Annals of Thoracic Medicine
GUIDELINES
Year
: 2019  |  Volume : 14  |  Issue : 1  |  Page : 3--48

The Saudi Initiative for Asthma - 2019 Update: Guidelines for the diagnosis and management of asthma in adults and children


Mohamed S Al-Moamary1, Sami A Alhaider2, Abdullah A Alangari3, Mohammed O Al Ghobain1, Mohammed O Zeitouni4, Majdy M Idrees5, Abdullah F Alanazi1, Adel S Al-Harbi6, Abdullah A Yousef7, Hassan S Alorainy8, Mohamed S Al-Hajjaj9,  
1 Department of Medicine, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
2 Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
3 Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia
4 Department of Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
5 Respiratory Division, Department of Medicine, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
6 Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
7 Department of Pediatrics, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
8 Department of Respiratory Care, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
9 Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates

Correspondence Address:
Prof. Mohamed S Al-Moamary
Department of Medicine, College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh
Saudi Arabia

Abstract

This is the fourth version of the updated guidelines for the diagnosis and management of asthma, developed by the Saudi Initiative for Asthma (SINA) group, a subsidiary of the Saudi Thoracic Society. The main objective of the SINA is to have guidelines that are up to date, simple to understand, and easy to use by healthcare workers dealing with asthma patients. To facilitate achieving the goals of asthma management, the SINA panel approach is mainly based on the assessment of symptom control and risk for both adults and children. The approach to asthma management is now more aligned for different age groups. The guidelines have focused more on personalized approaches reflecting better understanding of disease heterogeneity with integration of recommendations related to biologic agents, evidence-based updates on treatment, and role of immunotherapy in management. The medication appendix has also been updated with the addition of recent evidence, new indications for existing medication, and new medications. The guidelines are constructed based on the available evidence, local literature, and current situation at national and regional levels. There is also an emphasis on patient–doctor partnership in the management that also includes a self-management plan.



How to cite this article:
Al-Moamary MS, Alhaider SA, Alangari AA, Al Ghobain MO, Zeitouni MO, Idrees MM, Alanazi AF, Al-Harbi AS, Yousef AA, Alorainy HS, Al-Hajjaj MS. The Saudi Initiative for Asthma - 2019 Update: Guidelines for the diagnosis and management of asthma in adults and children.Ann Thorac Med 2019;14:3-48


How to cite this URL:
Al-Moamary MS, Alhaider SA, Alangari AA, Al Ghobain MO, Zeitouni MO, Idrees MM, Alanazi AF, Al-Harbi AS, Yousef AA, Alorainy HS, Al-Hajjaj MS. The Saudi Initiative for Asthma - 2019 Update: Guidelines for the diagnosis and management of asthma in adults and children. Ann Thorac Med [serial online] 2019 [cited 2019 May 26 ];14:3-48
Available from: http://www.thoracicmedicine.org/text.asp?2019/14/1/3/249804


Full Text

 Introduction



Asthma is a common heterogeneous inflammatory chronic disorder of the airways. It is “defined by the history of respiratory symptoms such as wheeze, shortness of breath, chest tightness, and cough that vary over time and in intensity often with variable expiratory airflow limitation can be demonstrated.”[1],[2] Asthma is one of the most common chronic diseases in Saudi Arabia, with increasing prevalence.[3] It has significant impact on patients, their families, and the community as a whole in terms of lost work and school days, poor quality of life, frequent emergency department (ED) visits, hospitalizations, and deaths.[4],[5],[6],[7],[8],[9],[10]

As part of the commitment of the Saudi Thoracic Society (STS) toward a long-term enhancement plan for promoting best practice in the field of respiratory diseases, the Saudi Initiative for Asthma (SINA) was launched in 2008 with special attention to nonasthma specialists, including primary care and general practice physicians.[11],[12],[13],[14] Sections related to asthma in children represent the views of a panel from the Saudi Pediatric Pulmonology Association, another subsidiary of the STS. The Saudi Allergy Asthma and Immunology Society has also contributed to this update. The SINA guidelines received a comprehensive update from the previous 2016 version with an emphasis on personalized approaches, reflecting better understanding of disease heterogeneity, with integration of recommendations related to biologic agents, evidence-based updates on treatment, and role of immunotherapy in management. The medication appendix was also updated with the addition of recent evidence, namely new indications for existing medication and new medications.

The SINA panel is a group of Saudi experts with well-respected academic backgrounds and experience in the field of asthma. Since the SINA aims to have updated guidelines, which are simple to understand and easy to use, the SINA expert panel realized the need to update the current guidelines with the available new evidence, new medications, new indications for existing medications, and changes in current practices. To streamline recommendations, the SINA expert panel has stratified the guidelines based on the following age groups: adults: age above 18 years; adolescents: age ≥13–18 years; and children who were stratified into two groups: 5–12 years and <5 years.

 Methods



The SINA guidelines document was initially based on the Global Initiative for Asthma strategies with reference to related major international guidelines.[1],[2] The SINA is supplemented by the available local literature and the current setting in Saudi Arabia. Consensus among the SINA panel was followed whenever there was lack of evidence.[15] The following criteria are used to grade the evidence:

Evidence Category A: Randomized controlled trials with rich body of dataEvidence Category B: Randomized controlled trials with limited body of dataEvidence Category C: Nonrandomized trials and observational studiesEvidence Category D: SINA panel consensus judgment. This category is only used in cases where the provision of some guidance was deemed valuable, but the clinical literature addressing the subject was insufficient to justify placement in one of the other categories.

For this update, the same approach used in previous updates has been employed, whereby each section has been internally reviewed by at least two other members. The SINA panel conducted frequent round-table discussions and online discussions. A panel of international experts reviewed that the guidelines and their recommendations were thoughtfully considered.

 Epidemiology



Asthma is one of the most common chronic illnesses in Saudi Arabia and local reports suggest that the prevalence of asthma is increasing.[16],[17],[18],[19] Inadequate knowledge, unfamiliarity with new drugs, and lack of awareness of the importance of disease control are common among primary care physicians who care for asthma patients in Saudi Arabia.[16],[20] In addition to these key factors, there are other attributes to the magnitude of disease burden, such as socioeconomic status, number of siblings, knowledge of caregivers, and income.[21],[22],[23],[24],[25],[26] Consequently, many asthma patients are uncontrolled and continue to be under-diagnosed, under-treated, and at risk of acute attacks, resulting in missed work or school, increased use of expensive acute healthcare services, and reduced quality of life.[16],[27] This was also observed among pregnant women with asthma as one study from Saudi Arabia showed that almost half of pregnant women had the intention to stop asthma medications during pregnancy.[28]

A meta-analysis on the variation in prevalence of asthma in different regions in Saudi Arabia showed a rise in the asthma prevalence from 1990 to 2000 with stabilization in the prevalence of asthma since 2000.[29] The pooled weighted prevalence rate of asthma was 14.3%, lifetime wheeze was 16.5%, and rhinitis was 21.4%. The overall prevalence of asthma in children from Saudi Arabia has been reported to range from 8% to 25%, based on studies conducted over the past three decades. The increasing prevalence of asthma in the past three decades may be attributed to rapid lifestyle changes related to the modernization of Saudi society, changes in dietary habits, and exposure to environmental factors, such as indoor allergens, dust, sand storms, and tobacco. In addition, this high prevalence of asthma could be attributed to an increase in asthma awareness in the general population and among healthcare workers, allowing more individuals to be diagnosed. Other explanations have attributed the increased prevalence to the hygiene hypothesis, which proposes that there is a lack of sufficient microbial exposure early in life due to pharmacological manipulations and vaccines.[30]

Most of the studies investigating the prevalence of asthma in various countries have focused on children age below 15 years or adults aged above 18 years. A study conducted by the STS investigated the prevalence of asthma and its associated symptoms in 16–18 years adolescents attending high schools in the city of Riyadh. This study utilized the International Study of Asthma and Allergies in Children (ISAAC) questionnaire tool. Of 3073 students, the prevalence of lifetime wheeze, wheeze during the past 12 months, and physician-diagnosed asthma was 25.3%, 18.5%, and 19.6%, respectively. The prevalence of exercise-induced wheezing and night coughing in the previous 12 months was 20.2% and 25.7%, respectively. The prevalence of rhinitis symptoms in students with lifetime wheeze, physician-diagnosed asthma, and exercise-induced wheeze was 61.1%, 59.9%, and 57.4%, respectively. Rhinitis symptoms were significantly associated with lifetime wheeze, physician-diagnosed asthma, and exercise-induced wheeze.[31] By utilizing the ISAAC questionnaire method, another study conducted among 5188 primary schoolchildren in Madinah showed that the prevalence of asthma was 23.6%, while 41.7% had symptoms suggestive of at least one allergic disorder.[32] A national Saudi household survey was conducted in 2013 estimated that the self-reported clinical diagnosis of asthma to be 4.05%.[33] Another survey using the European Community Respiratory Health Survey questionnaire conducted in Riyadh among a total of 2405 Saudi nationals aged 20–44 years showed that the prevalence of wheezing in the last 12 months was 18.2% and physician-diagnosed asthma reported was 11.3%. There were no significant differences between asthmatic and nonasthmatic patients with respect to living area, level of education, and vaping history.[3]

Inadequate knowledge, lack of familiarity with new drugs, and lack of awareness of the importance of disease control are common among primary care physicians who care for asthma patients in Saudi Arabia.[16],[20] In addition to these key factors, there are other attributes to the magnitude of disease burden, such as socioeconomic status, number of siblings, knowledge of caregivers, and income.[21],[22],[23],[24],[25],[26] Consequently, many asthma patients are uncontrolled and continue to be under-diagnosed, under-treated, and at risk of acute attacks resulting in missed work or school, increased use of expensive acute healthcare services, and reduced quality of life.[16],[27] This was also observed among pregnant women with asthma as one study from Saudi Arabia showed that almost half of pregnant women had the intention to stop asthma medications during pregnancy.[28]

 Pathophsiology of Asthma



Asthma is a chronic inflammatory airway disease that results in narrow airway lumen. The airway narrowing is caused by increased mucus secretion as well as bronchial wall thickening due to edema, smooth muscle hypertrophy, and subepithelial fibrosis. The pathophysiological mechanisms that underlie these changes are diverse and heterogeneous [Box 2.1]. They are driven by a variety of cell types including immune cells; mainly T-helper cells (Th2, Th17, Th1), mast cells, eosinophils, and neutrophils; as well as structural bronchial cells such as epithelial cells, myofibroblasts, and smooth muscle cells.[34] These mechanisms are broadly classified into four categories:[INLINE:1]

Type 2 eosinophilic inflammation: This is the most common type and includes at least 60% of all asthma patients. It is defined by sputum eosinophilia of ≥2% of leukocytes in a sample. Patients frequently have blood eosinophilia of ≥300/μl. Eosinophils secrete mediators such as major basic protein and eosinophil cationic protein that can cause bronchial epithelial damage and fibrosis. Those patients usually respond well to inhaled corticosteroids (ICS), especially if they have mild or moderate disease. It is further subdivided into two types:

Early-onset allergic eosinophilic airway inflammation (extrinsic asthma): This type usually starts in childhood and can be triggered by allergen exposure. Allergens are taken up by dendritic cells and presented to naive T-cells that develop into Th2 cells characterized by the secretion of type 2 cytokines: interleukin (IL)-4, IL-5, and IL-13. IL-4 and IL-13 are necessary for specific B-cell activation and switching into immunoglobulin E (IgE)-producing cells. IgE binds to its high affinity receptor on mast cells. Subsequent cross-linking of IgE molecules by the allergen will lead to mast cell degranulation and release of mediators, such as histamine and tryptase as well as type 2 cytokines. In addition, IL-13 causes smooth muscle and goblet cell hyperplasia. On the other hand, IL-5 is essential for eosinophil development and maturation and contributes with certain other chemokines to their recruitment to the bronchial airways [35],[36]Late-onset nonallergic eosinophilic airway inflammation (intrinsic asthma): This type usually starts during adulthood. Patients typically have no allergies but usually more severe airway limitation and airway hyperresponsiveness (AHR). It is triggered by microbes (bacteria and viruses), pollutants, and irritants. Bronchial epithelial cells will subsequently release IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) that will stimulate innate lymphoid cells type 2 to release IL-5 and IL-13.[37]

Neutrophilic inflammation: It variably defined as neutrophils of ≥40%–60% of leukocytes in an induced sputum sample. It is less clearly characterized and involves release of Th1-and Th17-related cytokines and IL8 and Granulocyte-macrophage colony-stimulating factor (GM-CSF) that attracts neutrophils to the airways. It is triggered by infections, irritants, and tobacco smoke and may be a manifestation of the use of steroids in patients with eosinophilic inflammation. Those patients are mostly adults and do not respond to ICS as well [38]Mixed inflammation: This type has features of both eosinophilic and neutrophilic inflammation, including their cytokines profile. It is less common than the two previous types and tends to be more severe and more difficult to treat [39]Paucigranulocytic phenotype: In this form, there is not as much inflammation. The airway limitation is supposedly driven by other mechanisms. It is the least common and patients usually have milder disease.[40]

Airway hyperresponsiveness

This is a major feature of all asthma phenotypes. Its mechanisms and mediators are poorly understood. It worsens during and immediately after asthma attacks. It is usually worse in patients with severe asthma. However, it does not correlate well with markers of inflammation. Smooth muscle hypertrophy and neurohumoral factors may play a role in determining AHR.[41]

Airway remodeling

This is a major feature of asthma that starts early in the disease and causes incomplete reversibility by bronchodilator. It is characterized by bronchial epithelial damage, thickening of the basement membrane, and muscle hypertrophy.[42],[43] It is influenced by ongoing airway inflammation and recurrent bronchoconstriction.[44]

Acute asthma

The pathophysiology of acute asthma is less clear due to the limited information. This is because of the difficulty in studying disease pathology and obtaining samples during the attack. The pathological manifestations generally depend on the trigger. At least 80% of cases of moderate-to-severe acute asthma are triggered not only by viruses, most commonly rhinovirus, but also by respiratory syncytial and influenza viruses.[45] Viral infections can cause significant epithelial damage, and symptoms tend to be more severe and last longer. On the other hand, allergen- or irritant-triggered attacks tend to be milder and resolve more quickly. Recurrent attacks may lead to progressive decline in lung function and increasing baseline asthma severity.[46],[47],[48]

 Diagnosis of Asthma in Adults and Adolescents



The diagnosis of asthma is based on clinical assessment by a detailed history and physical examination supported by spirometry with reversibility testing.

History

The symptoms of wheezing, cough, shortness of breath, and chest tightness are not specific for asthma and can be seen with other pulmonary diseases. However, the combination of these symptoms increases the probability of asthma. The pattern of symptoms is usually varying over time and the patient may be entirely asymptomatic between attacks.[49],[50] Symptoms are usually worse at night, particularly in children, and can be provoked by exercise or other triggering factors, such as viral infections and/or smoke. Asthma diagnosis can be supported by taking detailed history including patient's occupation, family history of asthma, other allergic disorders, and smoking and vaping. [Box 3.1] lists the relevant questions that are commonly considered when taking a history where the diagnosis of asthma is under consideration. Asthma control may be worsened by coexisting symptomatic gastroesophageal reflux disease (GERD), rhinosinusitis, obesity, sleep disorders, or the use of some medications, such as beta-blockers and nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin (ASA).[51],[52] Asthma and rhinosinusitis commonly coexist.[53],[54][INLINE:2]

Physical examination

It is important to note that the examination of the chest may be normal in stable and controlled asthma, but the presence of bilateral expiratory widespread, high-pitched, variable musical wheezing is a characteristic feature of asthma. This may be accompanied by shortness of breath or diminished oxygen saturation. Examination of the upper airways is important to look for evidence of allergic rhinitis, such as mucosal swelling, nasal polyps, and postnasal dripping. Other allergic manifestations, such as atopic dermatitis, also support the diagnosis of allergic asthma.[49],[55] The presence of a localized wheeze, crackles, stridor, clubbing, or heart murmurs should suggest alternative diagnoses.[56],[57] Therefore, a careful consideration of any alternative diagnoses before commencing asthma treatment by a physician should be made.

Investigations

Spirometry is necessary to confirm airflow obstruction and demonstrates significant reversibility by performing a spirometry. The degree of significant reversibility is defined as an improvement in forced expiratory volume in the 1st s (FEV1) ≥12% and ≥200 ml from the prebronchodilator value.[58] It may also help identify other alternative diagnoses such as upper airway obstruction. However, normal spirometry or failure to show reversibility does not rule out the diagnosis of asthma as it can be normal with the patient still being symptomatic.[59] Serial peak expiratory flow rate (PEFR) measurements may be helpful in the diagnosis of asthma by showing the characteristic increased variability and for follow-up after starting treatment. Bronchoprovocation testing is another tool to rule out asthma with atypical presentation and normal spirometry, but it is not routinely required. A diagnostic therapeutic trial with an ICS and a bronchodilator combination may be useful in confirming a diagnosis when it shows a favorable response.[60]

Chest X-ray (CXR) is not routinely recommended unless the diagnosis is in doubt, when symptoms are not typical or suggest alternative diagnoses. Peripheral eosinophilia and elevated IgE level are supportive of the diagnosis but are not routinely recommended unless dealing with moderate-to-severe asthma. Exhaled nitric oxide is an alternative method for detecting airway inflammation in eosinophilic asthma, but it is not widely available and can be suppressed with the use of ICS and in smokers.[61] Skin prick testing and radioallergosorbent test (RAST) may be helpful in identifying allergens to which the patient has been sensitized and in developing a strategy for avoiding allergen exposure.[62]

 Clinical Assessment in Adults and Adolescents



Principles of asthma assessment

The principles of optimal asthma management should initially consist of an assessment of asthma control.[63],[64] Before commencing a patient on treatment, the SINA expert panel recommends ensuring the following:

Assessment of asthma control bring [Box 4.1]Performance of pulmonary function testing with spirometry and/or PEFR to assess for airflow limitations and postbronchodilator reversibilityDocumentation of current treatment and any related issues such as side effects, adherence, and inhaler techniqueUtilization of a written asthma action planAssessment of comorbidities such as rhinosinusitis, GERD, obesity, obstructive sleep apnea, anxiety, and exercise-induced laryngeal obstruction [65]Close monitoring for patients with severe asthma and history of asthma attacksThe use of expectorated sputum eosinophilia and exhaled nitric oxide analysis in the assessment of asthma control are not recommended in routine practice.[INLINE:3]

Asthma-control test

Asthma severity was historically used as the entry point to determine the management strategy. This trend was replaced by the concept of asthma control.[66] Asthma control is a reflection of the adequacy of management by describing the clinical status of a patient as controlled, partially controlled, or uncontrolled. The control status may vary markedly over time and is recommended to entail short-term assessment of current asthma status, asthma burden, and medical management.[67] Focusing on asthma control may improve patient perceptions and expectations that improve symptoms reporting and subsequently treatment decisions by clinicians.[67]

The SINA expert panel recommends the utilization of asthma-control test (ACT) to initiate asthma treatment in adults and adjust it at follow-up.[68],[69],[70] The ACT is a commonly used tool to assess asthma control. It is a short, validated, self-administered questionnaire to assess asthma control Bring [Box 4.2]. It consists of five items including limitation of activity, shortness of breath, frequency of night symptoms, use of rescue medication, and rating of overall control of the disease over the past 4 weeks.[71] The score of ACT is the sum of the five questions where each is scored from 1 (worst) to 5 (best), leading to a maximum best score of 25. The clinically important significant change in ACT score is considered to be ≥3 units.[72] The level of asthma control is categorized into:[70],[71],[73][INLINE:4]

Controlled: An ACT score of ≥20Partially controlled: An ACT score of 16–19Uncontrolled: An ACT score of <16.

Assessment when control is not achieved

If asthma control is not achieved at any step during therapy, the SINA expert panel recommends assessing the following:

Medications and doses currently usedPatient's adherence and correct technique in using devicesSelection of the appropriate device and appropriate prescription of spacer with metered-dose inhaler (MDI) deviceObstacles taking prescribed the medications (e.g., cost, time, patients' concerns lack of perceived need)Environmental exposure to allergensAssessment of comorbidities such as rhinosinusitis, GERD, obesity, obstructive sleep apnea, and anxietyFuture risk of attacks and fixed airflow obstruction.

Assessment of risk factors for future asthma attacks

The future risk of adverse outcomes should be assessed. This is achieved by assessing future risk of attacks, fixed airflow obstruction, and adverse effect of medications. The SINA expert panel recommends assessment of risk factors for poor asthma outcomes, especially in patients experiencing attacks.[2] The presence of one or more of the following risk factors increases the risk of attack despite controlled asthma status:

High usage of relievers medication [2]ICS use [2]Low FEV1[2]Previous intensive care unit (ICU) admission [2]Severe asthma attack in the previous 12 months [2]Major psychological disorders or reduced socioeconomic status [2]Continuous exposure to allergens [2]Presence of comorbiditiesActive smoking and vapingFrequent use of oral steroidsPersistently elevated sputum or blood eosinophilia [2]Pregnancy.[2]

Asthma severity assessment in clinical practice

There is a trend in clinical practice to retrospectively assess asthma severity based on the step of treatment required to control symptoms and attacks.[74],[75],[76],[77] Before classifying asthma severity, it is essential to ensure that control is achieved and maintained while using the minimal level of medications over a few months. Since asthma severity level could change over years or months, therefore, asthma level of severity can be as classified as follows:

Mild asthma: Controlled asthma at step 1 or 2Moderate asthma: Controlled asthma at step 3Severe asthma: Asthma that requires treatment step 4 or 5.

 Non-Pharmacological Management



The long-term goal of asthma therapy is to achieve and maintain asthma control by utilizing pharmacological and nonpharmacological measures [Box 5.1]. Appropriate implementation of nonpharmacological measures is expected to lead to utilization of the least possible doses of medications to minimize the risk of their side effects, if any.[INLINE:5]

Developing a partnership with the patient

The development of a partnership between patients and healthcare professionals leads to enhancement of knowledge, skills, and attitude that lead toward better understanding of asthma and its management. Based on agreed goals of management, a written self-management action plan should be offered to patients. A wide variety of plans are available which vary from patient-based to physician-based plans. This is expected to be reflected positively on patient adherence, which is a major issue in the management. Factors leading to nonadherence may be related to poor inhaler technique, a regimen with multiple drugs or devices, concern regarding side effects from the drugs, or the cost of medications.[78],[79],[80] Other factors include lack of knowledge about asthma, lack of partnership in its management, inappropriate expectations, underestimation of asthma symptoms, use of unconventional therapy, and cultural issues.[81],[82]

Asthma education

The goal of asthma education is to provide patients with asthma (or the parents of a child with asthma) adequate training to enhance their knowledge and skills to be able to adjust treatment according to guided self-management.[64],[83],[84],[85],[86],[87] To enhance the level of knowledge and skills among asthma patients, education is recommended to include knowledge about asthma and skills related to prescribed inhaler devices as there may be misperceptions about the use of inhalers and the safety of ICS [Box 5.2].[88],[89],[90],[91] Asthma education is recommended to be conducted by a well-trained healthcare worker, who has good communication skills and is able to create an interactive dialog in a friendly environment. With the availability of appropriate information, patients will be encouraged to continue on the management plan and reassured about the control of their asthma.[92] It is essential to get the feedback from the patient to maintain a bidirectional rapport and an optimum environment. It has been documented that a well-structured asthma education program improves quality of life, reduces cost, and decreases the utilization of healthcare resources.[93],[94],[95],[96] Asthma should be structured based on the available resources.[INLINE:6]

Identify and reduce exposure to risk factors

Measures to prevent or reduce exposures to risk factors should be implemented wherever possible. There are different triggers leading to acute asthma attacks, which may include allergens, viral infections, pollutants, drugs, and occupational agents. These factors can be classified as indoor or outdoor allergens and occupational sensitizers.

Indoor allergens and air pollutants: There is a wide spectrum of indoor allergens that include dust mites, animals (mainly cats), cockroaches, and fungi (e.g., Alternaria and Aspergillous). Single allergen interventions are likely to fail. However, multifaceted, tailored, and intensive interventions most likely will help in improving asthma control. There are still several gaps in the literature in this area. It will take a few months for the allergen level to become significantly lower from the implementation of the control measures.[97] The most important indoor air pollutant is related to tobacco exposure. Measures to avoid tobacco exposure will lead to better asthma control and avoidance of long-term lung function impairmentOutdoor allergens and dust: Outdoor allergens such as pollens and molds are impossible to avoid completely; exposure may be reduced by closing windows and doors and using air conditioning if possible. It is recommended to avoid outdoor strenuous physical activities in cold weather, low humidity, or high air pollution. Sand storms do not usually lead to asthma attacks, but mild symptoms may worsen. It is advisable to avoid going out in the storm if possible, especially for those with uncontrolled asthma [98]Occupational exposures: Whenever an occupational sensitizer is identified, it is advisable to keep the affected person away from that environment. The earlier the removal of this sensitizer takes place, the higher the chance of complete recovery from occupational asthmaFood and drugs: Food and food additives are uncommon triggers of asthma. Avoidance cannot be recommended until it is documented by a specialist. However, certain drugs that could worsen asthma symptoms should be avoided (e.g., beta-blockers) if possibleVaccination: Annual influenza vaccination is advised for individuals with asthma, especially those with severe asthma.[99],[100],[101] It usually becomes available early on the fall season. It is advisable to get it as soon as it is available. Pneumococcal vaccination is also recommended as per local guidelines.[10]

 Pharmacological Management in Adults and Adolescent



The SINA expert panel recommends asthma treatment to be based on the following phases:

Initiation of treatmentAdjustment of treatmentMaintenance of treatment.

At each phase, the patient is recommended to have a clinical assessment that includes symptoms assessment by ACT, a physiological measurement with PEFR or spirometry, review of current medications and patients' adherence and inhaler technique, a risk for attacks, and the response to treatment. Based on clinical and physiological assessment, the patient is placed on the appropriate treatment step [Box 6.1]. Appendix 1 contains more information about medications used in asthma treatment. The SINA expert panel recommends the following strategies for asthma treatment:[INLINE:7]

A daily controller medication is the preferred recommendation for all steps, except for step 1. ICS is considered the most effective controller and the cornerstone of asthma treatment (Evidence A).[102],[103] Uncontrolled patients may require the addition of other controller medicationsRelievers or rescue medications must be available to patients at all steps. Increasing the use of reliever treatment is usually an early sign of worsening of asthma control (Evidence A).[104] The available relievers are:

A short acting bronchodilator agent (SABA) such as salbutamol that is recommended to be taken on “as-needed basis” to relieve symptomsFormoterol/ICS combination could be used as a reliever therapy on “as needed basis” as per physician prescription. Formoterol is an Long acting bronchodilator agent (LABA) with fast-acting bronchodilator effect (Evidence B).[105],[106],[107]

Regular assessment of adequate doses of treatment, proper technique, and adherenceRegular assessment for independent risk factors for attacks, especially severe attacks in the past 12 months or prior history of admission to an intensive care setting; especially if intubated.[108],[109] Other modifiable risk factors are recommended to be assessed, such as low initial FEV1, pregnancy, inadequate ICS, smoking and vaping, comorbidities, and major psychological conditionsRegular assessment of risk factors for fixed airway obstruction that include inadequate ICS treatment, exposure to tobacco smoke or other noxious substances, low initial FEV1, or sputum/blood eosinophilia [75],[110]Management of comorbidities with a special attention to concomitant rhinosinusitis. As this condition affects asthma control, its treatment is expected to improve asthma (Evidence A).[111],[112],[113],[114],[115],[116] Treatment includes nasal saline washes and/or steroids, leukotriene receptor antagonists (LTRAs), and antihistamines. Coexisting rhinosinusitis is recommended to be treated appropriately as well.

