 (IL-33) and innate lymphoid cells in disease pathogenesis and suggest that increased intra-epithelial neutrophils are associated with better asthma outcomes. Finally, the authors call for increased international collaboration to conduct randomized controlled trials (RCTs) of targeted treatments in the paediatric population. Management of comorbidity in the asthma population can improve patient outcomes. Porsbjerg and Menzies-Gow provide an overview of the prevalence and clinical impact of common comorbidities in severe asthma, and recommend diagnostic and management approaches.10 They emphasize the need to recognize and manage comorbidities as part of the systematic assessment and in confirming diagnosis. RCTs are required to determine the effect of treating specific comorbidities in severe asthma and further clarification is necessary to determine how comorbidities interact with different asthma phenotypes. A key aspect in a number of the publications in this series relates to the systematic or multidimensional assessment of severe asthma.5, 9, 10 Whilst this approach is a key recommendation of severe asthma guidelines,11 no level I or II evidence have been published reporting its effect. Clark et al. aimed to address this gap in knowledge by conducting a systematic review and meta-analysis of studies that reported multidimensional assessment of severe asthma.12 An important observation of this review was that whilst this approach is recommended, only six studies have reported outcomes. In the three studies that performed comparable outcome assessments, MDA improved patient health status, asthma control and reduced exacerbations. However, no RCT have been performed to determine the effect of MDA in severe asthma. Thus, again highlighting an important research area. Our purpose in this series was to generate discussion and interest in novel and innovative severe asthma research and clinical practice, accordingly our choice of topics and invited authors reflects our goals. It is an exciting time for severe asthma patients, clinicians and researchers, and we need to continue to champion the severe asthma agenda in order to improve the lives of patients with this debilitating and difficult disease. We hope that this review series has helped to achieve this. Further progress is urgently needed to address existing knowledge gaps, to integrate recent advances into clinical care and to improve patient outcomes. It's time to fix the previously considered unfixable! V.M.M. is supported by an NHMRC TRIP Fellowship, has participated in educational symposia funded by GlaxoSmithKline, AstraZeneca and Menarini and has participated in advisory boards for GlaxoSmithKline, Novartis, AstraZeneca and Menarini. P.G.G. holds an NHMRC Practitioner Fellowship, has participated in educational symposia funded by AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline and Novartis, and has participated in studies funded by GlaxoSmithKline and AstraZeneca.

Diagnosis and Management of Severe Asthma in Switzerland: Analysis of Survey Results Conducted with Specialists and General Practitioners