Initiation of treatment

Patients with asthma often underestimate the presence of symptoms and tend to assume that their asthma is controlled even when this is not the case. Therefore, the consensus among the SINA expert panel is to simplify the approach and supplement the initiation of asthma therapy by utilizing an objective measurement with the ACT questionnaire [Box 4.2]. The following initial steps are recommended for naive patients based on ACT score:

ACT score ≥20

Step 1: SABA (such as salbutamol) on “as-needed basis” for patients with mild and infrequent symptoms that occurs once or twice a week [1],[2]Step 2: Low-dose ICS for patient with symptoms more than twice a week, the aforementioned risk factors for attack or fixed airway obstruction, low-dose ICS is recommended (Evidence B).[70],[102],[117],[118] Early introduction of ICS leads to greater improvement of FEV1 and lower the future doses of ICS [118]Step 2: Patients with seasonal asthma who are symptomatic during the season are recommended to start low-dose ICS during the season and to be treated at step 1 for the rest of the year if their ACT score is ≥20 (Evidence D).

ACT score 16–19

Step 2: Low-dose ICS for patients with an ACT score of 16–19 (Evidence B).[70] Alternative options may be considered as described in the adjustment section includes starting formoterol/ICS combination on “as-needed basis” or leukotrienes modifiers.

ACT score <16

Step 3: A combination of regular low-dose ICS and LABA as maintenance treatment for patients with an ACT score of <16 (Evidence B)[70]Step 4: For patients who have poorly uncontrolled asthma at presentation, initiation of asthma treatment with a combination of medium-dose ICS and LABA as regular maintenance treatment (Evidence D). However, for patients with early signs of attack at presentation, an initial short course of oral steroids may be required together with the prescription of the maintenance therapy.

Adjustment of treatment

After initiation of asthma treatment, it is recommended to assess the patient at 1–3-month intervals (Evidence D). The SINA expert panel recommends the utilization of stepwise approach of therapy to achieve asthma control. The stepwise approach consists of five steps as shown in [Box 6.1]. On follow-up, it is recommended to either maintain treatment until patients have achieved control, to step up for those who did not achieve control, or to step down for those who have maintained control for an extended period. Relievers or rescue medications must be made available to patients at all steps. Increasing the use of reliever treatment is usually an early sign of asthma worsening (Evidence A).[104] The available relievers are detailed above.

The SINA panel recommends that the stepwise approach is not meant to be compartmental; it is rather a continuum of care based on patient engagement and close monitoring of the disease (Evidence D).[119] The following paragraphs will describe in detail each step.

Treatment at step 1

Recommended option: A reliever therapy on “as-needed basis” (described earlier in the section). Symptoms are usually mild and infrequent with an ACT score of ≥20[104]Some patients may be recommended for low-dose ICS if they are controlled at the time of assessment (an ACT score of ≥20) but have risk factors for attacks or fixed airway obstruction.[119],[120]

Treatment at step 2

Recommended option: A daily low-dose ICS (<500 mcg of beclomethasone or equivalent/day) with a reliever therapy on “as-needed basis” (Evidence A)[102],[121]Alternative options

Recent studies showed that the combination of budesonide/formoterol on “as-needed basis” is an alternative option (Evidence B).[106],[107] When compared to regular maintenance with low-dose ICS alone, it was found to be inferior with respect to controlling symptoms and noninferior with respect to the rate of severe asthma attacks and time to first attack. Of note, the combination of budesonide/formoterol on “as-needed basis” achieved the outcome with substantially lower ICS dose equivalent to 17%–25% of the maintenance dose of ICSLTRA (montelukast) is another alternative option, especially for those patients who are reluctant to use ICS or continue to have side effects (such as voice hoarseness) despite preventive measures (Evidence A).[122] It should be noted that LTRA is less effective than ICS in achieving asthma control and in reducing the risk of attacks.

Patients with mild and infrequent symptoms and an ACT score of ≥20 with risk factors for attack or fixed obstruction are recommended for low-dose ICS between asthma attacks (Evidence B)[102],[117]Patients with seasonal asthma who are symptomatic during the season are recommended to be treated with low-dose ICS before the beginning of the season; otherwise, it is recommended to be maintained at step 1 for the rest of the year (Evidence D).

Treatment at step 3

Recommended option: Adding an LABA to a low-medium-dose ICS in a combination device improves asthma control for patient whose asthma is not controlled at step 2 (Evidence A).[117],[123],[124] The patient is recommended to continue on reliever treatment on “as-needed basis” (Evidence A)ICSs in the form of beclomethasone dipropionate, budesonide, mometasone furoate, or fluticasone propionate are currently combined with either salmeterol or formoterol. These are normally prescribed twice daily. Once a day combination of ICS and LABA is also available [Appendix 1]If a formoterol/ICS combination is selected, patient may be advised to use this combination for both maintenance and rescue using extra puffs from the same inhaler (Evidence A).[105] The recommended dose is 1–2 puffs twice daily plus extra puffs that should not exceed 12 puffs per day. Those patients who require such high doses for 2–3 days should seek medical advice to step up maintenance therapy, and they may require the use of a short course of oral prednisolone (Evidence A)If salmeterol/ICS combination is selected, an escalation of the regular daily doses to maximum dosing achieves well-controlled asthma status in a majority of patients on steps 2 and 3 (Evidence A).[125] Salmeterol has a slow onset of action; therefore, it should only be used as a maintenance treatmentThe once a day combination of ICS/LABA can be prescribed based on availability. The approved product in the Saudi market is fluticasone furoate/vilanterol (Relvar) that can be prescribed for adults and children above 12 years at a dose of 100/25 μg (Evidence A).[126],[127] Vilanterol has the advantage of an onset of action within 15 min and a long half-life; therefore, patient can use it only as a maintenance treatmentInhaled LABA should not be used alone in asthma management.[128] Asthma patients taking inhaled LABA without inhaled ICS are at an increased risk of asthma attacks, hospitalizations, and death.[129] Based on this evidence, the Saudi Food and Drug Administration withdrew all LABA monotherapy medications from the Saudi market by the end of 2010.[130] Therefore, the SINA panel has limited the use of relievers to SABA or to formoterol when combined with ICSAlternative and generally less effective strategies include the continuation of ICS as a monotherapy by increasing the dose to the medium-high-dose range (Evidence A),[129],[131] or the addition of LTRA to a low-medium-dose ICS (Evidence A),[132],[133] especially in patients with concomitant rhinitis.[134] The addition of sustained release theophylline to a low-medium dose ICS is a possible but less favorable choice (Evidence B)[135]Tiotropium is a long-acting anticholinergic agent approved for the treatment of chronic obstructive pulmonary disease (COPD).[136],[137],[138] Evidence has shown that when tiotropium is added to an ICS, it improves symptoms, reduces risk of attack, and improves the lung function in patients with inadequately controlled asthma. Its effect appears to be at least equivalent to LABA (Evidence A).[139],[140],[141],[142] This evidence supports that tiotropium can be used as an alternative to LABA when added to ICSConsultation with an asthma specialist is recommended for patients whenever there is a difficulty in achieving control at step 3 (Evidence D).

Treatment at step 4

Recommended option: Escalation of treatment by combining medium-high-dose ICS with LABA (Evidence A)[92],[131],[133],[143]In addition to the currently available combinations of ICS/LABA mentioned in step 3 section, the once a day combination of fluticasone furoate/vilanterol (Relvar) can be prescribed for adults and children above 12 years at a dose of 200/25 μg dose [126],[127]If symptom control is not achieved, adding tiotropium to the combination of ICS and LABA is a recommended option as it significantly improves lung function in uncontrolled cases (Evidence A)[136],[144],[145]Adding LTRA to the combination of high-dose ICS and LABA is also recommended, but the evidence is less robust (Evidence B).[142],[146],[147]Adding theophylline to the combination of high-dose ICS and LABA is another less favorable alternative (Evidence B)[147],[148]If a patient is uncontrolled at step 4 despite adequate treatment and control of comorbid conditions, biologic therapy is recommended as described in step 5. Early consideration may save the patient from frequent or chronic use of oral corticosteroidsConsultation with an asthma specialist is recommended for patients who require this step of therapy (Evidence D).[149]

Treatment at step 5

Consultation with an asthma specialist is strongly recommended for patients requiring treatment at step 5 (Evidence D)To avoid frequent use of oral steroids, biologic therapy should be considered based on appropriate indications and availabilityAnti-IgE therapy (omalizumab) may be considered for those patients uncontrolled on maximum treatment at step 4 despite modification of any triggers and who have allergic asthma as determined by an IgE level in the appropriate therapeutic range, and positive skin test or RAST study (Evidence A), or a history of documented atopy (Evidence D).[131],[132],[143] If this treatment does not control asthma after 16 weeks of therapy, it should be stopped [150],[151],[152]Anti-IL-5 therapy can be considered for uncontrolled eosinophilic asthma at step 4 with frequent attacks [Appendix 1, medications section]. There are no data to determine the duration before deciding on treatment ineffectiveness. However, till this evidence is available, the treatment may be continued for up to 6–12 months before the decision of stopping treatment (Evidence D).[153] The available options are:Mepolizumab, an anti-IL-5 therapy that is indicated when eosinophil level is ≥150 cells/μL at treatment initiation or ≥300 cells/μL at any time in the prior 12 months. The recommended dose is 100 mg subcutaneously every 4 weeksBenralizumab, an anti-IL-5 receptor that is indicated when blood eosinophil level is ≥300 cells/μl at initiation of treatment. The recommended dose is 30 mg subcutaneously every 4 weeks for the first 3 months and then every 8 weeks thereafter

There is no available evidence that compares anti-IgE therapy to any of the anti-IL-5 therapies or directly comparing different anti-IL-5 agentsFor patients with evidence of both atopy and high blood eosinophils, to date, there is no available evidence to favor either anti-IgE therapy versus anti-IL-5 agents. Omalizumab led to more reduction of asthma attacks in a category of asthma patients who showed >50% reduction in blood eosinophils during therapy.[154],[155] A recent study showed that anti-IL-5 receptor therapy (benralizumab) reduced attacks by 46% and improved lung function in patients with severe, uncontrolled eosinophilic asthma, regardless of the serum IgE concentrations and atopy status.[156] When choosing a biologic, several factors should be considered including the frequency of administration, cost, side effect profile, age at onset of asthma, presence of comorbid conditions such as nasal polyps, previous response, and physician experience with the treatmentIf the patient does not have atopy, high blood eosinophils, or biologic therapy is not available or not adequately controlling the disease; the alternative approach is to use the lowest possible dose of long-term oral corticosteroids (Evidence D).[157] Other alternative are mentioned in the severe asthma section such as thermoplasty and long-term macrolidesFor patients who require long-term systemic corticosteroids, the following are recommended to be considered:Use the lowest possible dose to maintain controlClosely monitor the development of corticosteroid-related side effectsWhen asthma control is achieved, attempts to reduce the dose of systemic corticosteroids, preferably to every other day frequency. Maintaining high-dose ICS therapy may help reduce the dose of systemic corticosteroidUpward adjustment of the corticosteroid dose at the time of stress (e.g., infection, asthma attacks, surgery) is essentialStrongly consider concurrent treatments with calcium supplements, Vitamin D, and bone-sparing medications (e.g., bisphosphonates) in patients who have risk factors for osteoporosis or low bone mineral density (Evidence C).

Maintaining asthma control

Regular follow-up by a healthcare worker is essential. Depending on the level of asthma control, it is recommended to have a follow-up at 1–3-month intervals (Evidence D).[92],[158] Follow-up should include monitoring and reviewing the patient's written asthma action plan, medication adherence and inhaler technique, patient's behaviors, comorbidities, and possible side effects of the medications. Once asthma is well controlled and the control is maintained for at least 3 months, a step-down in pharmacologic therapy is recommended at the minimum level that can maintain the good control and minimize the side effects (Evidence D). The following are the general recommendations:

Reduction in therapy is recommended to be gradual and closely monitored based on clinical judgment of the individual patient's response to therapy and ACT score (Evidence D)If the patient is on ICS as monotherapy, the dose of ICS may be reduced by 25% every 3–6 months to the lowest dose possible that is required to maintain control (Evidence B)[85],[159],[160] and then changed to a single daily dose (Evidence A).[161] It is recommended to be clearly explained to the patient that asthma control may deteriorate if treatment is abruptly discontinued [162]If the patient is on combination of ICS/LABA at step 3 or 4, abrupt discontinuation of LABA is not recommended as it may lead to deterioration of the control [163]If the patient is on a combination of ICS and LABA, LTRA, or other controllers, then start by tapering ICS to the lowest possible dose (Evidence B).[164],[165] If control is achieved, LTRA may be discontinued (Evidence D)[164]For significant side effects, consider a change in therapy, reduction in the dose, or frequency of ICS (if possible), advise vigorous mouth washing after inhalation, use of spacer (concomitant with MDI devices), and/or use of appropriate local antifungal therapy for severe oral thrush [166]Patients should be informed that asthma control may deteriorate if treatment is completely discontinued.

Referral to an asthma specialist

Situations that require referral to an asthma specialist for consultation or comanagement include:

Uncertainty regarding the diagnosisDifficulty achieving or maintaining asthma controlImmunotherapy or biologic therapy is being consideredDifficulty to achieve asthma control at step 3 or higherAcute asthma attack requiring hospitalizationRequest of a patient for second opinion or further advice.

Allergen immunotherapy

The allergen immunotherapy (AIT) is a treatment modality to desensitize patients to specific allergens. It is considered for those with stable asthma and evidence of clinically relevant allergic sensitization at which the immunotherapy can be directed, especially if they have coexisting allergic rhinitis. Patients with poorly controlled asthma should not be started on immunotherapy.[167],[168] Although there are insufficient data on the impact of AIT on asthma attacks and quality of life scores, it has specifically been shown to:

Improve asthma symptoms and stepping down asthma treatment (Evidence A)[169]Improve AHR (Evidence B)[170]Decrease the progression of allergic rhinitis to asthma (Evidence B)[171]Decrease the chance of development of new sensitizations (Evidence B).[167]

AIT is likely to be cost-effective when appropriately used.[168] There are currently two types of AIT in clinical practice, subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT). Most studies that compared SCIT to SLIT showed a better clinical efficacy of SCIT. However, SLIT has a better safety profile than SCIT as SCIT may rarely cause anaphylaxis.[169] Patients at risk are mainly those with asthma, especially if uncontrolled. High level of caution should be taken in patients using beta-blockers due to the risk of more serious anaphylaxis that is resistant to treatment with epinephrine.[167] Data are limited in pediatrics, but AIT has been used safely in children >5 years of age and was shown to reduce long-term asthma medication use and improve FEV1.[172] Although beneficial effects may be observed a few months from starting AIT, treatment with AIT needs patient's commitment for at least 3 years to have sustained desensitization after stopping the treatment. Furthermore, AIT can be continued, but not initiated, during pregnancy. Most studied that allergen-specific immunotherapy is dust mites, Alternaria, grass pollens, ragweed, and cat. Omalizumab could improve tolerability to AIT in patients with moderate-to-severe asthma.[173] If the patient is considered a candidate for AIT, referral to an allergist is recommended to explore this option further.

Severe asthma

Severe asthma carries several names; each point to an aspect of the disease. Chronic severe asthma, steroid-dependent asthma, difficult-to-treat asthma, and refractory asthma are some of these terminologies.[174] Severe asthma is defined by the “requirement of asthma treatment with high-dose inhaled ICS and a second controller or oral prednisolone, which remains uncontrolled despite this therapy, or to prevent it from becoming “uncontrolled.”[77] Severe asthma probably accounts for 5%–10% of adult asthma, but the health cost is disproportionally high.[175] Morbidity and mortality are also higher compared to regular asthma patients because of increased side effects of treatment and much more frequent attacks and/or hospitalizations.[176],[177] Before a diagnosis of severe asthma is considered, patients must undergo a systematic assessment where the diagnosis of asthma is confirmed, and comorbidities are identified and treated.[52] Patients in whom poor asthma control is related to other factors, such as poor adherence or due to the presence of other diseases, are to be termed “difficult-to-treat asthma.” There are common comorbidities that need to be assessed in severe asthma such as allergic rhinoconjunctivitis (in 70% of cases), rhinosinusitis/nasal polyps (in 50%), COPD (in 20%), vocal cord dysfunction (in 32%–50%), anxiety/depression (in 4%–17%), obstructive sleep apnea (in 31%), GERD (in 17%–74%), bronchiectasis (in 25%–40%), and allergic bronchopulmonary aspergillosis (in 1%–2%).[178] The following steps are recommended for the assessment of patients with severe asthma:[179],[180],[181],[182],[183],[184]

Ensure that the patient is adherent to all medications with a good inhalation techniqueBe aware of possible misdiagnosis where the problem is not bronchial asthma to start with but another respiratory pathology that is mimicking asthma symptoms and not appropriately addressed, e.g., bronchiectasis, endobronchial tumors, vocal cord dysfunction, allergic bronchopulmonary aspergillosis, or Churg–Strauss syndrome [182],[185]Assess for the existence of comorbidities that can worsen bronchial asthma and make it difficult to manage (e.g., chronic rhinosinusitis, GERD, sleep apnea syndrome, Allergic bronchopulmonary aspergillosis (ABPA), obesity, and congestive heart failure [CHF])[186]Medications over use or side effectsManaging any psychosocial contributing factorsIdentify confounding factors (e.g., presence of allergens at home or work, active or passive smoking and vaping, or psychosocial problems).[182]

Asthma phenotyping

Phenotyping plays a major role in predicting the response to treatment of severe asthma. Inflammatory phenotyping is based on the type of and the extent of inflammatory reaction, while clinical phenotyping is based on combining clinical characteristics, physiological abnormalities, and inflammatory markers. Inflammatory phenotypes are based on the result of inflammatory cells identified in an induced sputum sample. There are four groups: neutrophilic asthma, eosinophilic asthma, mixed granulocytic asthma, and paucigranulocytic asthma.[178] Clinical phenotyping is based on age at onset, IgE-mediated allergy, eosinophilia or increased fractional exhaled nitric oxide, fixed airflow obstruction, and obesity. Clinical phenotypes can be recognized as an early-onset allergic phenotype, a later-onset obese phenotype, or a later-onset eosinophilic phenotype.

Selection of which biological agent is most appropriate for a particular patient can be achieved by clinical phenotyping. History of allergy, airflow obstruction, and attacks may predict a better effect of anti-IgE therapy. Eosinophilia combined with attacks may predict better effects of anti-IL5 therapy. However, patients with irreversible airflow limitation and frequent attacks may benefit from tiotropium.[187] Details of biological agents and their indications are discussed in detail in earlier sections.

As it may be difficult to achieve full control in many patients with severe asthma, the aim of treatment in this situation is to reach the best possible control.[187] After dealing with all comorbidities and other confounding factors that could have made asthma difficult to control, maximum therapy is recommended at step 5, which may include combination therapy of high-dose ICS/LABA, LTRA, long-acting antimuscarinic (cholinergic) agents (LAMA), and addition of one of the available biological therapies as appropriate.[152],[188],[189]

A significant percentage of patients with severe asthma do not respond adequately to high-dose ICS and other controller therapy; thus, they need frequent or continuous oral steroid therapy to achieve a reasonable response.[190] Such control may be lost when oral steroid is discontinued. Patients may differ in the degree of their responsiveness to oral steroids.[191] Some patients may fail to improve their FEV1 by >15% following treatment with oral prednisolone for 2 weeks, a condition called “corticosteroids-resistant asthma.”[192],[193] If oral steroids are necessary, then it is recommended to use the lowest possible dose and to shorten the duration as much as possible.[194] In this situation, osteoporosis prophylaxis is recommended.

For patients with severe asthma that do not qualify or respond to biologic therapy, other modalities of treatment of severe asthma are recommended for consideration that includes:

Macrolides: Due to their role in reducing neutrophilic airway inflammation, they were shown to have a role in the management of severe asthma. A recent study has assessed the benefit of azithromycin at a dose of 250–500 mg 3 days/week as add-on therapy for 48 weeks for patient with persistent symptomatic asthma.[195] Azithromycin significantly reduced the experience of at “least one asthma attack” from 61% to 44%. It has significantly improved asthma-related quality of life measures, and responses in eosinophilic asthma were greater than in those without eosinophilsBronchial thermoplasty (BT): Utilizing radiofrequency energy to alter the smooth muscles of the airways and possibly bronchial wall innervation, BT has been shown to reduce the risk of asthma attacks in clinical trial setting.[196] In well-selected patients with moderate-to-severe asthma, it may improve various aspects of asthma, including FEV1, quality of life, asthma control, attacks, and use of rescue medications.[197],[198],[199] Until solid evidence is available, it is recommended to perform it in the setting of clinical trials and approval of an independent, institutional review board.[77] Contraindications to BT include moderate and severe bronchiectasis, very high sputum production, and fixed airflow obstruction with FEV1 levels below 50% of predicted.

 Management of Acute Asthma in Adults and Adolescents



Acute asthma attack is a challenging clinical scenario that requires a systemic approach to rapidly diagnose the condition, evaluate its severity, and initiate therapy. The first step of managing acute asthma is the early recognition to prevent the occurrence of attacks. Asthma in general has a low mortality rate compared with other lung diseases.[45] Nevertheless, asthma may lead to mortality, especially among patients with poorly controlled asthma whose condition deteriorates over a period of days before the final fatal event.[108],[200],[201],[202],[203] It has been shown that over 80% of such attacks developed over >48 h, allowing enough time for effective action to reduce the number of attacks requiring hospitalization.[204],[205],[206],[207] The most specific marker associated with increased asthma mortality is a history of repeated hospital admissions, particularly if patients required intensive care treatment or ventilatory assistance.[203],[208] The characteristics of patients admitted with near-fatal asthma in Saudi Arabia were found to be younger and predominantly males and used less ICS/LABA combination.[209] Furthermore, it has been shown that a subgroup of patients who present with near-fatal asthma have blunted perception of dyspnea and have a history of frequent ED visits, hospitalizations, and near-fatal asthma events.[210] This section includes assessment of patient with acute asthma, initial management, and follow-up after initial management. More information about medications used in acute asthma can be found in Appendix 1.

Clinical assessment of acute asthma

The initial clinical assessment should rapidly determine whether the patient's presenting symptoms are related to an acute asthma attack or not. Of note, it is necessary to recognize that acute asthma is different from mild-to-moderate asthma attack secondary to poor asthma control that simply requires a step-up in the chronic asthma therapy. Although most acute asthma attacks develop over a period of days, patients with brittle asthma may present with a much more dramatic deterioration [Box 7.1]. It is important to realize that most patients who die from acute asthma attack had chronically uncontrolled asthma, had received inadequate treatment with ICS, and had inadequate monitoring of their asthma.[211],[212],[213],[214],[215] Management of acute asthma in adults is the extreme spectrum of uncontrolled asthma and represents the failure to reach adequate asthma control. The presence of the following features should be sought:[INLINE:8]

Previous history of near-fatal asthmaWhether the patient is taking three or more medicationsHeavy use of SABARepeated visits to the EDBrittle asthma.

On presentation, a patient should be carefully assessed to determine the severity of the attacks [Box 7.2] and the type of treatment required.[216],[217] PEFR and pulse oximetry measurements are complementary to history-taking and physical examination. Major causes linked with asthma-related deaths are cardiac arrhythmia and asphyxia. The risk of cardiac arrhythmia is theoretically increased by hypokalemia and QTc interval prolongation related to the use of high-dose SABA or intravenous (IV) aminophylline.[52],[218],[219],[220] However, in a series of patients with near-fatal attacks, only a few arrhythmias other than sinus tachycardia and bradycardia were reported.[108],[221] Hence, a more likely cause for death is probably related to asphyxia due to severe airflow obstruction and hypoxemia. This is supported by the pathologic evidence of extensive airway obstruction, mucous plugging, and dynamic hyperinflation found at autopsy in patients who died of acute severe asthma.[222] Treatment of acute asthma attacks requires a systematic approach similar to chronic asthma management. Acute asthma management is recommended to follow these steps:[INLINE:9]

Assess severity of the attackInitiate treatment to rapidly control the attackEvaluate continuously the response to treatment.

The following levels of acute asthma severity should be quickly identified as approach to management and prognosis varies significantly [Box 7.2].

Assessment of acute asthma severity

Mild acute asthma: Patients presenting with mild asthma attack are usually treated in an outpatient setting by stepping up in asthma management, including increasing the dose of ICS.[223] However, some cases may require short course of oral steroidsModerate acute asthma: Patients with moderate asthma attack are clinically stable. They are usually alert and oriented but may be agitated. They can communicate and talk in full sentences. They are tachypneic and may be using their respiratory accessory muscles. Heart rate is usually <120/min and blood pressure is normal. A prolonged expiratory wheeze is usually heard clearly over the lung fields, but examination of the chest may be relatively normal. Oxygen saturation is usually normal secondary to hyperventilation. The PEFR is usually in the range of 50%–75% of predicted or previously documented best. Measurement of arterial blood gases (ABGs) are not routinely required in this category; however, if done, it shows widened alveolar–arterial oxygen gradient and low PaCO2, secondary to increased ventilation–perfusion mismatch and hyperventilation, respectively. CXR is not usually required for moderate asthma attacks, unless pneumonia is suspectedSevere acute asthma: Patients are usually agitated and unable to complete full sentences. Their respiratory rate is usually >30/min and use of accessory muscles is common. Significant tachycardia (pulse rate >120/min) and hypoxia (SaO2 <92% on room air) are usually evident. Chest examination reveals prolonged distant wheeze secondary to severe airflow limitation and hyperinflation; more ominously, the chest may be silent on auscultation. The PEFR is usually in the range of 30%–50% of predicted. ABG reveals significant hypoxemia and elevated alveolar–arterial oxygen gradient. PaCO2 may be normal in patients with severe asthma attacks. Such finding is an alarming sign as it indicates fatigue, inadequate ventilation, and pending respiratory failure. Chest radiograph is required if complications are clinically suspected such as pneumothorax or pneumoniaLife-threatening acute asthma: Patients with life-threatening asthma are severely breathless and unable to talk. They can present in extreme agitation, confusion, drowsiness, or coma. The patient usually breathes at a respiratory rate >30/min and uses their accessory muscles secondary to increased work of breathing. Heart rate is usually >120/min; however, at a later stage, patients can be bradycardiac. Patient may have arrhythmia secondary to hypoxia and electrocardiography (ECG) monitoring is recommended. Oxygen saturation is usually low (<90%) and not easily corrected with oxygen. ABG is mandatory in this category and usually reveals significant hypoxia and normal or high PaCO2. Respiratory acidosis may be present. PEFR is usually very low (<30% of the predicted). CXR is mandatory in life-threatening asthma to rule out complications such as pneumothorax or pneumomediastinum. It is important to realize that some patients might have features from more than one level of acute asthma severity. For the patients' safety, they should be classified at the higher level and managed accordingly.

Initial treatment of acute asthma

After initial assessment of asthma attack, it is recommended to base treatment on severity level [Box 7.2]. More details of medications are available in Appendix 1.

Moderate asthma attackLow-flow oxygen is recommended to maintain saturation ≥92%.[224],[225] There is evidence that high-flow oxygen may be harmful for some patients.[226] Therefore, it is important to give a controlled dose of oxygen; patients who received 28% oxygen did better than those who received 100% oxygen [226]Salbutamol is recommended to be delivered by either:[227],[228]MDI with spacer: 4–10 puffs every 20 min for 1 h, then every 1–2 h according to response (Evidence A)[229],[230],[231]Nebulizer: Salbutamol 2.5–5 mg every 20 min for 1 h, then every 2 h according to response (driven by oxygen if patient is hypoxic) (Evidence A).[232]Steroid therapy: Oral prednisolone 1 mg/kg/day to maximum of 50 mg is recommended to be started as soon as possible.[233],[234]Severe asthma attacksAdjusted oxygen flow is recommended to keep saturation ≥92% (avoids excess oxygen)[225],[235],[236]Nebulized salbutamol (2.5–5 mg) is recommended to be repeated every 15–20 min for 1 h and then every 30–60 min according to response.[225] Oxygen-driven nebulizers are preferred for nebulizing salbutamol because of the risk of oxygen desaturation while using air-driven compressors (Evidence A)[233],[234],[237],[238]Ipratropium bromide is recommended to be added to salbutamol at a dose of 0.5 mg every 20 min for three doses by the nebulized route and then every 4–6 h as needed (Evidence B). Alternatively, ipratropium bromide can be administered by MDI at a dose of 4–8 puffs every 20 min and then every 4–6 h as needed [239],[240],[241],[242]Systemic steroid is recommended to be started as soon as possible (Evidence A). If patient can tolerate oral medications, oral prednisolone 1 mg/kg/day to maximum of 50 mg daily is recommended. Alternatively, the following may be prescribed: daily hydrocortisone dose of 200 mg IV or daily methylprednisolone dose of 80 mg, in divided doses [233],[243]If there is no adequate response to previous measures, it is recommended to administer a single dose of IV magnesium sulfate at a dose of 1–2 g over 20 min (Evidence B)[244]Request CXR, electrolytes, glucose, 12-lead ECG, and ABG,Life-threatening asthma

Patients in this category can progress rapidly to near-fatal asthma, respiratory failure, and death. Hence, an aggressive management approach and continuous monitoring are mandatory.[245] The following steps are recommended for further management:Consult ICU service. Intubation setting should be readily availableAdequate oxygen flow to keep saturation ≥92%[225]Deliver continuous nebulized salbutamol at a dose of 10–15 mg with ipratropium bromide at a dose of 1.5 mg over 1 h (Evidence A).[246],[247] Continuous treatment was found to be safe and well tolerated and led to better improvement in pulmonary functions and reduction in hospitalization when compared to intermittent delivery (Evidence A).[248] Oxygen-driven nebulizers are preferred due to the risk of oxygen desaturation while using air-driven compressors (Evidence A)[237],[238]Once the patient showed response to continuous nebulization, shift to intermittent delivery is recommended (Evidence D)Systemic steroid (Evidence A) to be started as soon as possible in one of the following forms: IV methylprednisolone 80 mg daily in divided doses or IV hydrocortisone 200 mg daily in divided doses [233],[239],[242],[243],[249],[250]Single dose of IV magnesium sulfate at a dose of 1–2 g over 20 min (Evidence B)[243],[250]Frequent clinical evaluation and CXR, electrolytes, glucose, 12-lead ECG, and ABG are recommended.

Follow-up after initial treatment

Close evaluation of treatment response is recommended that and includes patient's mental and physical status, respiratory rate, heart rate, blood pressure, oxygen saturation, and PEFR. Response to treatment is divided into three categories that are adequate, partial, or poor response [Box 7.3].[INLINE:10]

Adequate response

Adequate response is defined as:Improvement of respiratory symptomsStable vital signs with respiratory rate <25/min and heart rate <120/minOxygen saturation ≥92% on room airPEFR or FEV1 >50% of predicted.

Management

If the above criteria are met and maintained for at least 4 h, the patient can be safely discharged with the following recommendations:

Review and reverse of any treatable cause of the attackReview of inhaler technique and encourage adherenceStep up of asthma treatment to at least step 3Prescription of oral steroid for 5–7 daysAdequate reliever therapy on “as-needed basis”A clearly written asthma self-management action planA close follow-up appointment.

Partial responsePartial response is defined as:Minimal improvement of respiratory symptomsStable vital signs with respiratory rate <25/min and heart rate <120/minOxygen saturation ≥92% on oxygen therapyPEFR between 30% and 50% of predicted.

Management

Patients who only achieved partial response after 4 h of the above-described therapy are recommended for the following:

Continue bronchodilator therapy (salbutamol every 1–2 h with ipratropium bromide every 2–4 h), unless limited by side effects (significant arrhythmia or severe hypokalemia)Continue systemic steroid: Oral prednisolone 1 mg/kg to maximum of 50 mg g daily. Alternatively, IV hydrocortisone 200 mg daily or IV methylprednisolone 80 mg in divided dosesObserve closely for any signs of fatigue or exhaustionMonitor oxygen saturation, serum electrolytes, ECG, and PEFRAdmit to hospital if the patient fails to show adequate response.

Poor response

Poor response is defined as:No improvement of respiratory symptomsAltered level of consciousness, drowsiness, or severe agitationSigns of fatigue or exhaustionOxygen saturation <92% with high-flow oxygenABG analysis showing respiratory acidosis and/or rising PaCO2PEFR <30% of predicted.

Management

Patients showing poor response after 4 h of therapy should have the following recommendations:

Consider ICU admissionDeliver continuous nebulization of salbutamol and ipratropium bromide, unless limited by side effectsContinue systemic steroid: IV hydrocortisone 200 mg daily or IV methylprednisolone 80 mg in divided doses.Criteria for ICU referral

ICU referral is recommended for patients:Requiring ventilatory supportDeveloping acute severe or life-threatening asthmaFailing to respond to therapy, evidenced by:Deteriorating PEFRPersisting or worsening hypoxiaHypercapniaABG analysis showing respiratory acidosisExhaustion, shallow respirationDrowsiness, confusion, altered conscious state.

 Asthma in Special Situations



Cough-variant asthma

Patients with cough-variant asthma have chronic cough as their main symptom.[251],[252] Other diagnoses to be considered are drug-induced cough caused by angiotensin-converting enzyme inhibitors, GERD, chronic upper airway cough syndrome manifesting as postnasal drip, eosinophilic bronchitis, and chronic sinusitis. Once the diagnosis is established, treatment is recommended with ICS.[253],[254] This condition may be confused with eosinophilic bronchitis which is characterized by cough and sputum eosinophilia with normal spirometry and AHR.[255]

Rhinitis/sinusitis and nasal polyp

Most asthma patients have coexisting rhinitis and/or sinusitis, and around 40% of patients with rhinitis have asthma.[256] Rhinitis can be classified to allergic or nonallergic. Asking patients about rhinitis symptoms and examination of upper airways is recommended to be part of the routine management of asthma. Treatment with intranasal corticosteroids has been associated with a decrease in asthma hospitalization and ED visits but not asthma control.[257],[258]

Exercise-induced bronchoconstriction

Exercise-induced bronchoconstriction (EIB) is common in inadequately controlled asthma patients. However, asthma-like symptoms can sometimes be triggered only by physical activities. Normally, bronchodilation occurs during exercise and lasts for a few minutes. In patients with EIB, the initial bronchodilation is followed by bronchoconstriction that generally peaks within 10–15 min after completing the exercise and resolves within 60 min. EIB can be prevented using SABA a few minutes before exercise.[60],[259] A warm-up period before exercise may also reduce EIB symptoms. If this approach does not control the symptoms, the patient is recommended to have maintenance therapy with ICS.[133],[260] Regular use of LTRA may help in this condition, especially in children.[133],[260],[261]

Aspirin-exacerbated respiratory disease

ASA-exacerbated respiratory disease (AERD) is a special phenotype characterized by a triad of asthma, chronic rhinosinusitis with nasal polyposis, and respiratory reactions to ASA.[262] About 7% of adults with asthma and 14% with severe asthma suffer from attacks in response to ASA or NSAIDs that inhibit cyclooxygenase-1 (COX-1). This condition is more common in patients with severe asthma and poor lung function. Majority of patients experience first symptoms during their third to fourth decade of life. Once ASA or NSAID hypersensitivity develops, it persists for life. Characteristically, within minutes to 2 h following ingestion of ASA, an acute severe asthma attack develops. It is usually accompanied by rhinorrhea, nasal obstruction, conjunctival irritation, and scarlet flush of the head and neck.[263] A typical history of upper and lower respiratory reaction to ASA or NSAIDs is very suggestive for the diagnosis, which is confirmed by ASA challenge.[264] A normal sinus CT almost excludes AERD. Patients known to have ASA-induced asthma should avoid all ASA-containing products and NSAIDs. Where an NSAID is indicated, COX-2 inhibitors or alternative analgesics such as paracetamol are recommended.[265] Prophylactic low-dose ASA should also be avoided. However, referral to an allergy specialist for ASA desensitization is recommended for patients, for whom ASA is required as antiplatelet therapy, patients with difficult to manage polyposis, or patients with severe asthma who require recurrent courses of systemic steroids.[266],[267] ASA and NSAID can be used in asthma patients who do not have ASA-induced asthma.[268] Montelukast may help in the treatment of this type of asthma in some patients.[269] IgE-mediated reaction to individual NSAIDs is not related to AERD.

Gastroesophageal reflux disease

GERD disease is more prevalent in patients with asthma compared to the general population. The mechanisms by which GERD worsens asthma include vagal-mediated reflex and also reflux secondary to microaspiration of gastric contents into the upper and lower airways.[270] All patients with asthma should be questioned about symptoms of GERD. If symptoms are present, a trial of anti-GERD measures (including a proton pump inhibitor) is recommended for 6–8 weeks.[271],[272],[273] Benefit of proton pump inhibitors is limited to patients with symptomatic GERD and nighttime respiratory symptoms. Of note, patients with asymptomatic GERD do not benefit from empiric GERD therapy (Evidence A).[274]

Pregnancy

A study conducted in a tertiary care hospital in Saudi Arabia showed that almost half of pregnant women had the desire to stop asthma medications during pregnancy as they believed that asthma medications would harm them and their babies more than asthma itself.[28] The course of asthma during pregnancy is unpredictable; however, one-third of pregnant asthmatics may have a worsening of their asthma control.[275] Maintaining adequate control of asthma during pregnancy is essential for the health and well-being of both the mother and her baby. Occurrence of asthma attacks during the first trimester of pregnancy significantly increases the risk of a congenital malformation.[276] Identifying and avoiding triggers are recommended as the first step of therapy for asthma during pregnancy. Treatment is recommended to take the same stepwise approach as in the nonpregnant patient. Salbutamol is the preferred SABA due to its excellent safety profile. ICSs are the preferred treatment for long-term control.[277] ICS, theophylline, antihistamines, β2-agonists, and LTRA are generally safe, and they have not been shown to increase the risk of fetal abnormalities.[278],[279] Prolonged use of systemic steroids may be associated with pregnancy-related complications, especially in the first trimester.

Pregnant women are recommended to receive the same drug treatment for acute asthma as nonpregnant patients (Evidence B), including systemic steroids if indicated (Evidence C).[275],[280],[281],[282],[283] Fetal monitoring is recommended in severe asthma attack. If anesthesia is required during labor, regional anesthesia is recommended whenever possible (Evidence C).[284] The use of prostaglandin F2α may be associated with severe bronchospasm and should be avoided, if possible (Evidence D). If asthma is well controlled during pregnancy, acute asthma is rare during labor. In the absence of acute severe asthma, reserve cesarean section for the usual obstetric indications. Pregnant asthma patients should be encouraged to breastfeed after delivery and to continue their usual asthma medications during lactation.[285],[286],[287]

Occupational asthma

All patients with asthma should be asked about their work history and exposures for possible related causal factors. A simple screening test is to ask the patient if their symptoms improve when they are away from work.[288] Once identified, early identification and elimination of occupational sensitizers and removal of patients from further exposure are an essential aspect of management. Patients with suspected or confirmed occupational asthma are recommended for referral to an asthma expert for assessment and advice because of the legal implications of the diagnosis.[289],[290]

Asthma-chronic obstructive pulmonary disease overlap

COPD is common above the age of 40 years.[291] Distinguishing asthma from COPD becomes more difficult as many patients may show features of both diseases. This has been called the asthma-COPD overlap (ACO). ACO is a unique complex entity sharing features of both COPD and asthma. At this stage, there is no formal definition of ACO as there is inadequate data to describe its features, characteristics, and its optimal therapeutic intervention.[2] However, when a patient has features of both asthma and COPD, the diagnosis of ACO could be considered.

ACO has been estimated to account for approximately 15%–25% of the obstructive airway diseases in adults, and patients may experience worse outcomes compared with asthma or COPD alone.[2] Patients with ACO have the combined risk factors of smoking and atopy. They are generally younger than patients with COPD and have frequent attacks, poor quality of life, more rapid decline in lung function, higher mortality, greater health care utilization, and low quality of life, compared to patients with COPD alone.[292],[293],[294],[295],[296]

Spirometry is required to confirm the diagnosis of chronic airflow limitation. Postbronchodilator FEV1/FVC of <0.7 is usually present, and postbronchodilator increase in FEV1 by >12% and 200 mL from baseline is compatible with diagnosis of ACO. However, spirometry alone has limited value in distinguishing between asthma, COPD, and ACO.

If the initial assessment suggests asthma or ACO, or there is uncertainty about the diagnosis of COPD, it is prudent to start treatment for asthma (ICS with or without LABA) until further investigation has been performed to confirm or exclude this diagnosis. Of note, it is important that patients should not be treated with an LABA alone if there are features suggestive of asthma.[295],[296],[297] Treatment of ACO is recommended to include advice about other therapeutic strategies, including smoking cessation, pulmonary rehabilitation, vaccinations, and treatment of comorbidities.

 Management of Asthma in Children



Asthma represents the most common chronic illness of childhood.[2] It is also a leading cause for childhood morbidity as measured by school absences, ED visits, and hospitalizations.[298] From the prospective of both patient and society, the cost of not treating asthma is higher than the cost of asthma treatment.[66],[299]

Asthma diagnosis in children

Clinical considerations

Accurate diagnosis of asthma in children is crucial to prevent inappropriate management and reducing morbidity and mortality due to under- or over-diagnosis.[300],[301] Therefore, asthma diagnosis in children should be based on a careful clinical assessment that includes recurrent or chronic symptoms related to airway obstruction, such as wheezing, coughing, night symptoms, activity limitation, and shortness of breath. These symptoms typically result from AH or various stimuli that would be reversible either spontaneously or after receiving a bronchodilator. The diagnosis can be further supported by the presence of atopy, early sensitization, and family history of atopy. Whenever possible, spirometry is recommended to be performed to show reversibility of airway obstruction after bronchodilator therapy.[302] Generally, spirometry can be performed in children aged 5–12 years. It is preferably planned when the initial diagnosis is made and after 3–6 months of controller therapy initiation with subsequent follow-up assessment. [Box 9.1] presents a summary of signs and symptoms suggestive of the diagnosis of asthma in children.[INLINE:11]

Asthma mimics should be suspected when any of the following is present:

Failure to thriveOnset of symptoms during infancyVomiting associated with respiratory symptomsContinuous wheezingFailure to respond to asthma controller medicationClubbing or focal auscultation signsSymptoms that are not associated with typical triggers.

Clinical suspicion of asthma mimics is an acceptable indication for CXR in a child suspected of having asthma; however, a routine CXR is not recommended to be part of the initial routine workup of asthma in children.[303]

In preschool children, asthma diagnosis and management differ from that of older children and adolescent in many ways. Early childhood wheezing can evolve to different asthma phenotypes that can have variable response to standard therapy.[304] In addition to the diagnosis of asthma, wheezing in preschool children can be due to unique differential diagnoses (e.g., congenital defects, infections, especially viral bronchiolitis, bronchopulmonary dysplasia, and cystic fibrosis). In this age group, asthma diagnosis represents a challenging clinical judgment due to the lack of objective assessment (e.g., pulmonary function test or biomarkers). “Reactive airway disease” as a terminology is discouraged as it can restrain full clinical assessment and proper management of asthmatic children in this age group.[302],[305],[306]

Asthma phenotypes in children

Based on several longitudinal studies, wheezing has been categorized epidemiologically into transient and persistent wheeze phenotypes. It is also categorized based on symptoms into episodic/viral-induced and multi-trigger wheeze phenotypes.[307],[308] Different responses to treatment and variable outcomes have been attributed to phenotype heterogeneity, overlap, and instability over time. Major factors that may predict persistent symptoms are allergic disease, reduced lung function, viral respiratory infection, and bacterial colonization in infancy. Asthma wheeze phenotype in children has been classified as:[307],[309]

Early transient wheezing before the age of 3 years with resolution by the age of 6 yearsPersistent wheezing that starts before the age of 3 years and continues after the age of 6 yearsLate-onset wheezing between 3 and 6 years of age.

The allocation of children into these categories still remains a subject of debate as their clinical usefulness is still under investigation.[310]

Prediction of asthma in preschool children

For early identification of the risk for persistent asthma among preschool children, the SINA expert panel recommends the utilization of the modified asthma predictive index (modified-API). This tool is a clinical scoring instrument that can be used to predict whether a child with intermittent wheezing before the age of 3 years will develop persistent asthma pattern during school-age years [Box 9.2].[311],[312] Children with a history of four or more wheezing attacks (at least one is diagnosed by physician) and either one major or two minor criteria at 3 years of age will have 4–10-fold increase in the risk of having asthma later in their childhood. On the other side, children with negative modified-API will have 95% chance of outgrowing their asthma later on life.[313][INLINE:12]

Strategies of asthma management in children

The long-term goals of asthma management in children are not different from those of adults [Box 5.1].[66] Asthma management requires effective partnership between patients/caregivers and their healthcare providers.[314] Once established and strengthened, this relationship will positively impact asthma control. The asthma management strategy should include:

Assessment of asthma control combined with proper treatment

This implies a periodical assessment of asthma control combined with adjustments (if needed) of treatment based on the level of control. It is strongly recommended to use asthma treatment in a stepwise approach with the ultimate goal of achieving “optimal” control with “minimal” amount of medications and dosage.[315] Adherence to the prescribed medications and the proper use of their devices are recommended to be addressed before any modification of the treatment plan. It is extremely important to select the best device for optimal treatment delivery [Box 9.3].[INLINE:13]

Asthma control reflects the adequacy of management by describing the clinical status of a child as controlled, partially controlled, or uncontrolled. Focusing on asthma control may improve patient perceptions and expectations that improve symptoms reported by children and their caregivers and subsequently treatment decisions by clinicians.[67] In children, assessment of asthma control is recommended to cover two domains:[295]

Assessing future risk of adverse outcomes: This is achieved by assessing future risk of attacks, fixed airflow obstruction, and adverse effect of medications [Box 9.4]Assessing symptom control: Asthma symptom control has been estimated by physician assessment during clinic visit and/or perception of patients and their caregivers toward asthma control. During each clinic visit, the physician is recommended to utilize asthma control criteria to assess disease control [Box 9.5].

Different numerical tools have been developed and validated to objectively assess asthma control utilizing patients and their caregiver perception. However, as these tools have some limitations, they are recommended to be used as a complimentary tool rather than replacing physician assessment.[316]

The SINA expert panel recommends utilizing one of the following questionnaires based on age. The questionnaire is completed by patients and/or their caregiver before physician evaluation based on the age of the child:Age group 5–12 years: The Childhood-Asthma-Control Test (C-ACT)

The C-ACT is a validated test for children aged 5–12 years [Box 9.6]. C-ACT is a two-part questionnaire with a total of seven questions. The first part is to be answered by the patient and the second part by the caregiver. The final C-ACT score is made up of the sum of the scores of the two parts, ranging from 0 (poorest asthma control) to 27 (optimal asthma control). A score of ≤19 points suggests that a child's asthma is not adequately controlled.[317]

Age group <5 years: The Respiratory and Asthma Control in Kids (TRACK)

The TRACK is a validated test for children <5 years [Box 9.7]. It is a five-item standardized questionnaire, with four questions that address the impairment domain and one question that addresses the risk domain of asthma control. Each item is scored from 0 to 20 points on a 5-point Likert-type scale for a total score ranging from 0 to 100. Higher scores would indicate better respiratory and asthma control; a score of 80 points suggests that a child's asthma is not controlled.[318][INLINE:14][INLINE:15][INLINE:16][INLINE:17]

Role of patient education

Patient education is recommended to be an integral part of asthma management strategy in children. It is recommended to involve the basic knowledge of the disease pathophysiology, identifying and avoiding triggering factors, environmental controls (especially cigarette smoke exposures), proper use of treatment devices, and recognition of worsening asthma symptoms and the optimal time to seek advice.[319],[320] Proper asthma education can lead to a significant reduction in ED visits and hospitalizations, improve self-management of asthma attacks, and an overall reduction in the cost of asthma care.[321]

Setting asthma action plans

An action plan that documents medications, doses, and device technique should be provided to patients and their caregivers. The action plan is also recommended to include information for patient and caregiver on how to recognize worsening of asthma symptoms and advices of treatment modification in these situations [Box 9.8].[INLINE:18]

Prevention

Asthma attacks can be triggered by a variety of factors including allergens, viral infection, pollutants, and drugs. Eliminating these exposures improves the control of asthma and reduces medication needs. Parents/caregivers of children with asthma should be strictly advised not to smoke at home at all.[66],[322] Breastfeeding and Vitamin D supplementation may decrease the chance of developing early wheezing episodes, while probiotics benefit is still doubtful in preventing allergic disease.[323],[324],[325] A recent study on early-life use of probiotic supplementation did not show significant impact to prevent asthma or eczema at the age of 2 years for children at high risk.[326]

Outpatient management of asthma in children

Management of asthma should be adjusted continuously based on asthma control. If current treatment has failed to achieve control, then treatment should be stepped up until control is achieved. Whenever control is maintained for at least 3 months, then treatment can be stepped down. This stepwise approach is essential to maintain optimum control with lowest step to maximize safety and minimize cost. Although the stepwise approach is stratified into age categories (<5 years and ≥5 years), there are common concepts in the two age groups that include:

Controller therapy

ICSs are considered the most effective first-line maintenance monotherapy for childhood asthma (Evidence A).[327],[328] Chronic use of ICS for >3 months in prepubertal-aged children can suppress growth velocity which is dose dependent. However, asthmatic children when treated with low-dose ICS attain normal adult height but at a later age (Evidence A).[329],[330] Any potential adverse effects of ICS need to be weighed against the well-established benefit to control persistent asthma. More details of the use of ICS in children are available in Appendix 1There are insufficient data to recommend short courses of high-dose ICS in children with mild intermittent asthma attacks (Evidence B).[331] Safety of this approach has not been establishedChildren with frequent or severe asthma attacks are recommended to receive regular treatment with ICS (Evidence A).[332] Doubling the dose or even quintupling it at the early stages of loss of control did not result in reduction of asthma attacks or improvement in other outcomes [333]The clinical benefits of intermittent inhaled or systemic steroid for children with intermittent and viral-induced wheezing remain controversial. This practice is recommended to be discouraged until clear evidence-based practices are available on this strategy of asthma management (Evidence C).[334],[335]

Reliever therapy

Oral bronchodilator therapy is not recommended to be prescribed due to slower onset of action and higher side effects [336],[337]LABA should not be used alone as maintenance monotherapy in children (Evidence A).[338] LABA should be used only in combination with ICS. There are different combinations available in the Saudi market [Appendix 1].

Devices

As inhalers are the main method of delivering medications, it is recommended to choose the appropriate device [Box 9.3]. Use of valved-holding spacer, with mouthpiece when possible, is recommended when an MDI is prescribed (Evidence B).[339] Breath-actuated devices (e.g., dry powder inhalers) represent an effective and simpler option for maintenance therapy in children 5–12 years of age (Evidence C).[340],[341] For more information about medications, refer to Appendix 1Nebulizers are not superior to MDI delivered by spacer in both acute and chronic asthma management (Evidence A).[342]

The SINA expert panel recommends ensuring consistency in the approach of asthma in adults, adolescents, and children. Therefore, outpatient treatment will be described in three phases: initiation, adjustment, and maintenance. The recommendations in the following sections are further stratified based on age groups: <5 years and ≥5 years.

Initiation of Asthma Treatment in Children

Before initiating asthma treatment in children, it is recommended to document important findings obtained during the initial clinical assessment, such as the status of asthma control, assessing for risk factors, obtaining C-CAT score for children aged ≥5 years, and TRACK score for children <5 years. It is also recommended to provide teaching of inhalers technique and action plan and ensure that patient has a follow-up visit. The SINA expert panel recommends placing the child on one of the steps based on the common clinical scenarios described below:

Step 1SABA (such as salbutamol) on “as-needed basis” for a child with minimal symptoms (less than twice a week) that qualify for a controlled status based on physician assessment and are complemented with a C-ACT score of ≥20 for a child aged 5–12 years or TRACK score of >80 for a child aged <5 yearsSABA (such as salbutamol) on “as-needed basis for a child with intermittent viral-induced wheeze.[343],[344],[345]Step 2

Personalizing the treatment options for children in step 2 may be predicted by stratification based on asthma phenotype, assessment of aeroallergen sensitization, and determining the eosinophil count. Positive sensitization and high eosinophil count may favor ICS as a primary controller intervention.[346] The following are recommended:Low-dose ICS for a child with more symptoms (more than twice a week) that qualify to partially controlled status based on physician assessment and are complemented with a C-ACT score of ≤19 for a child aged 5–12 years or TRACK score of ≤80 for a child aged <5 years (Evidence A).[347],[348],[349] Different options of ICS are available in Appendix 1LTRA for a child who cannot or will not use ICSs though it is a less-effective option (Evidence B)[350],[351],[352]Low-dose ICS for a child <5 years with a history of asthma attack in the past year or has ever been admitted to ICU (Evidence D)In addition to a low-to-moderate dose of ICS, a short course of oral prednisolone is recommended to be considered for a child aged 5–12 years with early signs of asthma attack at presentation.Step 3For a child <5 years with more persistent symptoms, commence treatment on double dose of ICS.[353],[354]

Adjustment of asthma treatment in children

Assessment of adherence, proper device use, control of environment, and confirmation of the diagnosis, especially if there is a failure to respond to therapy, are recommended each time before treatment adjustments.[355] For a child seen in the clinic for the first time while on controller treatment, the managing physician should ensure that the child is receiving the appropriate treatment based on recommendations given in the section on treatment initiation.

Adjustment of therapy is recommended after 1–3 months depending on the level of asthma control upon presentation and the C-ACT score for children aged 5–12 years or TRACK score for children aged <5 years. Patient should be clinically assessed regarding medications and doses, compliance to treatment, accuracy of inhalers technique, and any related environmental factors. Based on clinical assessment and the level of asthma control, the following are recommended [Box 9.9] and [Box 9.10]:[INLINE:19][INLINE:20]

A child with uncontrolled asthma: Escalation of treatment to at least the next step. Uncontrolled status is determined based on physician assessment complemented by a C-ACT score of ≤19 for a child aged 5–12 years or TRACK score of ≤80 for a child aged <5 yearsA child with controlled asthma: Treatment is recommended to be maintained at the same step; however, stepping down may be considered during low seasons for asthma attacks. Controlled status is determined based on physician assessment complemented by a C-ACT score of ≥20 for a child aged 5–12 years or TRACK score of >80 for a child aged <5 years.

The SINA expert panel recommends the following concepts of treatment adjustment based on age in the following section.

Children aged 5–12 years [Box 9.9]A child is not controlled at step 1: The preferred option is escalating to step 2 with low dose ICS (step 2) (Evidence A)[327],[328]A child with asthma control is not achieved at step 2: Escalation of treatment to step 3 by adding LABA to low-dose ICS (Evidence A).[117] Alternatively, LTRA can be added to low-dose ICS or the dose of ICS escalated to moderate dose (Evidence A)[356],[357],[358],[359],[360],[361]A child is not controlled at step 3: It is recommended to escalate to step 4 by changing the combination inhaler to medium dose of ICS/LABA (step 4). LTRA may be added to this combination if control is not achieved.Whenever there is a difficulty to control asthma at step 4, it is strongly recommended to refer patient to a physician specialized in asthma for further evaluationThere is growing evidence to support the use of anti-IgE in children 6–12 years of age who fulfill the following criteria (Evidence A): Severe persistent allergic asthma with frequent daytime symptoms or night-time awakenings and who have multiple documented severe asthma attacks despite daily high-dose ICS plus LABA.[362],[363] However, this line of management is recommended to only be restricted to physicians specialized in asthma (Evidence C)[364],[365]Data related to specific immunotherapy in pediatrics are limited, but it can be used for children >5 years of age and was shown to reduce long-term asthma medication use and improve FEV1 as detailed in immunotherapy subsection.[172] It should be initiated by an asthma and allergy specialistThere is no evidence to support the use of LAMA in children <12 years.

Children aged <5 years [Box 9.10]A child is not controlled at step 1: The preferred option is to escalate to step 2 with low-dose ICS (Evidence A)[327],[328]A child with asthma control is not achieved at step 2: It is recommended to escalate treatment to step 3. The recommended option is to double the dose of ICS (Evidence A).[359],[366],[367] Alternatively, adding LTRA to low-dose ICS is another option although this is considered as less effective.[353],[354]A child is not controlled at step 3: It is recommended to escalate treatment to step 4 by the addition of LTRA to moderate-dose ICS (Evidence B)[368],[369],[370]Whenever there is a difficulty to control asthma at step 4, it is strongly recommended to refer patient to a physician specialized in asthma for further evaluation and options in step 5There is no evidence to support the use of LABA in children <5 years

It is recommended to provide the caregiver an asthma action plan and a follow-up visit in 1–3 months depending on clinical status. Uncontrolled asthma in preschool children can lead to developmental disadvantages due to the negative impact of uncontrolled asthma on their social interaction and sleep. Caregivers of preschool children should be educated that asthma control is an achievable target and affected children should not be prevented from engagement in age-appropriate activities.

Maintenance of asthma treatment in children

On follow-up, it is recommended to perform a full clinical assessment including asthma control status and obtaining C-ACT score for children aged 5–12 years or TRACK score for children aged <5 years. Based on clinical assessment and asthma control status [Box 9.6] and [Box 9.7], the SINA expert panel recommends the following:

Step up treatment for children who are uncontrolled based on physician assessment and complemented by a C-ACT score of ≤19 for a child aged 5–12 years or TRACK score of ≤80 for a child aged <5 years. It is recommended to rule out any modifiable factors preventing reaching optimal asthma controlPatient should be clinically assessed regarding medications and doses, compliance to treatment, accuracy of inhalers technique, and any related environmental factorsMaintain treatment for children who reached controlled status based on physician assessment complemented by a C-ACT score of ≥20 for a child aged 5–12 years or TRACK score of >80 for a child aged <5 yearsConsider stepping down treatment for children who are controlled for at least 3 months.

Reduction in therapy should be gradual and closely monitored based on clinical judgment complemented by either C-ACT score or TRACK score. Furthermore, close monitoring on treatment stepping down is recommended for patient who has risk of asthma attack, especially during seasonal variation or for those with prior acute asthma attack in the past year or history of ICU admission.

The SINA expert panel recommends the following concepts for stepping down treatment based on age.

Children aged 5–12 years [Box 9.9].

If the patient is on ICS as monotherapy, the dose of ICS may be reduced by 25%–50% every 3–6 months to the lowest possible dose that is required to maintain control (Evidence B).[159],[160],[161] It should be clearly explained to the patient and/or caregiver that asthma control may deteriorate if treatment is abruptly discontinued.[162] In such a situation, an action plan that contains instruction on resuming controller therapy if asthma symptoms recurred is recommended to be provided to patients and their caregiver.

If the patient is on combination of ICS/LABA at step 3 or 4, abrupt discontinuation of LABA may lead to deterioration of asthma control [163]If the patient is on a combination of ICS with LABA or LTRA, taper ICS to the lowest possible dose (Evidence B).[164],[165] If control is maintained, LABA or LTRA may then be discontinued (Evidence D)[164]For significant local side effects of ICS, consider a change in therapy, reduction in the dose or frequency of ICS (if possible), advice for a vigorous mouth washing after inhalation, enforce use of MDI with spacer, and/or use of appropriate local antifungal therapy for severe oral thrush [166]For patients on continuous oral steroids, the dose is recommended to be tapered to the lowest dose and preferably to every other day (Evidence D). It is recommended to refer the child to a specialized physician in asthma management.

Children aged <5 years [Box 9.10]The need for continuation of ICS should be regularly assessed as wheeze remits in a significant portion of children [371]If the patient is on ICS as monotherapy, the dose of ICS may be reduced by 25%–50% every 3–6 months to the lowest possible dose that is required to maintain control (Evidence B).[159],[160] It is recommended to be clearly explained to the caregiver that asthma control may deteriorate if treatment is abruptly discontinued.[162] If asthma symptom is recurred, an action plan that contains instruction on resuming controller therapy is recommended to be provided to patients and their caregiverFor significant side effects, consider a change in therapy, reduction in the dose or frequency of ICS (if possible), advice for a mouth washing after inhalation if possible, enforce use of MDI with spacer, and/or use of appropriate local antifungal therapy for severe oral thrush [166]Uncontrolled asthma in preschool children can lead to developmental disadvantages due to the negative impact of uncontrolled asthma on their social interaction and sleep. Caregivers of preschool children are recommended to be educated that asthma control is an achievable target and affected children should not be prevented from engagement in age-appropriate activities.

Referral to an asthma specialist

Referral to an asthma specialist for consultation or co-management is recommended in the following situations:

There is uncertainty regarding the diagnosisThere is difficulty achieving or maintaining control of asthmaImmunotherapy or omalizumab is being consideredThe patient requires step 4 care or higherThe patient has had an asthma attack requiring a hospitalization or 2 or more oral corticosteroids in the past 12 months.

 Management of Acute Asthma in Children



Early recognition of acute asthma

Recognition of early signs of acute asthma is essential especially for those <5 years. Early symptoms of acute asthma include (Evidence D):

An attack of shortness of breath with wheeze or increase of shortness of breath with wheezeCough, especially at night although this is nonspecificImpairment of daily activityAn increased need for or poor response to SABAFor a child <2 years, the presence of lethargy and poor feeding should raise the suspicion of acute asthma attack. However, viral bronchiolitis is a common differential diagnosis in this age group during winter season.

In a child aged 2–5 years, the combination of the above features can predict approximately 70% of acute asthma attacks with low false-positive rate.[372] Moreover, upper respiratory tract infection (URTI) may frequently precede acute asthma attack in children. Clinical assessment is essential in children as the utilization of objective measure such as Pulmonary function tests (PFT) is problematic, especially in the younger age groups.

Initial management of acute asthma at home

The SINA expert panel recommends management of a child with asthma to include an action plan that enable the caregiver to recognize worsening of asthma and the advices for initial treatment (Evidence D). The action plan is recommended to include features that mandate the need for urgent medical care that includes acute distress of the child, difficulty to complete few words in one breath, and poor response to SABA treatment at home.

In the case of acute attack, initial management at home by the caregiver should be started with salbutamol inhaler 2–4 puffs by a spacer that may be repeated every 20 min for a total of three doses. If the child improves, asthma therapy is recommended to be stepped up as per instructions in the action plan and medical advice should be sought as soon as possible. If the child does not adequately improve within or after the initial period, urgent medical care is recommended.

Assessment of asthma severity in the emergency department

Assessment of acute asthma severity in children has an important role in various components of acute asthma management such as pharmacological interventions, need for hospitalization, and need for ICU admission. The assessment of acute asthma severity in young children is also important for clinical decision-making and evaluation of treatment effectiveness.[67],[98],[373],[374],[375],[376],[377],[378],[379],[380],[381],[382] This is supported by the fact that PFT measurement is not feasible as more than half of asthma attacks in children presented to EDs for children <5 years.[374]

The Pediatric Respiratory Assessment Measure (PRAM) has been found to be feasible, valid, responsive, and reliable tool to determine acute asthma severity in children aged 2–17 years.[374],[383] The PRAM represents a useful means to record clinical signs in a standardized fashion [Box 10.1].[67] The PRAM score is a 12-point score consisting of oxygen saturation, suprasternal retractions, scalene muscle contraction, air entry, and wheezing.[381] Clinical pathways based on PRAM for inpatient asthma management has been shown to decrease the length of stay and bronchodilator use with no adverse outcomes or increased acute care encounters.[384],[385] The SINA expert panel recommends measuring PRAM score for asthmatic patients in emergency as it can categorize the risk of hospitalization:[INLINE:21]

Total score of 1–3: Low risk with a chance of <10% for hospital admissionTotal score of 4–7: Moderate risk with a chance of 10%–50% for hospital admissionTotal score of 8–12: High risk with a chance of >50% for hospital admission.

Management of acute asthma in the emergency department

After performing the necessary clinical assessment, the SINA expert panel recommends the utilization of PRAM as a tool to assess patients in the ED and guide further management as well. The PRAM score should be obtained at the initial assessment and after initiation of treatment as well. After initial clinical assessment and starting initial appropriate therapy, managing physician is recommended to focus on obtained history to identify risk factors for ICU admission, including:[386]

Previous life-threatening asthma attackPrevious ICU admissionPrevious intubationDeterioration while already on systemic steroid.

In addition, managing physician is recommended to be aware of the following clinical features of severe or life-threatening asthma that require immediate medical attention:

Child is unable to speak or drinkCentral cyanosisConfusion or drowsinessSignificant subcostal or subglottic retractionOxygen saturation <92%Silent chest on auscultationTachycardia.

Implementation of clinical pathway that utilizes PRAM score for acute asthma management in children with moderate-to-severe asthma attacks markedly decrease the rate of hospitalization without increasing the rate of return to emergency care (Evidence B) [Box 10.2].[384],[387],[388],[389] This has been supported by a study showing that PRAM score after 3 h of initial management was associated with a significant improvement in the prediction of admission rate compared to pure clinical judgment at triage.[383] Ancillary investigation that includes CXR and ABG are not routinely recommended.[386] ABG is indicated in severe bronchial asthma that failed to respond to maximum therapy and required ICU admission. However, CXR is recommended in the following conditions:[INLINE:22]

Suspected bacterial pneumonia that presents with fever >39°C and presence of focal finding of decreased breath sound and cracklesTo rule out bronchial asthma complications such as pneumothoraxSevere disease that does not respond to maximum treatmentUncertainty about the diagnosisHypoxemia apparently disproportionate to the attack severity.

Viral infection is the usual cause of asthma attacks in children, and thus, routine use of antibiotics is strongly discouraged.[390] Antibiotics are recommended when bacterial pneumonia is clinically suspected.[387],[388]

Acute asthma management based on Pediatric Respiratory Assessment Measure:

The SINA expert panel recommends managing asthma based on PRAM score obtained at initial assessment:

Mild-Pediatric Respiratory Assessment Measure score of 1–3

Management

Obtain vital signs initially and at dischargePrescribe appropriate oxygen dose to keep saturation ≥92%Salbutamol dose based on weight:[342],[391]

Less than 20 kg: 5 puffs by MDI/spacer or 2.5 mg by nebulizer20 kg or more: 10 puffs by MDI/spacer or 5 mg by nebulizer-titrate MDI dose based on response)In mild cases, SABA with spacer is not inferior to nebulized SABA.

Ipratropium bromide may be considered at a dose of 4 puffs by MDI/spacer or 250 mcg by nebulizer every 20 min for the 1st h only [392]Consider oral steroid if there is no response to the first dose of salbutamol. Prednisolone dose is 1–2 mg/kg up to a maximum dose based on age. The maximum dose is 20 mg for children <2 years, 30 mg for children 2–5 years, and 60 mg for children 5–12 years. Dexamethasone dose of 0.6 mg/kg up to maximum dose of 16 mg [250]Re-assess PRAM after 1 h.

Management after initial treatment based on PRAM score

PRAM score is 1–3

The child may be discharged on salbutamol inhaler and ICS inhaler with a spacerIf oral steroids course is given initially, dexamethasone is recommended for extra one day and prednisolone for total of 3–5 daysIt is recommended to offer the child an action plan, education on inhalers technique, and a follow-up visit within 1 week to the appropriate clinic.

PRAM score is 4–7: Treat as a moderate asthma attack (see below).PRAM score is 8–12: Treat as a severe asthma attack (see below).

Moderate-Pediatric Respiratory Assessment Measure score of 4–7

Management

Obtain vital signs.Prescribe appropriate oxygen dose to keep saturation ≥92%.Salbutamol dose based on weight:[342],[391]

Less than 20 kg: 5 puffs by MDI/spacer or 2.5 mg by nebulizer20 kg or more: 10 puffs by MDI/spacer or 5 mg by nebulizer-titrate MDI dose based on responseIpratropium bromide at a dose of 4 puffs or 250 mcg by nebulizer every 20 min for the 1st h only.[391],[392],[393]

The combination of salbutamol and ipratropium bromide has been shown to be effective in this situation (Evidence B)[391]Systemic steroids after the first dose of SABA. Prednisolone dose is 1–2 mg/kg up to a maximum dose based on age. The maximum dose is 20 mg for children <2 years, 30 mg for children 2–5 years, and 60 mg for children 5–12 years. Dexamethasone dose of 0.6 mg/kg up to maximum dose 16 mg [233],[250]Re-assess PRAM after 1 h.If PRAM score after 1 h is 1–3, observe for another hour.

Management after initial treatment based on PRAM score:

PRAM score is 1–:

The child may be discharged on salbutamol inhaler with a spacer and ICS if the patient is not already on controller treatmentComplete the course of oral steroids. Dexamethasone is recommended for extra 1 day and prednisolone for total of 3–5 days; both as once daily doseIt is recommended to offer the child an action plan, education on inhalers technique, and a follow-up visit within 1 week to the appropriate clinic.

PRAM score is 4–7: It is recommended to continue treatment with salbutamol every 30 min for three doses and to assess PRAM score every 30 min. Further evaluation is based on PRAM re-assessment:

If PRAM score improves to 1–3, the child can be managed as aboveIf PRAM score does not improve, IV magnesium sulfate is recommended as a single dose of 40–50 mg/kg to a maximum of 2 g by slow IV infusion over 20–30 min. The child needs close monitoring for blood pressure and appropriate IV fluids. Admission is recommended to be considered.[394],[395],[396]

PRAM score is 8–12: Treat as severe asthma attacks (see below).

Severe-Pediatric Respiratory Assessment Measure score of 8–12

Management

Obtain vital signs every 20 min till improvementPrescribe appropriate oxygen dose to keep saturation ≥94%Salbutamol nebulizer at a dose of 2.5 mg for those weighted <20 kg or 5 mg for those weighted ≥20 kg and ipratropium bromide at a dose of 250 mcg by nebulizer every 20 min for the 1st h.[391],[392],[393],[397] This combination has been shown to be effective in this situation (Evidence B)[391]Systemic steroids after the first dose of SABA. Prednisolone dose is 1–2 mg/kg up to a maximum dose based on age. The maximum dose is 20 mg for children <2 years, 30 mg for children 2–5 years, and 60 mg for children 5–12 years. Dexamethasone dose of 0.6 mg/kg up to maximum dose 16 mg [233],[250]Re-assess PRAM after 1 hConsider IV access and appropriate IV fluidsIf PRAM score after 1 h is 1–3, Observe for another hour.

Management after initial treatment based on PRAM score:

PRAM score is 1–3:

The child may be discharged on salbutamol inhaler with a spacer and ICS if the patient is not already on controller treatmentComplete the course of oral steroids. Dexamethasone is recommended for extra 1 day and prednisolone for total of 3–5 days; both as once daily dose [233],[250]It is recommended to offer the child/care giver an action plan, education on inhalers technique, and a follow-up visit within one week to the appropriate clinic.

PRAM score is 4–7: It is recommended to continue treatment with salbutamol every 30 min for three doses and to assess PRAM score every 30 min. Further evaluation is based on PRAM re-assessment:

If PRAM score improves to 1–3, the child can be managed as aboveIf PRAM score does not improve, IV Magnesium sulfate is recommended as a single dose of 40–50 mg/kg to a maximum of 2 g by slow IV infusion over 20–30 min. The child needs close monitoring for blood pressure and appropriate IV fluids. Admission is recommended to be considered.[394],[395],[396]

PRAM score is 8–12: Deterioration of clinical status despite adequate treatment in the initial period warrants special care and attention. It is recommended to:

Establish IV access and to start on appropriate IV fluidsContinue nebulized salbutamol back-to-back every 20 min or use continuous salbutamol nebulization at a dose of 7.5 mg/h for those weighted <10 kg, 11.25 mg/h for those weighted 10–20 kg, or 15 mg/h for those weighted >20 kg [248],[398]If PRAM score does not improve, IV magnesium sulfate is recommended as a single dose of 40–50 mg/kg to a maximum of 2 g by slow IV infusion over 20–30 minIf no improvement in PRAM score, start IV salbutamol at a dose of 1 mcg/kg/min, then titrate based on response for a maximum dose of 10 mcg/kg/min [395],[396]ABG, CXR, and electrolyte are recommended to be obtained and the pediatrics critical care or equivalent service must be consulted.

Appendix 1: Medications Used for the Treatment of Asthma

The objective of asthma treatment is to achieve and maintain control of the disease. Medications used to treat asthma can be classified as controllers or relievers. Controllers are medications taken daily on a long-term basis to keep asthma under clinical control through their anti-inflammatory effects.[399] Relievers are medications used on an “as-needed basis” that act quickly to reverse bronchoconstriction and relieve symptoms.

Controller medications

Inhaled corticosteroids

ICSs are currently the most effective anti-inflammatory medications for the treatment of asthma.[45],[102],[400] They reduce symptoms, improve quality of life, improve lung function, decrease airway hyperreactivity, control airway inflammation, reduce frequency and severity of asthma attacks, and reduce asthma mortality. Early initiation of low-dose ICS in asthma leads to improvement in lung functions.[118] When they are discontinued prematurely or abruptly, deterioration of clinical control follows within weeks to months in most patients. ICSs differ in their potency and bioavailability. Most of the benefits from ICS are achieved in adults and children at relatively low doses [Box 11.1] and [Box 11.2]. Exposure to tobacco smoking or vaping, including secondary and tertiary, reduces the responsiveness to ICS. To reach control, add-on therapy with another class of controller is preferred to increase the dose of ICS.[129],[401][INLINE:23][INLINE:24]

Local adverse effects can occur and include oropharyngeal candidiasis and dysphonia; with MDIs, these effects are reduced using a spacer device. Mouth and throat washing after inhalation may reduce oral candidiasis. The small risk of adverse events from the use of ICS is well balanced by their efficacy.[402] Therefore, low-medium dose of ICS is generally safe and well tolerated in children. Formulations with small size particles are believed to be more effective and safer as it leads to better deposition in the peripheral small airways.[403],[404] Some studies have shown that ciclesonide had relatively lower local and systemic side effects, especially in children.[405] Systemic side effects are occasionally reported with high doses and long-term treatment.

Special considerations for use of inhaled corticosteroids in children

Growth retardation may be seen with all ICS when a high-dose ICS is chronically used. Systematic reviews showed a reduction may affect height velocity in prepubertal children over 12 months use of low-to-medium dose of ICS, especially during the 1st year of life.[406] Although this effect was statistically significant, it is not clear if that will be of significant clinical impact. For instance, use of moderate-dose ICS resulted in 1.2 cm reduction in the final adult height after more than 4 years use.[407] Moreover, more studies demonstrated the negative impact of medium-to-high doses ICS on bone mineralization.[408],[409],[410] However, it is crucial to remember that long-term use of ICS is safer than frequent bursts of oral corticosteroids on bone mineralization. Adequate nutrition with sufficient intake of calcium and Vitamin D can blunt these effects.[411] In summary, the potential adverse effects of ICS need to be weighed against the well-established benefit to control persistent asthma. Therefore, it is important to target the lowest possible ICS dose that maintains adequate asthma control.

Long-acting inhaled β2-agonists

The commonly used long-acting inhaled β2-agonists, formoterol and salmeterol, are used on a twice daily basis. Novel LABA agents with a 24-h duration of action are available, e.g., indacaterol, vilanterol, and olodaterol.[412],[413],[414],[415],[416],[417],[418] Due to lack of anti-inflammatory effect, LABA should not be used alone as monotherapy in asthma as this can lead to increased mortality, and indeed, they should only be prescribed in combination in the same device with ICS. When used in combination with ICS, there is an improvement in symptoms, decreased nocturnal asthma, improved lung function, decreased use of inhaled β2-agonists, reduced number of asthma attacks, and better control at a lower dose of ICS. LABA provides longer protection to prevent exercise-induced bronchospasm than short-acting inhaled β2-agonists (SABA).[419] Their side effects are limited to tachycardia, tremor, headaches, muscle cramps, and sometimes hypokalemia. Regular use of LABA combined with ICS may lead to a reduction in their side effects. Furthermore, patients rarely develop tolerance to LABA. The effect of LABA has not been adequately studied in children of <5 years.

Fixed combination of inhaled corticosteroids and LABA

Fixed combination of ICS and LABA is considered more convenient for patients. Combination therapy is generally safe and did not result in a significantly higher risk of serious asthma-related events than treatment with an inhaled glucocorticoid alone but resulted in significantly fewer asthma attacks.[420] They increase adherence and ensure that LABA is always accompanied by ICS. Although salmeterol and formoterol provide a similar duration of bronchodilation and protection against bronchoconstriction, formoterol has a more rapid onset of action than salmeterol. Therefore, combination inhalers containing formoterol may be used for both rescue and maintenance of control.[105],[420] Fixed combination inhalers of ICS and LABA have been available in the form of fluticasone propionate and salmeterol (Seretide) or budesonide and formoterol (Symbicort). However, new formulations are available in different devices in the Saudi market [Box 11.3] such as beclomethasone and formoterol (Foster), fluticasone propionate and salmeterol (Rolenium), and fluticasone propionate and formoterol (Flutiform).[421],[422],[423],[424][INLINE:25]

Once a day dry powder combination of ICS/LABA with fluticasone furoate and vilanterol (Relvar) is available in two strengths of 100/25 and 200/25 μg with dispensed equivalent dose of 92/22 and 184/22 μg, respectively.[126],[127] The dose of fluticasone furoate of 100 mcg is equivalent to fluticasone propionate 250 mcg.[425] Such a combination has a potential adherence advantage while maintaining the same safety as the combination of fluticasone propionate and salmeterol.[426]

Leukotriene modifiers

Leukotriene-modifying agents reduce airway inflammation and improve asthma symptoms and lung function, but with a less consistent effect on asthma attacks, especially when compared to ICS. They may be used as an alternative treatment to ICS for patients with mild asthma, especially in those who have clinical rhinitis. Some patients with ASA-sensitive asthma respond well to the LTRA. However, when used alone as a controller, their effects are generally less than that of low-dose ICS. When added to ICS, LTRA may reduce the dose of ICS required by patients with uncontrolled asthma and may improve asthma control.[427],[428] LTRA are generally well tolerated. In children, studies have shown that LTRA may be useful for reducing the number of asthma attacks induced by viruses and for reducing bronchial inflammation in atopic children.[429],[430],[431],[432] There are no clinical data to support their use under the age of 6 months.

Long-acting antimuscarinic agents

LAMAs inhibit the effect of acetylcholine on M3 receptors. Tiotropium was the first agent used in managing patient with COPD. Tiotropium use has been extended to asthma. The more recent LAMAs (such as aclidinium bromide and glycopyrronium) have not been studied in asthma yet. Given tiotropium's bronchodilatation duration of action of >24 h, it is used on a daily base.[433],[434] The earlier studies on tiotropium were conducted using the HandiHaler device. Later studies were conducted using the new Respimat device. Till date, tiotropium is available in the Saudi market in the HandiHaler device in an 18-mcg capsule format. The Respimat device is not yet widely available in the Saudi market. Tiotropium was first shown to be effective in treatment stepping-down when added to a combination of ICS/LABA.[435] Tiotropium was found to be not inferior to salmeterol in the management of asthma not adequately controlled on ICS or combination of ICS/LABA.[14],[137],[138],[436] If symptom control is not achieved, adding tiotropium to the combination of ICS and LABA is a recommended option as it significantly improves lung function in uncontrolled cases and reduces attacks (Evidence A).[136],[144],[145] Anticholinergic drugs are considered to be safe. The main side effect is dryness of mouth. Although mild prostatic symptoms have been reported, there is no evidence of a direct causal relationship.

Theophylline

Theophylline is a weak bronchodilator with modest anti-inflammatory properties. It may provide benefits as an add-on therapy in patients who do not achieve control with ICS alone but is less effective than LABA or LTRA. Theophylline is not recommended for use as monotherapy in asthma treatment. Low-dose theophylline (300 mg/day) may have an important role in improving steroid resistance in patients with severe asthma requiring high-dose ICS.[437],[438] Side effects include gastrointestinal symptoms, cardiac arrhythmias, seizures, and even death. Nausea and vomiting are the early symptoms of toxicity. Liver disease and CHF may increase the risk of toxicity. Use of lower doses may decrease these side effects. Theophylline has drug interaction with quinolones, and some macrolides may increase the risk of toxicity.

Oral β2-agonists

The side effect profile is much higher than that of inhaled β2-agonists. Therefore, their use is highly discouraged in asthma management. Oral route is not recommended in children.

Cromones

Cromones (sodium cromoglycate and nedocromil sodium) are not recommended for preschool children. They have limited role in the long-term treatment of older children. Evidence showed that low-dose ICS is superior to cromones in the management of asthma.[439] They are no longer available as an option to treat asthma.

Systemic corticosteroids

Long-term oral steroid therapy (excluding short courses for acute attacks of asthma for a period of 1–2 weeks) may be required to control difficult-to-treat asthma despite maximum standard therapy. The dose should be reduced to the lowest possible and other controllers are recommended to be maximized to minimize the side effects from the oral corticosteroids. Its use is limited by the risk of significant adverse effects. Use of intramuscular long-acting steroids is highly discouraged because of the increased risk of side effects. The side effects include osteoporosis, hypertension, diabetes, adrenal insufficiency, obesity, cataracts, glaucoma, skin thinning, and muscle weakness. Withdrawal can elicit adrenal failure. In patients prescribed long-term systemic corticosteroids, prophylactic treatment for osteoporosis is recommended.

Reliever medications

Relievers are medications used on an “as-needed basis” and act quickly to reverse bronchoconstriction and relieve symptoms.

Rapid-onset inhaled β2-agonists

Short-acting bronchodilators, such as salbutamol, are the medications of choice for relief of symptoms of acute attacks of asthma and for the pretreatment of exercise-induced bronchoconstriction. Use of MDI with a chamber is as effective as the nebulized route in treatment of acute episodes of wheeze in children.[230] Regular long-term use of SABA is not recommended. Formoterol is an LABA that has a fast-acting component but is not available alone in the Saudi market in a single inhaler; however, it can be used as a rescue medication in formoterol containing combination with ICS.[105],[106],[107] Vilanterol is another LABA used once a day that has a fast onset of action within 15 min and long half-life; hence, the patient should be advised to only use it once a day on a regular basis and not a rescue medication.[126],[127]

In acute asthma, inhaled salbutamol is the preferred choice.[227],[232] Repeated doses are recommended to be given at 15–20 min intervals. Alternatively, continuous nebulization (salbutamol at 5–10 mg/h) could be used for 1 h if there is an inadequate response to initial treatment. However, a meta-analysis of randomized controlled trials of adults with acute asthma found no significant differences between the continuous or intermittent methods in terms of pulmonary function or hospital admission; nevertheless, patients treated by continuous nebulization had fewer side effects.[440] In patients who are able to use the inhaler devices, 6–12 puffs of MDI with a spacer are equivalent to 5 mg of salbutamol by nebulizer. As the inhaled route has a faster onset of action and fewer adverse effects, the use of IV β2-agonists in the initial treatment of patients with acute severe asthma is not generally recommended.[441] IV therapy should not be considered routinely and only used cautiously if the response to the inhaled drug is poor or if the patient cannot tolerate the inhaled route.

Anticholinergics

Anticholinergics are less effective than SABA in asthma. However, when used in combination with SABA in acute asthma, they provide an additional benefit.[391] It can also be an alternative bronchodilator for patients who experience adverse effects, such as tachycardia, arrhythmia, and tremor from rapid-acting β2-agonists. Their side effects include dryness of the mouth and a bitter taste.

In moderate-to-severe acute asthma, combining ipratropium bromide with salbutamol was shown to have additional bronchodilation effect and faster improvement in lung function, compared to salbutamol alone.[239],[242] A systematic review showed the combination therapy has an added benefit in reducing hospitalizations.[241] Combining both agents led to reduction in hospital admission rates by 38%–57%, improvement in lung function, and substantial cost saving.[242],[442],[443] No evidence of benefit for length of hospital stay and other markers of response when inhaled anticholinergics are added to short-acting β2-agonists in hospitalized asthmatic children with acute attacks.[444] The adult dosing of nebulized ipratropium bromide is 500 μg every 20 min for three doses, then as needed. Alternatively, ipratropium bromide can be administered by MDI at a dose of 4–8 puffs (80–160 μg) every 20 min, then as needed for up to 3 h.

Theophylline

There is no evidence supporting the routine use of theophylline in treating acute asthma and its routine use is discouraged. Similarly, routine use of IV aminophylline in acute asthma is strongly discouraged as there is no evidence to show added benefit and the drug has high levels of toxicity and side effects.[445]

Intravenous magnesium sulfate

In a systematic review, magnesium sulfate was shown to reduce hospitalizations in patients with severe or life-threatening asthma attacks that failed to respond to initial treatment.[446] A single dose of IV magnesium sulfate at a dose of 1–2 g over 20 min is safe and effective in acute severe asthma.[244]

Aerosol devices used in asthma

Medication aerosol can be delivered using three devices:

Small-volume nebulizer

It is the most popular for patients and clinicians in acute asthma. Small-volume nebulizer (SVNs) are predominately powered by a compressed gas (air or oxygen) to convert one or more drug solutions or suspensions at any concentrations and dose into aerosols. One of its main advantages is that it requires minimal patient cooperation and is therefore suitable for all ages, with normal breathing and no inspiratory pause required. One of its main disadvantages is importability, time to deliver the medication (10–25 min), and potential of contamination. There are high-output aerosol nebulizers that have an output rate of 30–50 ml/h and a flow rate of 10–15 L/min. It provides up to 8 h of continuous nebulization and has a 240-ml reservoir.

Pressurized metered-dose inhaler

It is a pre-pressurized inhaler with medication and a propellant, which when actuated will give one dose of the drug for a single inspiration. An MDI typically requires slow inspiratory flow (≤30 L/min). One of its main advantages is that it is premixed and the ability to provide multiple doses in a short period. It is also small and portable with limited contamination. Disadvantages include the need of patient training to coordinate inhalation with actuation, and if this is not done properly, there is a potential of high deposition of drug in the oropharynx and poor drug delivery. Furthermore, because it does not have dose counter, it is difficult to determine the dose remaining in the canister. Compared to the older chlorofluorocarbon propellant formulations, hydrofluroalkane formulations provide smaller particle size aerosols with less oral deposition, hence less oral side effects and greater proportion of lung deposition.

Dry powder inhaler

It is not pressurized (no propellant) and therefore requires high inspiratory flows (60-90 L/min) to disperse a full dose. In addition to its portability, advantages include easier inhaler technique and a built-in dose counter. Disadvantages include the need for adequate inspiratory flow to disperse a full dose. If not used properly, high oropharyngeal impaction may occur and exhaled humidity into mouthpiece might affect the function of some devices. Therefore, it may not be suitable for very young or very old patients. The commonly available devices in Saudi Arabia include Turbohaler, Diskus, Handihaler, Easi-Breathe, Ellipta, and Breezhaler devices.

Breath-actuated inhalers

These inhalers automatically release a spray of medication when the person begins to inhale. They are easy to use and improve asthma control and compliance to medications.[447],[448],[449],[450]

Biologics in asthma treatment

The recent progress in biologic therapy in asthma has made a step forward toward the practice of precision medicine for asthma patients. This section describes the biologic agents that received appropriate approvals.[451] We also included agents that are potential therapies in the near future, while other agents are still in the pipeline and yet being evaluated by ongoing trials.

Anti-immunoglobulin E

Omalizumab is a recombinant humanized monoclonal antibody against soluble IgE. It prevents binding of IgE to its high affinity receptor and subsequently lowers its expression and the activation of mast cells, basophils, and dendritic cells. Omalizumab is indicated for patients ≥6 years of age with severe allergic asthma (at least one positive aeroallergen on skin prick testing or an elevated specific aeroallergen IgE level) uncontrolled on high-dose ICS combined with LABA and other controllers and who have an IgE level of within therapeutic range. It was shown to reduce attacks, reduce hospitalizations, and allow stepping down of ICS dose.[452],[453] Baseline IgE level does not predict response but is necessary, in addition to the weight, to calculate the dose. The side effects include pain and bruising at injection site and very rarely anaphylaxis (0.1%). This drug requires careful monitoring and should only be initially prescribed by an expert physician in asthma treatment. There is an extensive experience with omalizumab of >15 years. It is classified as category B for use in pregnant women based on the current cumulative experience. Therefore, it is not recommended to start omalizumab during pregnancy but can be continued for those who already use it if the benefit outweighs the risk.

Anti-interleukin 5

IL-5 is critical for the development and maturation of eosinophils. Anti-IL-5 monoclonal antibody treatment is directed to patients with severe eosinophilic asthma who are not controlled on step 4 of treatment with two or more attacks in the past year and who have peripheral blood eosinophils according to specific anti-IL-5 agent. Anti-IL-5 therapy reduces attacks by 40%–60% with improvement in lung function and allows about 50% reduction of oral glucocorticoids.[454],[455],[456] They are approved for patients ≥12 years (reslizumab is approved for patients ≥18 years). Patients with more severe disease and higher eosinophil counts are expected to benefit more.[457] There is no available evidence that compares anti-IgE therapy to any of the anti-IL-5 therapies or directly comparing different anti-IL-5 agents. As there are currently no data to guide when to stop anti-IL5 therapy, the treatment may be continued for up to 6–12 months before the stopping decision (Evidence D).[153]

These medications should be avoided in patients with active helminthic infection. No enough data regarding use during pregnancy. There are currently three different anti-IL5 medications in clinical use:

Mepolizumab binds circulating IL5. Blood eosinophils should be >150/μl at the time of treatment initiation or >300/μl within the last 12 months. It is given as 100 mg monthly subcutaneously by injectionsReslizumab binds circulating IL5. Blood eosinophils should be >400/μl. It is given as monthly IV infusion of 3 mg/kg over 20–50 min.[458] Oropharyngeal pain and elevated creatine phosphokinase (CPK) were reported in <10% of patients. Since the dose is weight adjusted, reslizumab could be more efficacious when fixed-dose mepolizumab is not adequate [459]Benralizumab binds to the α chain of IL5 receptor, leading to eosinophil apoptosis.[460] Blood eosinophils should be >300/μl. It is given as 30 mg by subcutaneous injection once every 4 weeks for the first three doses and once every 8 weeks thereafter.

Anti-interleukin 4 receptor α

Dupilumab is a monoclonal antibody against α chain of the IL-4 receptor. This chain is shared with the IL-13 receptor. Therefore, this biologic impedes the signaling of both IL-4 and IL-13, two important cytokines in the development of TH2 cells and IgE-producing B-cells. It was recently approved for the treatment of moderate-to-severe eosinophilic asthma with blood eosinophils >300/μl and oral steroid-dependent severe asthma, regardless of blood eosinophils in patients ≥12 years of age. It improves asthma symptoms, improves lung function, and reduces the rate of attacks.[461],[462] The initial dose for the eosinophilic phenotype is 400 mg subcutaneously and then 200 mg every 2 weeks, while initial dose for oral steroid dependent asthma is 600 mg subcutaneously and then 300 mg every 2 weeks Adverse effects include URTIs and injection site reaction. Patients on dupilumab should avoid live vaccines.

Potential future biologic therapies

There are different biologic agents under development that target the inflammatory pathway. It did not receive any regulatory agent approval yet.

Fevipiprant is an oral treatment for asthma that is intended for the treatment of uncontrolled severe asthma.[463] It competitively and reversibly antagonizes the prostaglandin D2 receptorTezepelumab is a human monoclonal antibody specific for the epithelial-cell–derived cytokine TSLP that is intended to patients whose asthma remained uncontrolled despite treatment.[464]

Acknowledgment

The panel of SINA would like to thank the reviewers of the SINA 2019 for their valuable comments: Prof. Eric Batman, University of Cape Town, Cape Town, South Africa and Prof. Andrew Bush, Imperial College, National Heart and Lung Institute, Royal Brompton and Harefield NHS Foundation Trust, London, United Kingdom.

The panel would also like to thank the following consultant reviewers for previous versions on 2009, 2012 and 2016 for their valuable reviews: Prof. Mark FitzGerald and Prof. Sheldon Spier from the University of British Columbia, Vancouver, British Columbia, Canada; Prof. Qutayba Hamid and Prof. Ronald Olivenstein from the Meakins-Christie Laboratories, McGill University, Montreal, Quebec, Canada; and Prof. Eric Bateman from the University of Cape Town Lung Institute, Cape Town, South Africa; and Prof. Andrew Bush, Imperial College, National Heart and Lung Institute, London, United Kingdom.

Financial support and sponsorship

The SINA received financial and logistic support from the STS.

Conflicts of interest

The SINA is fully sponsored by the STS.

Disclaimer

These guidelines for the diagnosis and management of asthma in adults and children, developed by the SINA panel, are not meant to replace clinical judgments of physicians but to be used as tools to help the practicing physicians to manage asthma patients. Although a lot of effort was exerted to ensure the accurate names and doses of medications, the authors encourage the readers to refer to the relevant information of specific drugs for further clarification.

References

1Reddel HK, Bateman ED, Becker A, Boulet LP, Cruz AA, Drazen JM, et al. A summary of the new GINA strategy: A roadmap to asthma control. Eur Respir J 2015;46:622-39.
2Asthma GI. Global Strategy for Asthma Management and Prevention: GINA; 2018. Available from: http://www.ginasthma.org/. [Last accessed on 2018 Nov 16].
3Al Ghobain MO, Algazlan SS, Oreibi TM. Asthma prevalence among adults in Saudi Arabia. Saudi Med J 2018;39:179-84.
4Stewart WF, Ricci JA, Chee E, Morganstein D. Lost productive work time costs from health conditions in the United States: Results from the American productivity audit. J Occup Environ Med 2003;45:1234-46.
5Al-Mobeireek A. Prescribing for asthmatic children in primary care. Are we following the guidelines? Saudi Med J 2003;24:1274.
6Dashash NA, Mukhtar SH. Prescribing for asthmatic children in primary care. Are we following guidelines? Saudi Med J 2003;24:507-11.
7AR Jazieh on Behalf of Saudi Lung Cancer Guidelines Association, Saudi Lung Cancer Guidelines Members, Jazieh AR, Al Kattan K, Bamousa A, Al Olayan A, Abdelwarith A, et al. Saudi lung cancer management guidelines 2017. Ann Thorac Med 2017;12:221-46.
8Al-Jahdali H, Alshimemeri A, Mobeireek A, Albanna AS, Al Shirawi NN, Wali S, et al. The Saudi thoracic society guidelines for diagnosis and management of noncystic fibrosis bronchiectasis. Ann Thorac Med 2017;12:135-61.
9Alharbi AS, Alqwaiee M, Al-Hindi MY, Mosalli R, Al-Shamrani A, Alharbi S, et al. Bronchiolitis in children: The Saudi initiative of bronchiolitis diagnosis, management, and prevention (SIBRO). Ann Thorac Med 2018;13:127-43.
10Alharbi NS, Al-Barrak AM, Al-Moamary MS, Zeitouni MO, Idrees MM, Al-Ghobain MO, et al. The Saudi thoracic society pneumococcal vaccination guidelines-2016. Ann Thorac Med 2016;11:93-102.
11Al-Moamary MS, Al-Hajjaj MS, Idrees MM, Zeitouni MO, Alanezi MO, Al-Jahdali HH, et al. The Saudi initiative for asthma. Ann Thorac Med 2009;4:216-33.
12Al-Moamary MS, Alhaider SA, Al-Hajjaj MS, Al-Ghobain MO, Idrees MM, Zeitouni MO, et al. The Saudi initiative for asthma – 2012 update: Guidelines for the diagnosis and management of asthma in adults and children. Ann Thorac Med 2012;7:175-204.
13Al-Moamary MS, Alhaider SA, Idrees MM, Al Ghobain MO, Zeitouni MO, Al-Harbi AS, et al. The Saudi initiative for asthma – 2016 update: Guidelines for the diagnosis and management of asthma in adults and children. Ann Thorac Med 2016;11:3-42.
14Almakrami IH, Alzahrani EA, Alqarni SA. Assessment of knowledge and adherence of pediatric residents to Saudi initiative asthma (SINA) guidelines in Saudi Arabia. Egypt J Hosp Med 2018;70:686-91.
15Jadad AR, Moher M, Browman GP, Booker L, Sigouin C, Fuentes M, et al. Systematic reviews and meta-analyses on treatment of asthma: Critical evaluation. BMJ 2000;320:537-40.
16Al-Jahdali HH, Al-Hajjaj MS, Alanezi MO, Zeitoni MO, Al-Tasan TH. Asthma control assessment using asthma control test among patients attending 5 tertiary care hospitals in Saudi Arabia. Saudi Med J 2008;29:714-7.
17Al-Ghamdi BR, Mahfouz AA, Abdelmoneim I, Khan MY, Daffallah AA. Altitude and bronchial asthma in South-Western Saudi Arabia. East Mediterr Health J 2008;14:17-23.
18Rabe KF, Adachi M, Lai CK, Soriano JB, Vermeire PA, Weiss KB, et al. Worldwide severity and control of asthma in children and adults: The global asthma insights and reality surveys. J Allergy Clin Immunol 2004;114:40-7.
19Abudahish A, Bella H. Primary care physicians perceptions and practices on asthma care in Aseer region, Saudi Arabia. Saudi Med J 2006;27:333-7.
20Al-Kabbaa AF, Al-Shamrani KM, Salih MA. Does the management of bronchial asthma by family physicians meet standards of the national protocol? J Family Community Med 2002;9:21-5.
21Alamoudi O. Prevalence of respiratory diseases in hospitalized patients in Saudi Arabia: A 5 years study 1996-2000. Ann Thorac Med 2006;1:76-80.
22BinSaeed AA. Caregiver knowledge and its relationship to asthma control among children in Saudi Arabia. J Asthma 2014;51:870-5.
23BinSaeed AA, Torchyan AA, Alsadhan AA, Almidani GM, Alsubaie AA, Aldakhail AA, et al. Determinants of asthma control among children in Saudi Arabia. J Asthma 2014;51:435-9.
24Al Zahrani SS, El Morsy E, Laila S, Dorgham L. The impact of bronchial asthma on quality of life among affected children and adolescents in Taif city, Saudi Arabia. Life Sci J 2014;11:283-91.
25Ahmed AE, Al-Jahdali H, Al-Harbi A, Khan M, Ali Y, Al Shimemeri A, et al. Factors associated with poor asthma control among asthmatic patient visiting emergency department. Clin Respir J 2014;8:431-6.
26Al-Jahdali H, Anwar A, Al-Harbi A, Baharoon S, Halwani R, Al Shimemeri A, et al. Factors associated with patient visits to the emergency department for asthma therapy. BMC Pulm Med 2012;12:80.
27Al-Zahrani JM, Ahmad A, Al-Harbi A, Khan AM, Al-Bader B, Baharoon S, et al. Factors associated with poor asthma control in the outpatient clinic setting. Ann Thorac Med 2015;10:100-4.
28Al Ghobain MO, AlNemer M, Khan M. Assessment of knowledge and education relating to asthma during pregnancy among women of childbearing age. Asthma Res Pract 2018;4:2.
29Mohamed Hussain S, Ayesha Farhana S, Mohammed Alnasser S. Time trends and regional variation in prevalence of asthma and associated factors in Saudi Arabia: A systematic review and meta-analysis. Biomed Res Int 2018;2018:8102527.
30Duran-Tauleria E, Rona RJ. Geographical and socioeconomic variation in the prevalence of asthma symptoms in English and Scottish children. Thorax 1999;54:476-81.
31Al Ghobain MO, Al-Hajjaj MS, Al Moamary MS. Asthma prevalence among 16- to 18-year-old adolescents in Saudi Arabia using the ISAAC questionnaire. BMC Public Health 2012;12:239.
32Nahhas M, Bhopal R, Anandan C, Elton R, Sheikh A. Prevalence of allergic disorders among primary school-aged children in Madinah, Saudi Arabia: Two-stage cross-sectional survey. PLoS One 2012;7:e36848.
33Moradi-Lakeh M, El Bcheraoui C, Daoud F, Tuffaha M, Kravitz H, Al Saeedi M, et al. Prevalence of asthma in Saudi adults: Findings from a National Household Survey, 2013. BMC Pulm Med 2015;15:77.
34Pavord ID, Beasley R, Agusti A, Anderson GP, Bel E, Brusselle G, et al. After asthma: Redefining airways diseases. Lancet 2018;391:350-400.
35Del Giacco SR, Bakirtas A, Bel E, Custovic A, Diamant Z, Hamelmann E, et al. Allergy in severe asthma. Allergy 2017;72:207-20.
36Lambrecht BN, Hammad H. The immunology of asthma. Nat Immunol 2015;16:45-56.
37Brusselle GG, Maes T, Bracke KR. Eosinophils in the spotlight: Eosinophilic airway inflammation in nonallergic asthma. Nat Med 2013;19:977-9.
38Amelink M, de Nijs SB, de Groot JC, van Tilburg PM, van Spiegel PI, Krouwels FH, et al. Three phenotypes of adult-onset asthma. Allergy 2013;68:674-80.
39Papi A, Brightling C, Pedersen SE, Reddel HK. Asthma. Lancet 2018;391:783-800.
40Israel E, Reddel HK. Severe and difficult-to-treat asthma in adults. N Engl J Med 2017;377:965-76.
41Park JA, Sharif AS, Tschumperlin DJ, Lau L, Limbrey R, Howarth P, et al. Tissue factor-bearing exosome secretion from human mechanically stimulated bronchial epithelial cells in vitro and in vivo. J Allergy Clin Immunol 2012;130:1375-83.
42Brightling CE, Gupta S, Gonem S, Siddiqui S. Lung damage and airway remodelling in severe asthma. Clin Exp Allergy 2012;42:638-49.
43Bergeron C, Al-Ramli W, Hamid Q. Remodeling in asthma. Proc Am Thorac Soc 2009;6:301-5.
44Grainge CL, Lau LC, Ward JA, Dulay V, Lahiff G, Wilson S, et al. Effect of bronchoconstriction on airway remodeling in asthma. N Engl J Med 2011;364:2006-15.
45Alangari AA. Corticosteroids in the treatment of acute asthma. Ann Thorac Med 2014;9:187-92.
46O'Byrne PM, Pedersen S, Lamm CJ, Tan WC, Busse WW; START Investigators Group, et al. Severe exacerbations and decline in lung function in asthma. Am J Respir Crit Care Med 2009;179:19-24.
47O'Brian AL, Lemanske RF Jr., Evans MD, Gangnon RE, Gern JE, Jackson DJ, et al. Recurrent severe exacerbations in early life and reduced lung function at school age. J Allergy Clin Immunol 2012;129:1162-4.
48Russell RJ, Brightling C. Pathogenesis of asthma: Implications for precision medicine. Clin Sci (Lond) 2017;131:1723-35.
49Stempel DA, McLaughin TP, Stanford RH, Fuhlbrigge AL. Patterns of asthma control: A 3-year analysis of patient claims. J Allergy Clin Immunol 2005;115:935-9.
50Horne R, Price D, Cleland J, Costa R, Covey D, Gruffydd-Jones K, et al. Can asthma control be improved by understanding the patient's perspective? BMC Pulm Med 2007;7:8.
51Alharbi M, Almutairi A, Alotaibi D, Alotaibi A, Shaikh S, Bahammam AS, et al. The prevalence of asthma in patients with obstructive sleep apnoea. Prim Care Respir J 2009;18:328-30.
52Tiwari A, Guglani V, Jat KR. Ketamine versus aminophylline for acute asthma in children: A randomized, controlled trial. Ann Thorac Med 2016;11:283-8.
53Berlow BA. Eight key questions to ask when your patient with asthma doesn't get better. Am Fam Physician 1997;55:183-9, 192-4.
54Price D. Asthma and allergic rhinitis: Linked in treatment and outcomes. Ann Thorac Med 2010;5:63-4.
55Fireman P. Rhinitis and asthma connection: Management of coexisting upper airway allergic diseases and asthma. Allergy Asthma Proc 2000;21:45-54.
56Al-Mobeireek AF, Al-Sarhani A, Al-Amri S, Bamgboye E, Ahmed SS. Chronic cough at a non-teaching hospital: Are extrapulmonary causes overlooked? Respirology 2002;7:141-6.
57Al-Otair H, Bahammam AS. Unusual cause of respiratory distress misdiagnosed as refractory asthma. Ann Thorac Med 2006;1:28-30.
58Standardization of spirometry, 1994 update. American thoracic society. Am J Respir Crit Care Med 1995;152:1107-36.
59Cowie RL, Underwood MF, Field SK. Asthma symptoms do not predict spirometry. Can Respir J 2007;14:339-42.
60Tashkin DP, Altose MD, Connett JE, Kanner RE, Lee WW, Wise RA, et al. Methacholine reactivity predicts changes in lung function over time in smokers with early chronic obstructive pulmonary disease. The Lung Health Study Research Group. Am J Respir Crit Care Med 1996;153:1802-11.
61Song WJ, Kim HJ, Shim JS, Won HK, Kang SY, Sohn KH, et al. Diagnostic accuracy of fractional exhaled nitric oxide measurement in predicting cough-variant asthma and eosinophilic bronchitis in adults with chronic cough: A systematic review and meta-analysis. J Allergy Clin Immunol 2017;140:701-9.
62Witteman AM, Stapel SO, Perdok GJ, Sjamsoedin DH, Jansen HM, Aalberse RC, et al. The relationship between RAST and skin test results in patients with asthma or rhinitis: A quantitative study with purified major allergens. J Allergy Clin Immunol 1996;97:16-25.
63Humbert M, Holgate S, Boulet LP, Bousquet J. Asthma control or severity: That is the question. Allergy 2007;62:95-101.
64Bateman ED, Boushey HA, Bousquet J, Busse WW, Clark TJ, Pauwels RA, et al. Can guideline-defined asthma control be achieved? The gaining optimal asthma control study. Am J Respir Crit Care Med 2004;170:836-44.
65Halvorsen T, Walsted ES, Bucca C, Bush A, Cantarella G, Friedrich G, et al. Inducible laryngeal obstruction: An official joint european respiratory society and European Laryngological Society statement. Eur Respir J 2017;50. pii: 1602221.
66Pedersen SE, Hurd SS, Lemanske RF Jr., Becker A, Zar HJ, Sly PD, et al. Global strategy for the diagnosis and management of asthma in children 5 years and younger. Pediatr Pulmonol 2011;46:1-7.
67Cope SF, Ungar WJ, Glazier RH. International differences in asthma guidelines for children. Int Arch Allergy Immunol 2009;148:265-78.
68Lababidi H, Hijaoui A, Zarzour M. Validation of the arabic version of the asthma control test. Ann Thorac Med 2008;3:44-7.
69Alanezi M, Al-Jahdali HH, Al-Hajjaj MS, Zeitoni MO, Al-Tasan TH. Levels of acceptance of asthma control test questionnaire among saudi patients attending 5 tertiary care hospitals in Saudi Arabia. Saudi Med J 2009;30:546-9.
70Al Moamary MS, Al-Kordi AG, Al Ghobain MO, Tamim HM. Utilization and responsiveness of the asthma control test (ACT) at the initiation of therapy for patients with asthma: A randomized controlled trial. BMC Pulm Med 2012;12:14.
71Nathan RA, Sorkness CA, Kosinski M, Schatz M, Li JT, Marcus P, et al. Development of the asthma control test: A survey for assessing asthma control. J Allergy Clin Immunol 2004;113:59-65.
72Schatz M, Kosinski M, Yarlas AS, Hanlon J, Watson ME, Jhingran P, et al. The minimally important difference of the asthma control test. J Allergy Clin Immunol 2009;124:719-230.
73Schatz M, Sorkness CA, Li JT, Marcus P, Murray JJ, Nathan RA, et al. Asthma control test: Reliability, validity, and responsiveness in patients not previously followed by asthma specialists. J Allergy Clin Immunol 2006;117:549-56.
74Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. Global Initiative for Asthma 2015; 2015.
75Reddel HK, Taylor DR, Bateman ED, Boulet LP, Boushey HA, Busse WW, et al. An official American Thoracic Society/European Respiratory Society Statement: Asthma control and exacerbations: Standardizing endpoints for clinical asthma trials and clinical practice. Am J Respir Crit Care Med 2009;180:59-99.
76Taylor DR, Bateman ED, Boulet LP, Boushey HA, Busse WW, Casale TB, et al. A new perspective on concepts of asthma severity and control. Eur Respir J 2008;32:545-54.
77Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J 2014;43:343-73.
78Al-Jahdali HH, Al-Zahrani AI, Al-Otaibi ST, Hassan IS, Al-Moamary MS, Al-Duhaim AS, et al. Perception of the role of inhaled corticosteroids and factors affecting compliance among asthmatic adult patients. Saudi Med J 2007;28:569-73.
79Alsheri MA. Comparative study of different inhaler devices in asthmatic children. Ann Saudi Med 2003;23:349-53.
80Al-Wasil MA, Al-Mohaimeed A. Assessment of inhalation technique in primary care asthmatic patients using metered-dose inhalers with or without a spacer. Ann Saudi Med 2003;23:264-9.
81Al-Haddad N, Nour A, Koshak E. Asthma care: Structural foundations at primary health care at Al-Qassim region, Saudi Arabia. Ann Thorac Med 2006;1:8-11.
82Al Moamary MS. Unconventional therapy use among asthma patients in a tertiary care center in Riyadh, Saudi Arabia. Ann Thorac Med 2008;3:48-51.
83Al-Haddad N, Al-Ansari SS, Al-Shari AT. Impact of asthma education program on asthma knowledge of general practitioners. Ann Saudi Med 1997;17:550-2.
84Barnes NC. Can guideline-defined asthma control be achieved? The gaining optimal asthma control study. Am J Respir Crit Care Med 2004;170:830-1.
85Gibson PG, Powell H. Written action plans for asthma: An evidence-based review of the key components. Thorax 2004;59:94-9.
86Gibson PG, Powell H, Coughlan J, Wilson AJ, Hensley MJ, Abramson M, et al. Limited (information only) patient education programs for adults with asthma. Cochrane Database Syst Rev 2002;(2):CD001005.
87Guevara JP, Wolf FM, Grum CM, Clark NM. Effects of educational interventions for self management of asthma in children and adolescents: Systematic review and meta-analysis. BMJ 2003;326:1308-9.
88Zaraket R, Al-Tannir MA, Bin Abdulhak AA, Shatila A, Lababidi H. Parental perceptions and beliefs about childhood asthma: A cross-sectional study. Croat Med J 2011;52:637-43.
89Al-Binali AM, Mahfouz AA, Al-Fifi S, Naser SM, Al-Gelban KS. Asthma knowledge and behaviours among mothers of asthmatic children in aseer, South-West Saudi Arabia. East Mediterr Health J 2010;16:1153-8.
90Al-Yami SM, Mohajer KA, Al-Jeraisy MI, Batarfi AM, Abolfotouh MA. Recurrent visits and admissions of children with asthma in central Saudi Arabia. Saudi Med J 2010;31:921-4.
91Basyouni MH, BinDhim NF, Saini B, Williams KA. Online health information needs for patients with asthma in Saudi Arabia. J Consum Health Internet 2015;19:13-24.
92Al-Shimemeri A, Al-Ghadeer H, Giridhar H, Al-Jahdali M, Al-Moamary M, Khan J. Impact of an extensive asthma education campaign for physicians on their drug prescription practices. Ann Thorac Med 2006;1:20-5.
93Al-Mobeireek A. The efficacy of a management protocol in reducing emergency visits and hospitalizations in chronic asthmatics. Saudi Med J 2003;24:694.
94Alamoudi OS. The efficacy of a management protocol in reducing emergency visits and hospitalizations in chronic asthmatics. Saudi Med J 2002;23:1373-9.
95Al-Jahdali HH, Al-Omar AM, Al-Moamary MS, Al-Duhaim AS, Al-Hodeib AS, Hassan IS, et al. Implementation of the national asthma management guidelines in the emergency department. Saudi Med J 2004;25:1208-11.
96Alotaibi G. Status of respiratory care profession in Saudi Arabia: A national survey. Ann Thorac Med 2015;10:55-60.
97Gold DR, Adamkiewicz G, Arshad SH, Celedón JC, Chapman MD, Chew GL, et al. NIAID, NIEHS, NHLBI, and MCAN workshop report: The indoor environment and childhood asthma-implications for home environmental intervention in asthma prevention and management. J Allergy Clin Immunol 2017;140:933-49.
98Alangari AA, Riaz M, Mahjoub MO, Malhis N, Al-Tamimi S, Al-Modaihsh A, et al. The effect of sand storms on acute asthma in Riyadh, Saudi Arabia. Ann Thorac Med 2015;10:29-33.
99Bueving HJ, van der Wouden JC, Raat H, Bernsen RM, de Jongste JC, van Suijlekom-Smit LW, et al. Influenza vaccination in asthmatic children: Effects on quality of life and symptoms. Eur Respir J 2004;24:925-31.
100Nicholson KG, Nguyen-Van-Tam JS, Ahmed AH, Wiselka MJ, Leese J, Ayres J, et al. Randomised placebo-controlled crossover trial on effect of inactivated influenza vaccine on pulmonary function in asthma. Lancet 1998;351:326-31.
101Zeitouni MO, Al Barrak AM, Al-Moamary MS, Alharbi NS, Idrees MM, Al Shimemeri AA, et al. The saudi thoracic society guidelines for influenza vaccinations. Ann Thorac Med 2015;10:223-30.
102Pauwels RA, Pedersen S, Busse WW, Tan WC, Chen YZ, Ohlsson SV, et al. Early intervention with budesonide in mild persistent asthma: A randomised, double-blind trial. Lancet 2003;361:1071-6.
103Barnes PJ, Pedersen S. Efficacy and safety of inhaled corticosteroids in asthma. Report of a workshop held in Eze, France, October 1992. Am Rev Respir Dis 1993;148:S1-26.
104Berger WE. Levalbuterol: Pharmacologic properties and use in the treatment of pediatric and adult asthma. Ann Allergy Asthma Immunol 2003;90:583-91.
105O'Byrne PM, Bisgaard H, Godard PP, Pistolesi M, Palmqvist M, Zhu Y, et al. Budesonide/formoterol combination therapy as both maintenance and reliever medication in asthma. Am J Respir Crit Care Med 2005;171:129-36.
106Bateman ED, Reddel HK, O'Byrne PM, Barnes PJ, Zhong N, Keen C, et al. As-needed budesonide-formoterol versus maintenance budesonide in mild asthma. N Engl J Med 2018;378:1877-87.
107O'Byrne PM, FitzGerald JM, Bateman ED, Barnes PJ, Zhong N, Keen C, et al. Inhaled combined budesonide-formoterol as needed in mild asthma. N Engl J Med 2018;378:1865-76.
108Turner MO, Noertjojo K, Vedal S, Bai T, Crump S, Fitzgerald JM, et al. Risk factors for near-fatal asthma. A case-control study in hospitalized patients with asthma. Am J Respir Crit Care Med 1998;157:1804-9.
109Miller MK, Lee JH, Miller DP, Wenzel SE; TENOR Study Group. Recent asthma exacerbations: A key predictor of future exacerbations. Respir Med 2007;101:481-9.
110Ulrik CS. Outcome of asthma: Longitudinal changes in lung function. Eur Respir J 1999;13:904-18.
111Leynaert B, Bousquet J, Neukirch C, Liard R, Neukirch F. Perennial rhinitis: An independent risk factor for asthma in nonatopic subjects: Results from the European Community Respiratory Health Survey. J Allergy Clin Immunol 1999;104:301-4.
112Taramarcaz P, Gibson PG. Intranasal corticosteroids for asthma control in people with coexisting asthma and rhinitis. Cochrane Database Syst Rev 2003;(4):CD003570.
113Dahl R, Nielsen LP, Kips J, Foresi A, Cauwenberge P, Tudoric N, et al. Intranasal and inhaled fluticasone propionate for pollen-induced rhinitis and asthma. Allergy 2005;60:875-81.
114Philip G, Nayak AS, Berger WE, Leynadier F, Vrijens F, Dass SB, et al. The effect of montelukast on rhinitis symptoms in patients with asthma and seasonal allergic rhinitis. Curr Med Res Opin 2004;20:1549-58.
115Vignola AM, Humbert M, Bousquet J, Boulet LP, Hedgecock S, Blogg M, et al. Efficacy and tolerability of anti-immunoglobulin E therapy with omalizumab in patients with concomitant allergic asthma and persistent allergic rhinitis: SOLAR. Allergy 2004;59:709-17.
116Wilson AM, Dempsey OJ, Sims EJ, Lipworth BJ. A comparison of topical budesonide and oral montelukast in seasonal allergic rhinitis and asthma. Clin Exp Allergy 2001;31:616-24.
117O'Byrne PM, Barnes PJ, Rodriguez-Roisin R, Runnerstrom E, Sandstrom T, Svensson K, et al. Low dose inhaled budesonide and formoterol in mild persistent asthma: The OPTIMA randomized trial. Am J Respir Crit Care Med 2001;164:1392-7.
118Selroos O. Effect of disease duration on dose-response of inhaled budesonide in asthma. Respir Med 2008;102:1065-72.
119O'Byrne PM, Jenkins C, Bateman ED. The paradoxes of asthma management: Time for a new approach? Eur Respir J 2017;50. pii: 1701103.
120Reddel HK, Busse WW, Pedersen S, Tan WC, Chen YZ, Jorup C, et al. Should recommendations about starting inhaled corticosteroid treatment for mild asthma be based on symptom frequency: A post-hoc efficacy analysis of the START study. Lancet 2017;389:157-66.
121Powell H, Gibson PG. Initial starting dose of inhaled corticosteroids in adults with asthma: A systematic review. Thorax 2004;59:1041-5.
122Drazen JM, Israel E, O'Byrne PM. Treatment of asthma with drugs modifying the leukotriene pathway. N Engl J Med 1999;340:197-206.
123Godard P, Greillier P, Pigearias B, Nachbaur G, Desfougeres JL, Attali V, et al. Maintaining asthma control in persistent asthma: Comparison of three strategies in a 6-month double-blind randomised study. Respir Med 2008;102:1124-31.
124Kankaanranta H, Lahdensuo A, Moilanen E, Barnes PJ. Add-on therapy options in asthma not adequately controlled by inhaled corticosteroids: A comprehensive review. Respir Res 2004;5:17.
125Bateman ED, Bousquet J, Keech ML, Busse WW, Clark TJ, Pedersen SE, et al. The correlation between asthma control and health status: The GOAL study. Eur Respir J 2007;29:56-62.
126O'Byrne PM, Bleecker ER, Bateman ED, Busse WW, Woodcock A, Forth R, et al. Once-daily fluticasone furoate alone or combined with vilanterol in persistent asthma. Eur Respir J 2014;43:773-82.
127Woodcock A, Bleecker ER, Lötvall J, O'Byrne PM, Bateman ED, Medley H, et al. Efficacy and safety of fluticasone furoate/vilanterol compared with fluticasone propionate/salmeterol combination in adult and adolescent patients with persistent asthma: A randomized trial. Chest 2013;144:1222-9.
128Chowdhury BA, Dal Pan G. The FDA and safe use of long-acting beta-agonists in the treatment of asthma. N Engl J Med 2010;362:1169-71.
129Szefler SJ, Martin RJ, King TS, Boushey HA, Cherniack RM, Chinchilli VM, et al. Significant variability in response to inhaled corticosteroids for persistent asthma. J Allergy Clin Immunol 2002;109:410-8.
130Koshak EA. New FDA safety warnings for LABAs: A call for asthma guidelines revisit for solo beta agonist. Ann Thorac Med 2010;5:65-6.
131Powell H, Gibson PG. Inhaled corticosteroid doses in asthma: An evidence-based approach. Med J Aust 2003;178:223-5.
132Vaquerizo MJ, Casan P, Castillo J, Perpiña M, Sanchis J, Sobradillo V, et al. Effect of montelukast added to inhaled budesonide on control of mild to moderate asthma. Thorax 2003;58:204-10.
133Joos S, Miksch A, Szecsenyi J, Wieseler B, Grouven U, Kaiser T, et al. Montelukast as add-on therapy to inhaled corticosteroids in the treatment of mild to moderate asthma: A systematic review. Thorax 2008;63:453-62.
134Zeiger RS, Szefler SJ, Phillips BR, Schatz M, Martinez FD, Chinchilli VM, et al. Response profiles to fluticasone and montelukast in mild-to-moderate persistent childhood asthma. J Allergy Clin Immunol 2006;117:45-52.
135Evans DJ, Taylor DA, Zetterstrom O, Chung KF, O'Connor BJ, Barnes PJ, et al. A comparison of low-dose inhaled budesonide plus theophylline and high-dose inhaled budesonide for moderate asthma. N Engl J Med 1997;337:1412-8.
136Kerstjens HA, van den Berge M. Regular treatment for moderate asthma: Guidelines hold true. Lancet Respir Med 2015;3:88-9.
137Beeh KM, Moroni-Zentgraf P, Ablinger O, Hollaenderova Z, Unseld A, Engel M, et al. Tiotropium respimat® in asthma: A double-blind, randomised, dose-ranging study in adult patients with moderate asthma. Respir Res 2014;15:61.
138Tian JW, Chen JW, Chen R, Chen X. Tiotropium versus placebo for inadequately controlled asthma: A meta-analysis. Respir Care 2014;59:654-66.
139Peters SP, Kunselman SJ, Icitovic N, Moore WC, Pascual R, Ameredes BT, et al. Tiotropium bromide step-up therapy for adults with uncontrolled asthma. N Engl J Med 2010;363:1715-26.
140Bateman ED, Kornmann O, Schmidt P, Pivovarova A, Engel M, Fabbri LM, et al. Tiotropium is noninferior to salmeterol in maintaining improved lung function in B16-arg/arg patients with asthma. J Allergy Clin Immunol 2011;128:315-22.
141Smith LJ. Anticholinergics for patients with asthma? N Engl J Med 2010;363:1764-5.
142Sobieraj DM, Baker WL, Nguyen E, Weeda ER, Coleman CI, White CM, et al. Association of inhaled corticosteroids and long-acting muscarinic antagonists with asthma control in patients with uncontrolled, persistent asthma: A systematic review and meta-analysis. JAMA 2018;319:1473-84.
143Pauwels RA, Löfdahl CG, Postma DS, Tattersfield AE, O'Byrne P, Barnes PJ, et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and corticosteroids establishing therapy (FACET) international study group. N Engl J Med 1997;337:1405-11.
144Kerstjens HA, Disse B, Schröder-Babo W, Bantje TA, Gahlemann M, Sigmund R, et al. Tiotropium improves lung function in patients with severe uncontrolled asthma: A randomized controlled trial. J Allergy Clin Immunol 2011;128:308-14.
145Kerstjens HA, Engel M, Dahl R, Paggiaro P, Beck E, Vandewalker M, et al. Tiotropium in asthma poorly controlled with standard combination therapy. N Engl J Med 2012;367:1198-207.
146Virchow JC Jr., Prasse A, Naya I, Summerton L, Harris A. Zafirlukast improves asthma control in patients receiving high-dose inhaled corticosteroids. Am J Respir Crit Care Med 2000;162:578-85.
147American Lung Association Asthma Clinical Research Centers. Clinical trial of low-dose theophylline and montelukast in patients with poorly controlled asthma. Am J Respir Crit Care Med 2007;175:235-42.
148Rivington RN, Boulet LP, Côté J, Kreisman H, Small DI, Alexander M, et al. Efficacy of uniphyl, salbutamol, and their combination in asthmatic patients on high-dose inhaled steroids. Am J Respir Crit Care Med 1995;151:325-32.
149Al-Hajjaj MS. Difficult-to-treat asthma, is it really difficult? Ann Thorac Med 2011;6:1-2.
150Bousquet J, Rabe K, Humbert M, Chung KF, Berger W, Fox H, et al. Predicting and evaluating response to omalizumab in patients with severe allergic asthma. Respir Med 2007;101:1483-92.
151Bousquet J, Siergiejko Z, Swiebocka E, Humbert M, Rabe KF, Smith N, et al. Persistency of response to omalizumab therapy in severe allergic (IgE-mediated) asthma. Allergy 2011;66:671-8.
152Poon AH, Hamid Q. Personalized medicine for asthma: Are we there yet? Ann Thorac Med 2012;7:55-6.
153Bousquet J, Brusselle G, Buhl R, Busse WW, Cruz AA, Djukanovic R, et al. Care pathways for the selection of a biologic in severe asthma. Eur Respir J 2017;50. pii: 1701782.
154Skiepko R, Ziętkowski Z, Lukaszyk M, Budny W, Skiepko U, Milewski R, et al. Changes in blood eosinophilia during omalizumab therapy as a predictor of asthma exacerbation. Postepy Dermatol Alergol 2014;31:305-9.
155Massanari M, Holgate ST, Busse WW, Jimenez P, Kianifard F, Zeldin R, et al. Effect of omalizumab on peripheral blood eosinophilia in allergic asthma. Respir Med 2010;104:188-96.
156Chipps BE, Newbold P, Hirsch I, Trudo F, Goldman M. Benralizumab efficacy by atopy status and serum immunoglobulin E for patients with severe, uncontrolled asthma. Ann Allergy Asthma Immunol 2018;120:504-11.
157Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J 2014;43(2):343-73. doi: 10.1183/09031936.00202013.
158Ignacio-Garcia JM, Gonzalez-Santos P. Asthma self-management education program by home monitoring of peak expiratory flow. Am J Respir Crit Care Med 1995;151:353-9.
159Hawkins G, McMahon AD, Twaddle S, Wood SF, Ford I, Thomson NC, et al. Stepping down inhaled corticosteroids in asthma: Randomised controlled trial. BMJ 2003;326:1115.
160Powell H, Gibson PG. High dose versus low dose inhaled corticosteroid as initial starting dose for asthma in adults and children. Cochrane Database Syst Rev 2004;(2):CD004109.
161Boulet LP, Drollmann A, Magyar P, Timar M, Knight A, Engelstätter R, et al. Comparative efficacy of once-daily ciclesonide and budesonide in the treatment of persistent asthma. Respir Med 2006;100:785-94.
162Rank MA, Hagan JB, Park MA, Podjasek JC, Samant SA, Volcheck GW, et al. The risk of asthma exacerbation after stopping low-dose inhaled corticosteroids: A systematic review and meta-analysis of randomized controlled trials. J Allergy Clin Immunol 2013;131:724-9.
163Brozek JL, Kraft M, Krishnan JA, Cloutier MM, Lazarus SC, Li JT, et al. Long-acting β2-agonist step-off in patients with controlled asthma. Arch Intern Med 2012;172:1365-75.
164Masoli M, Weatherall M, Holt S, Beasley R. Budesonide once versus twice-daily administration: Meta-analysis. Respirology 2004;9:528-34.
165Bateman ED, Fairall L, Lombardi DM, English R. Budesonide/formoterol and formoterol provide similar rapid relief in patients with acute asthma showing refractoriness to salbutamol. Respir Res 2006;7:13.
166Randell TL, Donaghue KC, Ambler GR, Cowell CT, Fitzgerald DA, van Asperen PP, et al. Safety of the newer inhaled corticosteroids in childhood asthma. Paediatr Drugs 2003;5:481-504.
167Cox L, Nelson H, Lockey R, Calabria C, Chacko T, Finegold I, et al. Allergen immunotherapy: A practice parameter third update. J Allergy Clin Immunol 2011;127:S1-55.
168Dhami S, Kakourou A, Asamoah F, Agache I, Lau S, Jutel M, et al. Allergen immunotherapy for allergic asthma: A systematic review and meta-analysis. Allergy 2017;72:1825-48.
169Dominguez-Ortega J, Delgado J, Blanco C, Prieto L, Arroabarren E, Cimarra M, et al. Specific allergen immunotherapy for the treatment of allergic asthma: A review of current evidence. J Investig Allergol Clin Immunol 2017;27:1-35.
170Demoly P, Makatsori M, Casale TB, Calderon MA. The potential role of allergen immunotherapy in stepping down asthma treatment. J Allergy Clin Immunol Pract 2017;5:640-8.
171Jacobsen L, Niggemann B, Dreborg S, Ferdousi HA, Halken S, Høst A, et al. Specific immunotherapy has long-term preventive effect of seasonal and perennial asthma: 10-year follow-up on the PAT study. Allergy 2007;62:943-8.
172Rice JL, Diette GB, Suarez-Cuervo C, Brigham EP, Lin SY, Ramanathan M Jr., et al. Allergen-specific immunotherapy in the treatment of pediatric asthma: A systematic review. Pediatrics 2018;141. pii: e20173833.
173Elliott J, Kelly SE, Johnston A, Skidmore B, Gomes T, Wells GA, et al. Allergen immunotherapy for the treatment of allergic rhinitis and/or asthma: An umbrella review. CMAJ Open 2017;5:E373-85.
174Currie GP, Douglas JG, Heaney LG. Difficult to treat asthma in adults. BMJ 2009;338:b494.
175Sullivan SD, Rasouliyan L, Russo PA, Kamath T, Chipps BE; TENOR Study Group, et al. Extent, patterns, and burden of uncontrolled disease in severe or difficult-to-treat asthma. Allergy 2007;62:126-33.
176Serra-Batlles J, Plaza V, Morejón E, Comella A, Brugués J. Costs of asthma according to the degree of severity. Eur Respir J 1998;12:1322-6.
177Chen H, Blanc PD, Hayden ML, Bleecker ER, Chawla A, Lee JH, et al. Assessing productivity loss and activity impairment in severe or difficult-to-treat asthma. Value Health 2008;11:231-9.
178Porsbjerg C, Ulrik C, Skjold T, Backer V, Laerum B, Lehman S, et al. Nordic consensus statement on the systematic assessment and management of possible severe asthma in adults. Eur Clin Respir J 2018;5:1440868.
179Lee JH, Haselkorn T, Borish L, Rasouliyan L, Chipps BE, Wenzel SE, et al. Risk factors associated with persistent airflow limitation in severe or difficult-to-treat asthma: Insights from the TENOR study. Chest 2007;132:1882-9.
180Sturdy PM, Victor CR, Anderson HR, Bland JM, Butland BK, Harrison BD, et al. Psychological, social and health behaviour risk factors for deaths certified as asthma: A national case-control study. Thorax 2002;57:1034-9.
181Butler C, Heaney LG. Risk factors of frequent exacerbations in difficult-to-treat asthma. Eur Respir J 2006;27:1324-5.
182Gaga M, Papageorgiou N, Yiourgioti G, Karydi P, Liapikou A, Bitsakou H, et al. Risk factors and characteristics associated with severe and difficult to treat asthma phenotype: An analysis of the ENFUMOSA group of patients based on the ECRHS questionnaire. Clin Exp Allergy 2005;35:954-9.
183Sullivan SD, Wenzel SE, Bresnahan BW, Zheng B, Lee JH, Pritchard M, et al. Association of control and risk of severe asthma-related events in severe or difficult-to-treat asthma patients. Allergy 2007;62:655-60.
184Robinson DS, Campbell DA, Durham SR, Pfeffer J, Barnes PJ, Chung KF, et al. Systematic assessment of difficult-to-treat asthma. Eur Respir J 2003;22:478-83.
185Natarajan S, Subramanian P. Allergic bronchopulmonary aspergillosis: A clinical review of 24 patients: Are we right in frequent serologic monitoring? Ann Thorac Med 2014;9:216-20.
186Jani AL, Hamilos DL. Current thinking on the relationship between rhinosinusitis and asthma. J Asthma 2005;42:1-7.
187Koczulla AR, Vogelmeier CF, Garn H, Renz H. New concepts in asthma: Clinical phenotypes and pathophysiological mechanisms. Drug Discov Today 2017;22:388-96.
188Saji J, Arai M, Yamamoto T, Mineshita M, Miyazawa T. Efficacy of omalizumab in patients with severe asthma using the asthma health questionnaire and asthma control test. Arerugi 2014;63:1338-47.
189Storms W, Bowdish MS, Farrar JR. Omalizumab and asthma control in patients with moderate-to-severe allergic asthma: A 6-year pragmatic data review. Allergy Asthma Proc 2012;33:172-7.
190Heaney LG, Brightling CE, Menzies-Gow A, Stevenson M, Niven RM; British Thoracic Society Difficult Asthma Network, et al. Refractory asthma in the UK: Cross-sectional findings from a UK multicentre registry. Thorax 2010;65:787-94.
191Adcock IM, Lane SJ, Brown CR, Peters MJ, Lee TH, Barnes PJ, et al. Differences in binding of glucocorticoid receptor to DNA in steroid-resistant asthma. J Immunol 1995;154:3500-5.
192Barnes PJ. Corticosteroid resistance in airway disease. Proc Am Thorac Soc 2004;1:264-8.
193Ayres JG. Pseudo-steroid resistant asthma. Thorax 1999;54:956.
194Campbell JD, Blough DK, Sullivan SD. Comparison of guideline-based control definitions and associations with outcomes in severe or difficult-to-treat asthma. Ann Allergy Asthma Immunol 2008;101:474-81.
195Gibson PG, Yang IA, Upham JW, Reynolds PN, Hodge S, James AL, et al. Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): A randomised, double-blind, placebo-controlled trial. Lancet 2017;390:659-68.
196D'Hooghe JN, Ten Hacken NH, Weersink EJ, Sterk PJ, Annema JT, Bonta PI, et al. Emerging understanding of the mechanism of action of bronchial thermoplasty in asthma. Pharmacol Ther 2018;181:101-7.
197Iyer VN, Lim KG. Bronchial thermoplasty: Where there is smoke, there is fire. Allergy Asthma Proc 2015;36:251-5.
198Michaud G, Ernst A. Counterpoint: Efficacy of bronchial thermoplasty for patients with severe asthma. Is there sufficient evidence? Not yet. Chest 2011;140:576-7.
199Wu Q, Xing Y, Zhou X, Wang D. Meta-analysis of the efficacy and safety of bronchial thermoplasty in patients with moderate-to-severe persistent asthma. J Int Med Res 2011;39:10-22.
200Abramson MJ, Bailey MJ, Couper FJ, Driver JS, Drummer OH, Forbes AB, et al. Are asthma medications and management related to deaths from asthma? Am J Respir Crit Care Med 2001;163:12-8.
201Omachi TA, Iribarren C, Sarkar U, Tolstykh I, Yelin EH, Katz PP, et al. Risk factors for death in adults with severe asthma. Ann Allergy Asthma Immunol 2008;101:130-6.
202Hessel PA, Mitchell I, Tough S, Green FH, Cockcroft D, Kepron W, et al. Risk factors for death from asthma. Prairie provinces asthma study group. Ann Allergy Asthma Immunol 1999;83:362-8.
203Plaza V, Serrano J, Picado C, Sanchis J; High Risk Asthma Research Group. Frequency and clinical characteristics of rapid-onset fatal and near-fatal asthma. Eur Respir J 2002;19:846-52.
204Ramnath VR, Clark S, Camargo CA Jr. Multicenter study of clinical features of sudden-onset versus slower-onset asthma exacerbations requiring hospitalization. Respir Care 2007;52:1013-20.
205Barr RG, Woodruff PG, Clark S, Camargo CA Jr. Sudden-onset asthma exacerbations: Clinical features, response to therapy, and 2-week follow-up. Multicenter airway research collaboration (MARC) investigators. Eur Respir J 2000;15:266-73.
206Kolbe J, Fergusson W, Garrett J. Rapid onset asthma: A severe but uncommon manifestation. Thorax 1998;53:241-7.
207Kolbe J, Fergusson W, Vamos M, Garrett J. Case-control study of severe life threatening asthma (SLTA) in adults: Psychological factors. Thorax 2002;57:317-22.
208Mitchell I, Tough SC, Semple LK, Green FH, Hessel PA. Near-fatal asthma: A population-based study of risk factors. Chest 2002;121:1407-13.
209Al-Dorzi HM, Al-Shammary HA, Al-Shareef SY, Tamim HM, Shammout K, Al Dawood A, et al. Risk factors, management and outcomes of patients admitted with near fatal asthma to a tertiary care hospital in riyadh. Ann Thorac Med 2014;9:33-8.
210Magadle R, Berar-Yanay N, Weiner P. The risk of hospitalization and near-fatal and fatal asthma in relation to the perception of dyspnea. Chest 2002;121:329-33.
211Reddel H, Ware S, Marks G, Salome C, Jenkins C, Woolcock A, et al. Differences between asthma exacerbations and poor asthma control. Lancet 1999;353:364-9.
212Badminton MN, Campbell AK, Rembold CM. Differential regulation of nuclear and cytosolic ca2+in heLa cells. J Biol Chem 1996;271:31210-4.
213Harrison B, Stephenson P, Mohan G, Nasser S. An ongoing confidential enquiry into asthma deaths in the Eastern region of the UK, 2001-2003. Prim Care Respir J 2005;14:303-13.
214Spitzer WO, Suissa S, Ernst P, Horwitz RI, Habbick B, Cockcroft D, et al. The use of beta-agonists and the risk of death and near death from asthma. N Engl J Med 1992;326:501-6.
215Suissa S, Blais L, Ernst P. Patterns of increasing beta-agonist use and the risk of fatal or near-fatal asthma. Eur Respir J 1994;7:1602-9.
216Al-Dawood KM. Pattern and risk factors associated with hospital emergency visits among schoolboys with bronchial asthma in Al-Khobar. Ann Saudi Med 2002;22:29-33.
217Courtney AU, McCarter DF, Pollart SM. Childhood asthma: Treatment update. Am Fam Physician 2005;71:1959-68.
218Crane J, Burgess CD, Graham AN, Maling TJ. Hypokalaemic and electrocardiographic effects of aminophylline and salbutamol in obstructive airways disease. N Z Med J 1987;100:309-11.
219Rodrigo C, Rodrigo G. High-dose MDI salbutamol treatment of asthma in the ED. Am J Emerg Med 1995;13:21-6.
220Rodrigo G, Rodrigo C. Metered dose inhaler salbutamol treatment of asthma in the ED: Comparison of two doses with plasma levels. Am J Emerg Med 1996;14:144-50.
221Molfino NA, Nannini LJ, Martelli AN, Slutsky AS. Respiratory arrest in near-fatal asthma. N Engl J Med 1991;324:285-8.
222Bai TR, Cooper J, Koelmeyer T, Paré PD, Weir TD. The effect of age and duration of disease on airway structure in fatal asthma. Am J Respir Crit Care Med 2000;162:663-9.
223Rowe BH, Keller JL, Oxman AD. Effectiveness of steroid therapy in acute exacerbations of asthma: A meta-analysis. Am J Emerg Med 1992;10:301-10.
224O'Driscoll BR, Howard LS, Davison AG; British Thoracic Society. BTS guideline for emergency oxygen use in adult patients. Thorax 2008;63 Suppl 6:vi1-68.
225Chien JW, Ciufo R, Novak R, Skowronski M, Nelson J, Coreno A, et al. Uncontrolled oxygen administration and respiratory failure in acute asthma. Chest 2000;117:728-33.
226Rodrigo GJ, Rodriquez Verde M, Peregalli V, Rodrigo C. Effects of short-term 28% and 100% oxygen on paCO2 and peak expiratory flow rate in acute asthma: A randomized trial. Chest 2003;124:1312-7.
227McFadden ER Jr. Critical appraisal of the therapy of asthma – An idea whose time has come. Am Rev Respir Dis 1986;133:723-4.
228Kerem E, Levison H, Schuh S, O'Brodovich H, Reisman J, Bentur L, et al. Efficacy of albuterol administered by nebulizer versus spacer device in children with acute asthma. J Pediatr 1993;123:313-7.
229Rodrigo C, Rodrigo G. Salbutamol treatment of acute severe asthma in the ED: MDI versus hand-held nebulizer. Am J Emerg Med 1998;16:637-42.
230Cates CJ, Crilly JA, Rowe BH. Holding chambers (spacers) versus nebulisers for beta-agonist treatment of acute asthma. Cochrane Database Syst Rev 2006;(2):CD000052.
231Cates CC, Bara A, Crilly JA, Rowe BH. Holding chambers versus nebulisers for beta-agonist treatment of acute asthma. Cochrane Database Syst Rev 2013;(9):CD000052. doi: 10.1002/14651858.CD000052.
232Rossing TH, Fanta CH, Goldstein DH, Snapper JR, McFadden ER Jr. Emergency therapy of asthma: Comparison of the acute effects of parenteral and inhaled sympathomimetics and infused aminophylline. Am Rev Respir Dis 1980;122:365-71.
233Rowe BH, Spooner C, Ducharme FM, Bretzlaff JA, Bota GW. Early emergency department treatment of acute asthma with systemic corticosteroids. Cochrane Database Syst Rev 2001;(1):CD002178.
234Rowe BH, Spooner C, Ducharme FM, Bretzlaff JA, Bota GW. Early emergency department treatment of acute asthma with systemic corticosteroids. Cochrane Database Syst Rev 2001;(1):CD002178.
235Tokuda Y, Miyagi S. Oxygen treatment for acute severe asthma. Home oxygenation would be more effective. BMJ 2001;323:1069.
236Inwald D, Roland M, Kuitert L, McKenzie SA, Petros A. Oxygen treatment for acute severe asthma. BMJ 2001;323:98-100.
237Gleeson JG, Green S, Price JF. Air or oxygen as driving gas for nebulised salbutamol. Arch Dis Child 1988;63:900-4.
238Douglas JG, Rafferty P, Fergusson RJ, Prescott RJ, Crompton GK, Grant IW, et al. Nebulised salbutamol without oxygen in severe acute asthma: How effective and how safe? Thorax 1985;40:180-3.
239Lanes SF, Garrett JE, Wentworth CE 3rd, Fitzgerald JM, Karpel JP. The effect of adding ipratropium bromide to salbutamol in the treatment of acute asthma: A pooled analysis of three trials. Chest 1998;114:365-72.
240Chassany O, Fullerton S. Meta-analysis of the effects of ipratropium bromide in adults with acute asthma. Am J Med 2000;108:596-7.
241Rodrigo G, Rodrigo C, Burschtin O. A meta-analysis of the effects of ipratropium bromide in adults with acute asthma. Am J Med 1999;107:363-70.
242Stoodley RG, Aaron SD, Dales RE. The role of ipratropium bromide in the emergency management of acute asthma exacerbation: A metaanalysis of randomized clinical trials. Ann Emerg Med 1999;34:8-18.
243Rowe BH, Spooner CH, Ducharme FM, Bretzlaff JA, Bota GW. Corticosteroids for preventing relapse following acute exacerbations of asthma. Cochrane Database Syst Rev 2007;(3):CD000195.
244Rowe BH, Bretzlaff JA, Bourdon C, Bota GW, Camargo CA Jr. Magnesium sulfate for treating exacerbations of acute asthma in the emergency department. Cochrane Database Syst Rev 2000;(2):CD001490.
245Alzeer AH, Al Otair HA, Khurshid SM, Badrawy SE, Bakir BM. A case of near fatal asthma: The role of ECMO as rescue therapy. Ann Thorac Med 2015;10:143-5.
246Shrestha M, Bidadi K, Gourlay S, Hayes J. Continuous vs intermittent albuterol, at high and low doses, in the treatment of severe acute asthma in adults. Chest 1996;110:42-7.
247Lin RY, Sauter D, Newman T, Sirleaf J, Walters J, Tavakol M, et al. Continuous versus intermittent albuterol nebulization in the treatment of acute asthma. Ann Emerg Med 1993;22:1847-53.
248Camargo CA Jr., Spooner CH, Rowe BH. Continuous versus intermittent beta-agonists in the treatment of acute asthma. Cochrane Database Syst Rev 2003;(4):CD001115.
249Fitzgerald JM, Baynham R, Powles AC. Use of oxygen therapy for adult patients outside the critical care areas of a university hospital. Lancet 1988;1:981-3.
250Rowe BH, Spooner CH, Ducharme FM, Bretzlaff JA, Bota GW. Corticosteroids for preventing relapse following acute exacerbations of asthma. Cochrane Database Syst Rev 2007;(3):CD000195.
251Dicpinigaitis PV. Angiotensin-converting enzyme inhibitor-induced cough: ACCP evidence-based clinical practice guidelines. Chest 2006;129:169S-73S.
252Dicpinigaitis PV. Chronic cough due to asthma: ACCP evidence-based clinical practice guidelines. Chest 2006;129:75S-9S.
253Morice AH, McGarvey L, Pavord I; British Thoracic Society Cough Guideline Group. Recommendations for the management of cough in adults. Thorax 2006;61 Suppl 1:i1-24.
254Spector SL, Tan RA. Effectiveness of montelukast in the treatment of cough variant asthma. Ann Allergy Asthma Immunol 2004;93:232-6.
255Desai D, Brightling C. Cough due to asthma, cough-variant asthma and non-asthmatic eosinophilic bronchitis. Otolaryngol Clin North Am 2010;43:123-30, x.
256Cruz AA, Popov T, Pawankar R, Annesi-Maesano I, Fokkens W, Kemp J, et al. Common characteristics of upper and lower airways in rhinitis and asthma: ARIA update, in collaboration with GA(2) LEN. Allergy 2007;62 Suppl 84:1-41.
257Cheng L, Zhang L. Introduction to allergic rhinitis and its impact on asthma (ARIA) guidelines 2010 revision. Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 2011;46:437-9.
258Brozek JL, Bousquet J, Baena-Cagnani CE, Bonini S, Canonica GW, Casale TB, et al. Allergic rhinitis and its impact on asthma (ARIA) guidelines: 2010 revision. J Allergy Clin Immunol 2010;126:466-76.
259Sears MR, Lötvall J. Past, present and future – Beta2-adrenoceptor agonists in asthma management. Respir Med 2005;99:152-70.
260Parsons JP, Hallstrand TS, Mastronarde JG, Kaminsky DA, Rundell KW, Hull JH, et al. An official American thoracic society clinical practice guideline: Exercise-induced bronchoconstriction. Am J Respir Crit Care Med 2013;187:1016-27.
261de Benedictis FM, del Giudice MM, Forenza N, Decimo F, de Benedictis D, Capristo A, et al. Lack of tolerance to the protective effect of montelukast in exercise-induced bronchoconstriction in children. Eur Respir J 2006;28:291-5.
262Laidlaw TM, Boyce JA. Aspirin-exacerbated respiratory disease – New prime suspects. N Engl J Med 2016;374:484-8.
263Szczeklik A, Stevenson DD. Aspirin-induced asthma: Advances in pathogenesis, diagnosis, and management. J Allergy Clin Immunol 2003;111:913-21.
264White AA, Stevenson DD. Aspirin-exacerbated respiratory disease. N Engl J Med 2018;379:1060-70.
265Woessner KM, Simon RA, Stevenson DD. The safety of celecoxib in patients with aspirin-sensitive asthma. Arthritis Rheum 2002;46:2201-6.
266Berges-Gimeno MP, Simon RA, Stevenson DD. Long-term treatment with aspirin desensitization in asthmatic patients with aspirin-exacerbated respiratory disease. J Allergy Clin Immunol 2003;111:180-6.
267Cahill KN, Boyce JA. Aspirin-exacerbated respiratory disease: Mediators and mechanisms of a clinical disease. J Allergy Clin Immunol 2017;139:764-6.
268Stevenson DD. Diagnosis, prevention, and treatment of adverse reactions to aspirin and nonsteroidal anti-inflammatory drugs. J Allergy Clin Immunol 1984;74:617-22.
269Park JS, Jang AS, Park SW, Lee YM, Uh ST, Kim YH, et al. Protection of leukotriene receptor antagonist against aspirin-induced bronchospasm in asthmatics. Allergy Asthma Immunol Res 2010;2:48-54.
270Al-Asoom LI, Al-Rubaish A, Al-Quorain AA, Qutub H, El-Munshid HA. The association of gastroesophageal reflux with bronchial asthma. Can asthma also trigger reflux? Hepatogastroenterology 2006;53:64-72.
271Bresci G, Sacco R. Pulmonary or otolaryngologic extraesophageal manifestations in patients with gastroesophageal reflux disease. World J Gastrointest Endosc 2010;2:47-9.
272Gaude GS. Pulmonary manifestations of gastroesophageal reflux disease. Ann Thorac Med 2009;4:115-23.
273Champion GL, Richter JE. Atypical presentation of gastroesophageal reflux disease: Chest pain, pulmonary, and ear, nose, throat manifestations. Gastroenterologist 1993;1:18-33.
274Asano K, Suzuki H. Silent acid reflux and asthma control. N Engl J Med 2009;360:1551-3.
275Schatz M, Harden K, Forsythe A, Chilingar L, Hoffman C, Sperling W, et al. The course of asthma during pregnancy, post partum, and with successive pregnancies: A prospective analysis. J Allergy Clin Immunol 1988;81:509-17.
276Blais L, Kettani FZ, Forget A, Beauchesne MF, Lemière C. Asthma exacerbations during the first trimester of pregnancy and congenital malformations: Revisiting the association in a large representative cohort. Thorax 2015;70:647-52.
277Murphy VE, Gibson PG, Smith R, Clifton VL. Asthma during pregnancy: Mechanisms and treatment implications. Eur Respir J 2005;25:731-50.
278Holland SM, Thomson KD. Acute severe asthma presenting in late pregnancy. Int J Obstet Anesth 2006;15:75-8.
279Hanania NA, Belfort MA. Acute asthma in pregnancy. Crit Care Med 2005;33:S319-24.
280Smy L, Chan AC, Bozzo P, Koren G. Is it safe to use inhaled corticosteroids in pregnancy? Can Fam Physician 2014;60:809-12, e433-5.
281Rahimi R, Nikfar S, Abdollahi M. Meta-analysis finds use of inhaled corticosteroids during pregnancy safe: A systematic meta-analysis review. Hum Exp Toxicol 2006;25:447-52.
282Gluck JC, Gluck PA. The effect of pregnancy on the course of asthma. Immunol Allergy Clin North Am 2006;26:63-80.
283Wendel PJ, Ramin SM, Barnett-Hamm C, Rowe TF, Cunningham FG. Asthma treatment in pregnancy: A randomized controlled study. Am J Obstet Gynecol 1996;175:150-4.
284Lao TT, Huengsburg M. Labour and delivery in mothers with asthma. Eur J Obstet Gynecol Reprod Biol 1990;35:183-90.
285Arora N, Mahajan K, Jana N, Maiti TK, Mandal D, Pandey R, et al. Successful pregnancy outcome among women with end-stage renal disease requiring haemodialysis. J Indian Med Assoc 2009;107:237-8.
286Fitzsimons R, Greenberger PA, Patterson R. Outcome of pregnancy in women requiring corticosteroids for severe asthma. J Allergy Clin Immunol 1986;78:349-53.
287Perlow JH, Montgomery D, Morgan MA, Towers CV, Porto M. Severity of asthma and perinatal outcome. Am J Obstet Gynecol 1992;167:963-7.
288Levy ML, Nicholson PJ. Occupational asthma case finding: A role for primary care. Br J Gen Pract 2004;54:731-3.
289Baur X, Aasen TB, Burge PS, Heederik D, Henneberger PK, Maestrelli P, et al. The management of work-related asthma guidelines: A broader perspective. Eur Respir Rev 2012;21:125-39.
290Legiest B, Nemery B. Management of work-related asthma: Guidelines and challenges. Eur Respir Rev 2012;21:79-81.
291Al Ghobain M, Al-Hajjaj MS, Wali SO. Prevalence of chronic obstructive pulmonary disease among smokers attending primary healthcare clinics in Saudi Arabia. Ann Saudi Med 2011;31:129-33.
292Gibson PG, Simpson JL. The overlap syndrome of asthma and COPD: What are its features and how important is it? Thorax 2009;64:728-35.
293Kauppi P, Kupiainen H, Lindqvist A, Tammilehto L, Kilpeläinen M, Kinnula VL, et al. Overlap syndrome of asthma and COPD predicts low quality of life. J Asthma 2011;48:279-85.
294Hardin M, Silverman EK, Barr RG, Hansel NN, Schroeder JD, Make BJ, et al. The clinical features of the overlap between COPD and asthma. Respir Res 2011;12:127.
295Asthma GI. The Global Strategy for Asthma Management and Prevention; 2015.
296Louie S, Zeki AA, Schivo M, Chan AL, Yoneda KY, Avdalovic M, et al. The asthma-chronic obstructive pulmonary disease overlap syndrome: Pharmacotherapeutic considerations. Expert Rev Clin Pharmacol 2013;6:197-219.
297Al-Kassimi FA, Alhamad EH, Al-Hajjaj MS, Abba AA, Raddaoui E, Shaikh SA, et al. Abrupt withdrawal of inhaled corticosteroids does not result in spirometric deterioration in chronic obstructive pulmonary disease: Effect of phenotyping? Ann Thorac Med 2012;7:238-42.
298Edmonds ML, Camargo CA Jr., Pollack CV Jr., Rowe BH. Early use of inhaled corticosteroids in the emergency department treatment of acute asthma. Cochrane Database Syst Rev 2012;12:CD002308. doi: 10.1002/14651858.CD002308.
299Denlinger LC, Sorkness CA, Chinchilli VM, Lemanske RF Jr. Guideline-defining asthma clinical trials of the national heart, lung, and blood institute's asthma clinical research network and childhood asthma research and education network. J Allergy Clin Immunol 2007;119:3-11.
300Glauber JH, Fuhlbrigge AL, Finkelstein JA, Homer CJ, Weiss ST. Relationship between asthma medication and antibiotic use. Chest 2001;120:1485-92.
301Seear M, Wensley D, West N. How accurate is the diagnosis of exercise induced asthma among vancouver schoolchildren? Arch Dis Child 2005;90:898-902.
302Weinberger M. Pediatric asthma and related allergic and nonallergic diseases: Patient-oriented evidence-based essentials that matter. Pediatr Health 2008;2:631-50.
303Hederos CA, Janson S, Andersson H, Hedlin G. Chest X-ray investigation in newly discovered asthma. Pediatr Allergy Immunol 2004;15:163-5.
304Chipps BE, Bacharier LB, Harder JM. Phenotypic expressions of childhood wheezing and asthma: Implications for therapy. J Pediatr 2011;158:878-840.
305Fahy JV, O'Byrne PM. “Reactive airways disease”. A lazy term of uncertain meaning that should be abandoned. Am J Respir Crit Care Med 2001;163:822-3.
306Weinberger MI, Sirey JA, Bruce ML, Heo M, Papademetriou E, Meyers BS, et al. Predictors of major depression six months after admission for outpatient treatment. Psychiatr Serv 2008;59:1211-5.
307Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan WJ, et al. Asthma and wheezing in the first six years of life. The group health medical associates. N Engl J Med 1995;332:133-8.
308Bubshait DK, Albuali WH, Yousef AA, Obeid OE, Alkharsah KR, Hassan MI, et al. Clinical description of human bocavirus viremia in children with LRTI, Eastern province, Saudi Arabia. Ann Thorac Med 2015;10:146-9.
309Just J, Gouvis-Echraghi R, Couderc R, Guillemot-Lambert N, Saint-Pierre P. Novel severe wheezy young children phenotypes: Boys atopic multiple-trigger and girls nonatopic uncontrolled wheeze. J Allergy Clin Immunol 2012;130:103-10.e8.
310Savenije OE, Kerkhof M, Koppelman GH, Postma DS. Predicting who will have asthma at school age among preschool children. J Allergy Clin Immunol 2012;130:325-31.
311Guilbert TW, Morgan WJ, Zeiger RS, Bacharier LB, Boehmer SJ, Krawiec M, et al. Atopic characteristics of children with recurrent wheezing at high risk for the development of childhood asthma. J Allergy Clin Immunol 2004;114:1282-7.
312Castro-Rodriguez JA. The asthma predictive index: A very useful tool for predicting asthma in young children. J Allergy Clin Immunol 2010;126:212-6.
313Chang TS, Lemanske RF Jr., Guilbert TW, Gern JE, Coen MH, Evans MD, et al. Evaluation of the modified asthma predictive index in high-risk preschool children. J Allergy Clin Immunol Pract 2013;1:152-6.
314Yousef AA, Al-Shamrani AS, Al-Haider SA, Said YS, Al Harbi S, Al-Harbi AS, et al. Pediatric pulmonary services in Saudi Arabia. Ann Thorac Med 2013;8:224-8.
315Yawn BP, Brenneman SK, Allen-Ramey FC, Cabana MD, Markson LE. Assessment of asthma severity and asthma control in children. Pediatrics 2006;118:322-9.
316Liu AH, Zeiger R, Sorkness C, Mahr T, Ostrom N, Burgess S, et al. Development and cross-sectional validation of the childhood asthma control test. J Allergy Clin Immunol 2007;119:817-25.
317Liu AH, Zeiger RS, Sorkness CA, Ostrom NK, Chipps BE, Rosa K, et al. The childhood asthma control test: Retrospective determination and clinical validation of a cut point to identify children with very poorly controlled asthma. J Allergy Clin Immunol 2010;126:267-73, 273.e1.
318Zeiger RS, Mellon M, Chipps B, Murphy KR, Schatz M, Kosinski M, et al. Test for respiratory and asthma control in kids (TRACK): Clinically meaningful changes in score. J Allergy Clin Immunol 2011;128:983-8.
319Welsh EJ, Hasan M, Li P. Home-based educational interventions for children with asthma. Cochrane Database Syst Rev 2003:CD000326.
320Wolf FM, Guevara JP, Grum CM, Clark NM, Cates CJ. Educational interventions for asthma in children. Cochrane Database Syst Rev 2003:CD000326.
321Wood MR, Bolyard D. Making education count: the nurse's role in asthma education using a medical home model of care. J pediatr nurs 2011;26:552-8.
322Becker A, Lemière C, Bérubé D, Boulet LP, Ducharme FM, FitzGerald M, et al. Summary of recommendations from the canadian asthma consensus guidelines, 2003. CMAJ 2005;173:S3-11.
323Nurmatov U, Devereux G, Sheikh A. Nutrients and foods for the primary prevention of asthma and allergy: Systematic review and meta-analysis. J Allergy Clin Immunol 2011;127:724-330.
324Pelucchi C, Chatenoud L, Turati F, Galeone C, Moja L, Bach JF, et al. Probiotics supplementation during pregnancy or infancy for the prevention of atopic dermatitis: A meta-analysis. Epidemiology 2012;23:402-14.
325Kozyrskyj AL, Pawlowski AN. Maternal distress and childhood wheeze: Mechanisms and context. Am J Respir Crit Care Med 2013;187:1160-2.
326Cabana MD, McKean M, Caughey AB, Fong L, Lynch S, Wong A, et al. Early probiotic supplementation for eczema and asthma prevention: A randomized controlled trial. Pediatrics 2017;140. pii: e20163000.
327Bisgaard H, Allen DB, Milanowski J, Kalev I, Willits L, Davies P, et al. Twelve-month safety and efficacy of inhaled fluticasone propionate in children aged 1 to 3 years with recurrent wheezing. Pediatrics 2004;113:e87-94.
328Leflein JG, Szefler SJ, Murphy KR, Fitzpatrick S, Cruz-Rivera M, Miller CJ, et al. Nebulized budesonide inhalation suspension compared with cromolyn sodium nebulizer solution for asthma in young children: Results of a randomized outcomes trial. Pediatrics 2002;109:866-72.
329Zhang L, Pruteanu AI, Prietsch SO, Chauhan BF, Ducharme FM. Cochrane in context: Inhaled corticosteroids in children with persistent asthma: Effects on growth and dose-response effects on growth. Evid Based Child Health 2014;9:1047-51.
330Pruteanu AI, Chauhan BF, Zhang L, Prietsch SO, Ducharme FM. Inhaled corticosteroids in children with persistent asthma: Dose-response effects on growth. Evid Based Child Health 2014;9:931-1046.
331Dufour V, Millon L, Faucher JF, Bard E, Robinet E, Piarroux R, et al. Effects of a short-course of amoxicillin/clavulanic acid on systemic and mucosal immunity in healthy adult humans. Int Immunopharmacol 2005;5:917-28.
332Adams NP, Bestall JB, Jones PW. Inhaled beclomethasone versus placebo for chronic asthma. Cochrane Database Syst Rev 2000;(4):CD002738.
333Jackson DJ, Bacharier LB, Mauger DT, Boehmer S, Beigelman A, Chmiel JF, et al. Quintupling inhaled glucocorticoids to prevent childhood asthma exacerbations. N Engl J Med 2018;378:891-901.
334Bacharier LB, Phillips BR, Zeiger RS, Szefler SJ, Martinez FD, Lemanske RF Jr., et al. Episodic use of an inhaled corticosteroid or leukotriene receptor antagonist in preschool children with moderate-to-severe intermittent wheezing. J Allergy Clin Immunol 2008;122:1127-35.
335Reddel HK, Foster JM. Inconclusive evidence about the efficacy of diverse strategies for intermittent versus daily inhaled corticosteroids for persistent asthma in adults and children. Evid Based Med 2014;19:e2.
336Kemp JP, Meltzer EO. Beta 2 adrenergic agonists – Oral or aerosol for the treatment of asthma? J Asthma 1990;27:149-57.
337Bonner S, Matte T, Rubin M, Fagan JK, Ahern J, Evans D, et al. Oral beta2-agonist use by preschool children with asthma in East and Central Harlem, New York. J Asthma 2006;43:31-5.
338Lazarus SC, Boushey HA, Fahy JV, Chinchilli VM, Lemanske RF Jr., Sorkness CA, et al. Long-acting beta2-agonist monotherapy vs. continued therapy with inhaled corticosteroids in patients with persistent asthma: A randomized controlled trial. JAMA 2001;285:2583-93.
339Deerojanawong J, Manuyakorn W, Prapphal N, Harnruthakorn C, Sritippayawan S, Samransamruajkit R, et al. Randomized controlled trial of salbutamol aerosol therapy via metered dose inhaler-spacer vs. jet nebulizer in young children with wheezing. Pediatr Pulmonol 2005;39:466-72.
340Agertoft L, Pedersen S. Importance of training for correct turbuhaler use in preschool children. Acta Paediatr 1998;87:842-7.
341Drblik S, Lapierre G, Thivierge R, Turgeon J, Gaudreault P, Cummins-McManus B, et al. Comparative efficacy of terbutaline sulphate delivered by turbuhaler dry powder inhaler or pressurised metered dose inhaler with nebuhaler spacer in children during an acute asthmatic episode. Arch Dis Child 2003;88:319-23.
342Castro-Rodriguez JA, Rodrigo GJ. Beta-agonists through metered-dose inhaler with valved holding chamber versus nebulizer for acute exacerbation of wheezing or asthma in children under 5 years of age: A systematic review with meta-analysis. J Pediatr 2004;145:172-7.
343Ducharme FM, Lemire C, Noya FJ, Davis GM, Alos N, Leblond H, et al. Preemptive use of high-dose fluticasone for virus-induced wheezing in young children. N Engl J Med 2009;360:339-53.
344Bisgaard H, Hermansen MN, Loland L, Halkjaer LB, Buchvald F. Intermittent inhaled corticosteroids in infants with episodic wheezing. N Engl J Med 2006;354:1998-2005.
345Papi A, Nicolini G, Baraldi E, Boner AL, Cutrera R, Rossi GA, et al. Regular vs prn nebulized treatment in wheeze preschool children. Allergy 2009;64:1463-71.
346Fitzpatrick AM, Jackson DJ, Mauger DT, Boehmer SJ, Phipatanakul W, Sheehan WJ, et al. Individualized therapy for persistent asthma in young children. J Allergy Clin Immunol 2016;138:1608-18.e12.
347Guilbert TW, Morgan WJ, Zeiger RS, Mauger DT, Boehmer SJ, Szefler SJ, et al. Long-term inhaled corticosteroids in preschool children at high risk for asthma. N Engl J Med 2006;354:1985-97.
348Nielsen KG, Bisgaard H. The effect of inhaled budesonide on symptoms, lung function, and cold air and methacholine responsiveness in 2- to 5-year-old asthmatic children. Am J Respir Crit Care Med 2000;162:1500-6.
349Szefler SJ, Baker JW, Uryniak T, Goldman M, Silkoff PE. Comparative study of budesonide inhalation suspension and montelukast in young children with mild persistent asthma. J Allergy Clin Immunol 2007;120:1043-50.
350Knorr B, Franchi LM, Bisgaard H, Vermeulen JH, LeSouef P, Santanello N, et al. Montelukast, a leukotriene receptor antagonist, for the treatment of persistent asthma in children aged 2 to 5 years. Pediatrics 2001;108:E48.
351Bisgaard H. Leukotriene modifiers in pediatric asthma management. Pediatrics 2001;107:381-90.
352Ducharme FM, Hicks GC. Anti-leukotriene agents compared to inhaled corticosteroids in the management of recurrent and/or chronic asthma in adults and children. Cochrane Database Syst Rev 2002;(3):CD002314.
353Chauhan BF, Ducharme FM. Addition to inhaled corticosteroids of long-acting beta2-agonists versus anti-leukotrienes for chronic asthma. Cochrane Database Syst Rev 2014;1:CD003137.
354Chong JK, Chauhan BF. Addition of antileukotriene agents to inhaled corticosteroids in children with persistent asthma. Paediatr Child Health 2014;19:473-4.
355Halwani R, Vazquez-Tello A, Horanieh N, Dulgom S, Al-Aseri Z, Al-Khamis N, et al. Risk factors hindering asthma symptom control in Saudi children and adolescents. Pediatr Int 2017;59:661-8.
356Shrewsbury S, Pyke S, Britton M. Meta-analysis of increased dose of inhaled steroid or addition of salmeterol in symptomatic asthma (MIASMA). BMJ 2000;320:1368-73.
357Matz J, Emmett A, Rickard K, Kalberg C. Addition of salmeterol to low-dose fluticasone versus higher-dose fluticasone: An analysis of asthma exacerbations. J Allergy Clin Immunol 2001;107:783-9.
358Vaessen-Verberne AA, van den Berg NJ, van Nierop JC, Brackel HJ, Gerrits GP, Hop WC, et al. Combination therapy salmeterol/fluticasone versus doubling dose of fluticasone in children with asthma. Am J Respir Crit Care Med 2010;182:1221-7.
359Verberne AA, Frost C, Duiverman EJ, Grol MH, Kerrebijn KF. Addition of salmeterol versus doubling the dose of beclomethasone in children with asthma. The Dutch asthma study group. Am J Respir Crit Care Med 1998;158:213-9.
360Ducharme FM, Ni Chroinin M, Greenstone I, Lasserson TJ. Addition of long-acting beta2-agonists to inhaled corticosteroids versus same dose inhaled corticosteroids for chronic asthma in adults and children. Cochrane Database Syst Rev 2010;(5):CD005535. doi: 10.1002/14651858.CD005535.
361Ducharme FM, Ni Chroinin M, Greenstone I, Lasserson TJ. Addition of long-acting beta2-agonists to inhaled steroids versus higher dose inhaled steroids in adults and children with persistent asthma. Cochrane Database Syst Rev 2010;(4):CD005533. doi: 10.1002/14651858.CD005533.
362Kulus M, Hébert J, Garcia E, Fowler Taylor A, Fernandez Vidaurre C, Blogg M, et al. Omalizumab in children with inadequately controlled severe allergic (IgE-mediated) asthma. Curr Med Res Opin 2010;26:1285-93.
363Lanier B, Bridges T, Kulus M, Taylor AF, Berhane I, Vidaurre CF, et al. Omalizumab for the treatment of exacerbations in children with inadequately controlled allergic (IgE-mediated) asthma. J Allergy Clin Immunol 2009;124:1210-6.
364Deschildre A, Marguet C, Langlois C, Pin I, Rittié JL, Derelle J, et al. Real-life long-term omalizumab therapy in children with severe allergic asthma. Eur Respir J 2015;46:856-9.
365Licari A, Marseglia A, Caimmi S, Castagnoli R, Foiadelli T, Barberi S, et al. Omalizumab in children. Paediatr Drugs 2014;16:491-502.
366Ni Chroinin M, Greenstone I, Lasserson TJ, Ducharme FM. Addition of inhaled long-acting beta2-agonists to inhaled steroids as first line therapy for persistent asthma in steroid-naive adults and children. Cochrane Database Syst Rev 2009;(4):CD005307.
367Ni Chroinin M, Lasserson TJ, Greenstone I, Ducharme FM. Addition of long-acting beta-agonists to inhaled corticosteroids for chronic asthma in children. Cochrane Database Syst Rev 2009;(3):CD007949.
368Ducharme FM. Anti-leukotrienes as add-on therapy to inhaled glucocorticoids in patients with asthma: Systematic review of current evidence. BMJ 2002;324:1545.
369Phipatanakul W, Cronin B, Wood RA, Eggleston PA, Shih MC, Song L, et al. Effect of environmental intervention on mouse allergen levels in homes of inner-city boston children with asthma. Ann Allergy Asthma Immunol 2004;92:420-5.
370Simons FE, Villa JR, Lee BW, Teper AM, Lyttle B, Aristizabal G, et al. Montelukast added to budesonide in children with persistent asthma: A randomized, double-blind, crossover study. J Pediatr 2001;138:694-8.
371Goksör E, Amark M, Alm B, Gustafsson PM, Wennergren G. Asthma symptoms in early childhood – What happens then? Acta Paediatr 2006;95:471-8.
372Swern AS, Tozzi CA, Knorr B, Bisgaard H. Predicting an asthma exacerbation in children 2 to 5 years of age. Ann Allergy Asthma Immunol 2008;101:626-30.
373Ducharme FM, Chalut D, Plotnick L, Savdie C, Kudirka D, Zhang X, et al. The pediatric respiratory assessment measure: A valid clinical score for assessing acute asthma severity from toddlers to teenagers. J Pediatr 2008;152:476-80, 480.e1.
374Birken CS, Parkin PC, Macarthur C. Asthma severity scores for preschoolers displayed weaknesses in reliability, validity, and responsiveness. J Clin Epidemiol 2004;57:1177-81.
375Parkin PC, Macarthur C, Saunders NR, Diamond SA, Winders PM. Development of a clinical asthma score for use in hospitalized children between 1 and 5 years of age. J Clin Epidemiol 1996;49:821-5.
376Bentur L, Kerem E, Canny G, Reisman J, Schuh S, Stein R, et al. Response of acute asthma to a beta 2 agonist in children less than two years of age. Ann Allergy 1990;65:122-6.
377Wennergren G, Engström I, Bjure J. Transcutaneous oxygen and carbon dioxide levels and a clinical symptom scale for monitoring the acute asthmatic state in infants and young children. Acta Paediatr Scand 1986;75:465-9.
378Tal A, Bavilski C, Yohai D, Bearman JE, Gorodischer R, Moses SW, et al. Dexamethasone and salbutamol in the treatment of acute wheezing in infants. Pediatrics 1983;71:13-8.
379Bentur L, Canny GJ, Shields MD, Kerem E, Schuh S, Reisman JJ, et al. Controlled trial of nebulized albuterol in children younger than 2 years of age with acute asthma. Pediatrics 1992;89:133-7.
380Tal A, Levy N, Bearman JE. Methylprednisolone therapy for acute asthma in infants and toddlers: A controlled clinical trial. Pediatrics 1990;86:350-6.
381Chalut DS, Ducharme FM, Davis GM. The preschool respiratory assessment measure (PRAM): A responsive index of acute asthma severity. J Pediatr 2000;137:762-8.
382Al-Muhsen S, Horanieh N, Dulgom S, Aseri ZA, Vazquez-Tello A, Halwani R, et al. Poor asthma education and medication compliance are associated with increased emergency department visits by asthmatic children. Ann Thorac Med 2015;10:123-31.
383Alnaji F, Zemek R, Barrowman N, Plint A. PRAM score as predictor of pediatric asthma hospitalization. Acad Emerg Med 2014;21:872-8.
384Jarvis SW, Kovacs C, Badriyah T, Briggs J, Mohammed MA, Meredith P, et al. Development and validation of a decision tree early warning score based on routine laboratory test results for the discrimination of hospital mortality in emergency medical admissions. Resuscitation 2013;84:1494-9.
385Johnson KB, Blaisdell CJ, Walker A, Eggleston P. Effectiveness of a clinical pathway for inpatient asthma management. Pediatrics 2000;106:1006-12.
386Ortiz-Alvarez O, Mikrogianakis A; Canadian Paediatric Society, Acute Care Committee. Managing the paediatric patient with an acute asthma exacerbation. Paediatr Child Health 2012;17:251-62.
387Norton SP, Pusic MV, Taha F, Heathcote S, Carleton BC. Effect of a clinical pathway on the hospitalisation rates of children with asthma: A prospective study. Arch Dis Child 2007;92:60-6.
388Lougheed MD, Olajos-Clow JG. Asthma care pathways in the emergency department. Curr Opin Allergy Clin Immunol 2010;10:181-7.
389Browne GJ, Giles H, McCaskill ME, Fasher BJ, Lam LT. The benefits of using clinical pathways for managing acute paediatric illness in an emergency department. J Qual Clin Pract 2001;21:50-5.
390Graham VA, Milton AF, Knowles GK, Davies RJ. Routine antibiotics in hospital management of acute asthma. Lancet 1982;1:418-20.
391Everard ML, Bara A, Kurian M, Elliott TM, Ducharme F, Mayowe V, et al. Anticholinergic drugs for wheeze in children under the age of two years. Cochrane Database Syst Rev 2005;(3):CD001279.
392Griffiths B, Ducharme FM. Combined inhaled anticholinergics and short-acting beta2-agonists for initial treatment of acute asthma in children. Cochrane Database Syst Rev 2013;8:CD000060.
393Griffiths B, Ducharme FM. Combined inhaled anticholinergics and short-acting beta2-agonists for initial treatment of acute asthma in children. Paediatr Respir Rev 2013;14:234-5.
394Cheuk DK, Chau TC, Lee SL. A meta-analysis on intravenous magnesium sulphate for treating acute asthma. Arch Dis Child 2005;90:74-7.
395Powell CV, Kolamunnage-Dona R, Lowe J, Boland A, Petrou S, Doull I, et al. MAGNEsium trial in children (MAGNETIC): A randomised, placebo-controlled trial and economic evaluation of nebulised magnesium sulphate in acute severe asthma in children. Health Technol Assess 2013;17:v-vi, 1-216.
396Powell C, Kolamunnage-Dona R, Lowe J, Boland A, Petrou S, Doull I, et al. Magnesium sulphate in acute severe asthma in children (MAGNETIC): A randomised, placebo-controlled trial. Lancet Respir Med 2013;1:301-8.
397Griffiths B, Ducharme FM. Combined inhaled anticholinergics and short-acting beta2-agonists for initial treatment of acute asthma in children. Cochrane Database Syst Rev 2013;8:CD000060.
398Scarfone RJ, Fuchs SM, Nager AL, Shane SA. Controlled trial of oral prednisone in the emergency department treatment of children with acute asthma. Pediatrics 1993;92:513-8.
399Creticos PS. Treatment options for initial maintenance therapy of persistent asthma: A review of inhaled corticosteroids and leukotriene receptor antagonists. Drugs 2003;63 Suppl 2:1-20.
400Lemanske RF Jr., Sorkness CA, Mauger EA, Lazarus SC, Boushey HA, Fahy JV, et al. Inhaled corticosteroid reduction and elimination in patients with persistent asthma receiving salmeterol: A randomized controlled trial. JAMA 2001;285:2594-603.
401Masoli M, Weatherall M, Holt S, Beasley R. Moderate dose inhaled corticosteroids plus salmeterol versus higher doses of inhaled corticosteroids in symptomatic asthma. Thorax 2005;60:730-4.
402Fouda MA, Al-Kassimi FA. Budesonide and fluticasone and adrenal suppression. Ann Thorac Med 2012;7:253.
403Leach C, Colice GL, Luskin A. Particle size of inhaled corticosteroids: Does it matter? J Allergy Clin Immunol 2009;124:S88-93.
404Menzies D, Nair A, Hopkinson P, McFarlane L, Lipworth BJ. Differential anti-inflammatory effects of large and small particle size inhaled corticosteroids in asthma. Allergy 2007;62:661-7.
405Kramer S, Rottier BL, Scholten RJ, Boluyt N. Ciclesonide versus other inhaled corticosteroids for chronic asthma in children. Cochrane Database Syst Rev 2013;(2):CD010352.
406Pruteanu AI, Chauhan BF, Zhang L, Prietsch SO, Ducharme FM. Inhaled corticosteroids in children with persistent asthma: Dose-response effects on growth. Cochrane Database Syst Rev 2014;(7):CD009878.
407Hoover RM, Erramouspe J, Bell EA, Cleveland KW. Effect of inhaled corticosteroids on long-term growth in pediatric patients with asthma and allergic rhinitis. Ann Pharmacother 2013;47:1175-81.
408Kelly HW, Van Natta ML, Covar RA, Tonascia J, Green RP, Strunk RC, et al. Effect of long-term corticosteroid use on bone mineral density in children: A prospective longitudinal assessment in the childhood asthma management program (CAMP) study. Pediatrics 2008;122:e53-61.
409Sidoroff VH, Ylinen MK, Kröger LM, Kröger HP, Korppi MO. Inhaled corticosteroids and bone mineral density at school age: A follow-up study after early childhood wheezing. Pediatr Pulmonol 2015;50:1-7.
410Stelmach I, Olszowiec-Chlebna M, Jerzynska J, Grzelewski T, Stelmach W, Majak P, et al. Inhaled corticosteroids may have a beneficial effect on bone metabolism in newly diagnosed asthmatic children. Pulm Pharmacol Ther 2011;24:414-20.
411Altintas DU, Karakoc GB, Can S, Yilmaz M, Kendirli SG. The effects of long term use of inhaled corticosteroids on linear growth, adrenal function and bone mineral density in children. Allergol Immunopathol (Madr) 2005;33:204-9.
412Lötvall J, Bateman ED, Bleecker ER, Busse WW, Woodcock A, Follows R, et al. 24-h duration of the novel LABA vilanterol trifenatate in asthma patients treated with inhaled corticosteroids. Eur Respir J 2012;40:570-9.
413Casarosa P, Kollak I, Kiechle T, Ostermann A, Schnapp A, Kiesling R, et al. Functional and biochemical rationales for the 24-hour-long duration of action of olodaterol. J Pharmacol Exp Ther 2011;337:600-9.
414Pearlman DS, Greos L, LaForce C, Orevillo CJ, Owen R, Higgins M, et al. Bronchodilator efficacy of indacaterol, a novel once-daily beta2-agonist, in patients with persistent asthma. Ann Allergy Asthma Immunol 2008;101:90-5.
415Sugihara N, Kanada S, Haida M, Ichinose M, Adachi M, Hosoe M, et al. 24-h bronchodilator efficacy of single doses of indacaterol in Japanese patients with asthma: A comparison with placebo and salmeterol. Respir Med 2010;104:1629-37.
416Cazzola M, Segreti A, Matera MG. Novel bronchodilators in asthma. Curr Opin Pulm Med 2010;16:6-12.
417Cazzola M, Matera MG. Novel long-acting bronchodilators for COPD and asthma. Br J Pharmacol 2008;155:291-9.
418LaForce C, Korenblat P, Osborne P, Dong F, Higgins M. 24-hour bronchodilator efficacy of single doses of indacaterol in patients with persistent asthma: Comparison with placebo and formoterol. Curr Med Res Opin 2009;25:2353-9.
419Cates CJ, Cates MJ. Regular treatment with formoterol for chronic asthma: Serious adverse events. Cochrane Database Syst Rev 2012;4:CD006923.
420Busse WW, Bateman ED, Caplan AL, Kelly HW, O'Byrne PM, Rabe KF, et al. Combined analysis of asthma safety trials of long-acting β2-agonists. N Engl J Med 2018;378:2497-505.
421Huchon G, Magnussen H, Chuchalin A, Dymek L, Gonod FB, Bousquet J, et al. Lung function and asthma control with beclomethasone and formoterol in a single inhaler. Respir Med 2009;103:41-9.
422Nolte H, Pavord I, Backer V, Spector S, Shekar T, Gates D, et al. Dose-dependent anti-inflammatory effect of inhaled mometasone furoate/formoterol in subjects with asthma. Respir Med 2013;107:656-64.
423Grekas N, Athanassiou K, Papataxiarchou K, Rizea Savu S, Silvestro L. Pharmacokinetic study for the establishment of bioequivalence of two inhalation treatments containing budesonide plus formoterol. J Pharm Pharmacol 2014;66:1677-85.
424Bodzenta-Lukaszyk A, Pulka G, Dymek A, Bumbacea D, McIver T, Schwab B, et al. Efficacy and safety of fluticasone and formoterol in a single pressurized metered dose inhaler. Respir Med 2011;105:674-82.
425Bateman ED, O'Byrne PM, Busse WW, Lötvall J, Bleecker ER, Andersen L, et al. Once-daily fluticasone furoate (FF)/vilanterol reduces risk of severe exacerbations in asthma versus FF alone. Thorax 2014;69:312-9.
426Busse WW, O'Byrne PM, Bleecker ER, Lötvall J, Woodcock A, Andersen L, et al. Safety and tolerability of the novel inhaled corticosteroid fluticasone furoate in combination with the β2 agonist vilanterol administered once daily for 52 weeks in patients >=12 years old with asthma: A randomised trial. Thorax 2013;68:513-20.
427Bjermer L, Diamant Z. The use of leukotriene receptor antagonists (LTRAs) as complementary therapy in asthma. Monaldi Arch Chest Dis 2002;57:76-83.
428Idrees MM, Al Moamary MS. Blocking leukotrienes optimize asthma control: The BLOC survey. Ann Thorac Med 2007;2:99-102.
429Bisgaard H; Study Group on Montelukast and Respiratory Syncytial Virus. A randomized trial of montelukast in respiratory syncytial virus postbronchiolitis. Am J Respir Crit Care Med 2003;167:379-83.
430Straub DA, Minocchieri S, Moeller A, Hamacher J, Wildhaber JH. The effect of montelukast on exhaled nitric oxide and lung function in asthmatic children 2 to 5 years old. Chest 2005;127:509-14.
431Straub DA, Moeller A, Minocchieri S, Hamacher J, Sennhauser FH, Hall GL, et al. The effect of montelukast on lung function and exhaled nitric oxide in infants with early childhood asthma. Eur Respir J 2005;25:289-94.
432Bisgaard H, Zielen S, Garcia-Garcia ML, Johnston SL, Gilles L, Menten J, et al. Montelukast reduces asthma exacerbations in 2- to 5-year-old children with intermittent asthma. Am J Respir Crit Care Med 2005;171:315-22.
433van Noord JA, Bantje TA, Eland ME, Korducki L, Cornelissen PJ. A randomised controlled comparison of tiotropium nd ipratropium in the treatment of chronic obstructive pulmonary disease. The dutch tiotropium study group. Thorax 2000;55:289-94.
434Maesen FP, Smeets JJ, Sledsens TJ, Wald FD, Cornelissen PJ. Tiotropium bromide, a new long-acting antimuscarinic bronchodilator: A pharmacodynamic study in patients with chronic obstructive pulmonary disease (COPD). Dutch study group. Eur Respir J 1995;8:1506-13.
435Fardon T, Haggart K, Lee DK, Lipworth BJ. A proof of concept study to evaluate stepping down the dose of fluticasone in combination with salmeterol and tiotropium in severe persistent asthma. Respir Med 2007;101:1218-28.
436Rodrigo GJ, Castro-Rodríguez JA. What is the role of tiotropium in asthma?: A systematic review with meta-analysis. Chest 2015;147:388-96.
437Elias JA, Lee CG, Zheng T, Ma B, Homer RJ, Zhu Z, et al. New insights into the pathogenesis of asthma. J Clin Invest 2003;111:291-7.
438Hamid Q, Tulic MK. New insights into the pathophysiology of the small airways in asthma. Ann Thorac Med 2007;2:28-33.
439Sridhar AV, McKean M. Nedocromil sodium for chronic asthma in children. Cochrane Database Syst Rev 2006;(3):CD004108.
440Rodrigo GJ, Rodrigo C. Continuous vs intermittent beta-agonists in the treatment of acute adult asthma: A systematic review with meta-analysis. Chest 2002;122:160-5.
441Travers AH, Rowe BH, Barker S, Jones A, Camargo CA Jr. The effectiveness of IV beta-agonists in treating patients with acute asthma in the emergency department: A meta-analysis. Chest 2002;122:1200-7.
442Rodrigo GJ, Rodrigo C. First-line therapy for adult patients with acute asthma receiving a multiple-dose protocol of ipratropium bromide plus albuterol in the emergency department. Am J Respir Crit Care Med 2000;161:1862-8.
443Rodrigo GJ, Rodrigo C. The role of anticholinergics in acute asthma treatment: An evidence-based evaluation. Chest 2002;121:1977-87.
444Vézina K, Chauhan BF, Ducharme FM. Inhaled anticholinergics and short-acting beta(2)-agonists versus short-acting beta2-agonists alone for children with acute asthma in hospital. Cochrane Database Syst Rev 2014;(7):CD010283.
445Parameswaran K, Belda J, Rowe BH. Addition of intravenous aminophylline to beta2-agonists in adults with acute asthma. Cochrane Database Syst Rev 2000;(4):CD002742.
446Silverman RA, Osborn H, Runge J, Gallagher EJ, Chiang W, Feldman J, et al. IV magnesium sulfate in the treatment of acute severe asthma: A multicenter randomized controlled trial. Chest 2002;122:489-97.
447Nair A, Menzies D, Barnes M, Burns P, McFarlane L, Lipworth BJ, et al. Respirable dose delivery of fluticasone propionate from a small valved holding chamber, a compact breath actuated integrated vortex device and a metered dose inhaler. Br J Clin Pharmacol 2008;66:20-6.
448Giraud V, Allaert FA, Roche N. Inhaler technique and asthma: Feasability and acceptability of training by pharmacists. Respir Med 2011;105:1815-22.
449Giraud V, Allaert FA. Improved asthma control with breath-actuated pressurized metered dose inhaler (pMDI): The SYSTER survey. Eur Rev Med Pharmacol Sci 2009;13:323-30.
450Donnell D. Inhaled corticosteroid delivery systems: Clinical role of a breath-actuated device. Eur Rev Med Pharmacol Sci 2001;5:7-16.
451Drazen JM, Harrington D. New biologics for asthma. N Engl J Med 2018;378:2533-4.
452Hanania NA, Wenzel S, Rosén K, Hsieh HJ, Mosesova S, Choy DF, et al. Exploring the effects of omalizumab in allergic asthma: An analysis of biomarkers in the EXTRA study. Am J Respir Crit Care Med 2013;187:804-11.
453Normansell R, Walker S, Milan SJ, Walters EH, Nair P. Omalizumab for asthma in adults and children. Cochrane Database Syst Rev 2014;(1):CD003559.
454Pavord ID, Korn S, Howarth P, Bleecker ER, Buhl R, Keene ON, et al. Mepolizumab for severe eosinophilic asthma (DREAM): A multicentre, double-blind, placebo-controlled trial. Lancet 2012;380:651-9.
455Ortega HG, Yancey SW, Mayer B, Gunsoy NB, Keene ON, Bleecker ER, et al. Severe eosinophilic asthma treated with mepolizumab stratified by baseline eosinophil thresholds: A secondary analysis of the DREAM and MENSA studies. Lancet Respir Med 2016;4:549-56.
456Bel EH, Wenzel SE, Thompson PJ, Prazma CM, Keene ON, Yancey SW, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med 2014;371:1189-97.
457FitzGerald JM, Bleecker ER, Menzies-Gow A, Zangrilli JG, Hirsch I, Metcalfe P, et al. Predictors of enhanced response with benralizumab for patients with severe asthma: Pooled analysis of the SIROCCO and CALIMA studies. Lancet Respir Med 2018;6:51-64.
458Castro M, Zangrilli J, Wechsler ME, Bateman ED, Brusselle GG, Bardin P, et al. Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: Results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet Respir Med 2015;3:355-66.
459Mukherjee M, Aleman Paramo F, Kjarsgaard M, Salter B, Nair G, LaVigne N, et al. Weight-adjusted intravenous reslizumab in severe asthma with inadequate response to fixed-dose subcutaneous mepolizumab. Am J Respir Crit Care Med 2018;197:38-46.
460Nair P, Wenzel S, Rabe KF, Bourdin A, Lugogo NL, Kuna P, et al. Oral glucocorticoid-sparing effect of benralizumab in severe asthma. N Engl J Med 2017;376:2448-58.
461Castro M, Corren J, Pavord ID, Maspero J, Wenzel S, Rabe KF, et al. Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma. N Engl J Med 2018;378:2486-96.
462Rabe KF, Nair P, Brusselle G, Maspero JF, Castro M, Sher L, et al. Efficacy and safety of dupilumab in glucocorticoid-dependent severe asthma. N Engl J Med 2018;378:2475-85.
463Bateman ED, Guerreros AG, Brockhaus F, Holzhauer B, Pethe A, Kay RA, et al. Fevipiprant, an oral prostaglandin DP2 receptor (CRTh2) antagonist, in allergic asthma uncontrolled on low-dose inhaled corticosteroids. Eur Respir J 2017;50. pii: 1700670.
464Corren J, Parnes JR, Wang L, Mo M, Roseti SL, Griffiths JM, et al. Tezepelumab in adults with uncontrolled asthma. N Engl J Med 2017;377:936-46.