Diagnosis and Management of Asthma – The Swiss Guidelines

Asthma is a chronic respiratory disease, usually associated with airway inflammation and airway hyperresponsiveness (AHR) to a multitude of stimuli. These abnormalities tend to persist even if symptoms are absent and lung function is normal, although they may normalize with treatment. AHR is, however, neither necessary nor sufficient to make the diagnosis. Indeed, bronchial provocation tests to assess AHR are moderately sensitive but modestly specific for a diagnosis of asthma [1, 2].

Asthma is defined by a history of respiratory symptoms such as wheeze, shortness of breath, chest tightness, and cough along with variable airflow limitation [3]. Both symptoms and airflow limitation characteristically vary over time and in intensity, and these variations are often triggered by factors such as exercise, allergen or irritant exposure, weather change, or respiratory (viral) infections. Symptoms and airflow limitation may resolve either spontaneously or with treatment, and may also be absent for weeks or months. However, asthmatic patients may also experience episodic flare-ups (exacerbations) of their disease that may be life threatening and constitute a significant burden for patients and community alike.

Asthma is a highly heterogeneous condition, with different underlying disease processes. Recognizable clusters of demographic, clinical and/or pathophysiological features are often called “asthma phenotypes” [3-7]. In this regard, several phenotypes have been identified. Phenotypes are helpful to understand the heterogeneous manifestations and outcomes of asthma but should not be used alone for therapeutic choices or considered as mutually exclusive. One patient may belong to two or more clusters. The most common phenotypes are mentioned in what follows.

This phenotype is often characterized by onset in childhood, past and/or family history of allergic disease, sputum eosinophilia, and good response to inhaled corticosteroid (ICS) treatment. Asthma symptoms may be present even in the absence of allergen exposure.

In patients with adult-onset asthma, the onset of bronchial symptoms is often preceded by a long history of chronic sinusitis. Symptoms manifest perennially and allergy plays a minor role. In addition, exacerbations are generally associated with peripheral eosinophilia. Initially, eosinophilic inflammation and asthma symptoms respond well to therapeutic corticosteroids. However, quite often systemic daily dosing is necessary to reach asthma control. In cases of severe asthma of this phenotype, the eosinophilic inflammation may become refractory to oral corticosteroids (OCS; e.g., prednisone and prednisolone). Long-acting parenteral corticosteroids may still have an action [8].

This phenotype is not stable over time. It may represent a distinct entity. However, it may also be found in individuals with eosinophilic asthma being treated with high doses of systemic corticosteroids and in cases of chronic bronchial infection with Chlamydia pneumoniae.

In some patients with long-standing disease, airway wall remodeling may cause fixed airflow limitation.

In obese patients, asthma tends to be associated with little eosinophilic airway inflammation and prominent respiratory symptoms.

Asthma affects an estimated 300 million individuals worldwide with global prevalence ranging from 1 to 16% of the population in different countries [9-19]. In Switzerland, the prevalence of asthma in children aged 13–14 years is 2.3% according to the Global Burden of Asthma Report, while 7% of the adult population reports a physician-diagnosed asthma [9, 20] However, asthma diagnosis in the community is difficult. Studies suggest overdiagnosis in 30% of cases and physician-diagnosed asthma in the community may warrant reassessment [21, 22].

Asthma is a clinically highly heterogeneous condition, but chronic airway inflammation is a consistent feature in most patients even when symptoms are absent. Chronic inflammation, which involves a multitude of inflammatory cells and mediators, affects all airways, although its physiological effects are more pronounced in medium-sized bronchi. In allergic asthma, the pattern of inflammation is characterized by increased numbers of activated mast cells, eosinophils, natural killer T cells and Th2 lymphocytes [23]. However, neutrophils may contribute to the inflammatory response, particularly in severe asthma [6]. The mechanisms underlying airway eosinophilia in nonallergic asthma are less well understood, although type 2 innate lymphoid cells (ILC2s), nonspecific innate immune effectors, may play a role [24].

Structural cells of asthmatic airways also contribute to persistent inflammation by producing several inflammatory mediators [25, 26]. In addition to the inflammatory response, a number of structural changes collectively referred to as “airway remodeling” takes place in the airways of asthmatic patients [27]. Airway remodeling, smooth muscle contraction, edema, and mucus hypersecretion contribute to the narrowing of the airways, the final common pathway leading to symptoms and physiological abnormalities in asthma [28-30].

The diagnosis of asthma is based on a combination of respiratory symptoms (e.g., wheezing, dyspnea, chest tightness or cough) and variable expiratory airway limitation, which vary substantially over time and in magnitude either spontaneously or with treatment (Table 1). The variability in lung function is even greater in individuals with poorly controlled asthma [31].

A number of features (e.g., onset of symptoms in childhood, history or family history of allergy) increase the likelihood that the patient has asthma, but they are neither specific nor observed in all asthma phenotypes. The most common finding on chest auscultation is expiratory wheezing (which may be heard also, among others, with upper airway dysfunction, chronic obstructive pulmonary disease [COPD] or infections); otherwise, physical examination is often normal. Wheezing may also be absent during severe asthma exacerbations (“silent chest”), but in such cases other respiratory signs are usually present.

A ratio of forced expiratory volume in 1 second (FEV₁) to forced vital capacity below the lower limit of normal value indicates airflow obstruction. The Global Lung Initiative provides reference values for spirometry for all ages facilitating the diagnosis of airflow obstruction [32].

However, a reduced FEV₁ may be seen in several lung conditions. Once an obstructive defect has been documented, obtaining evidence of excessive variability in lung function (FEV₁ or peak expiratory flow [PEF]) is an essential component of the diagnosis of asthma (Table 1). Spirometry with bronchodilation is a key element for asthma diagnosis. Indeed, normalization of obstructive spirometry after bronchodilation or a large increase in FEV₁ (> 400 ml) favor asthma diagnosis. AHR is generally established either with a direct-acting bronchial provocation test such as methacholine challenge testing [33] or with an indirect challenge test such as mannitol or exercise challenge testing [34]. While methacholine challenge testing has an excellent sensitivity and low specificity, indirect challenge tests have a moderate sensitivity and higher specificity for diagnosing asthma [1, 2]. The spirometry with bronchodilation and PEF variability when appropriate should be performed before starting long-term controller therapy because variability of lung function decreases with treatment (as lung function improves); in addition, airflow limitation may become irreversible over time. In selected cases, allergy tests (skin prick test or serum specific IgE) may aid in establishing a diagnosis of asthma, although the presence of atopy is neither specific for asthma nor is it present in all asthma phenotypes.

In patients with isolated chronic cough, the differential diagnosis includes cough-variant asthma; cough induced by angiotensin-converting enzyme inhibitors; gastroesophageal reflux (GER); chronic upper airway cough syndrome; chronic sinusitis; and vocal cord dysfunction [35]. Cough-variant asthma is associated with AHR, while lung function may be normal. In addition, it is more common in children and tends to be more troublesome at night.

Asthma acquired in the workplace is frequently missed. Yet, early diagnosis is essential, as persistent exposure is associated with worse outcome [36, 37]. A positive history of occupational exposures and improvement of symptoms and lung function while away from work are critical elements for establishing a diagnosis of occupational asthma.

In the elderly, the diagnosis of asthma may be challenging due to a number of factors, including poor perception of airflow limitation, lack of fitness, and presence of concomitant conditions that can cause similar respiratory symptoms that worsen on exercise or at night such as cardiovascular disease or left ventricular failure [38]. In patients with a history of smoking or exposure to environmental factors such as gases, dust or fumes, COPD, and asthma-COPD overlap (ACO) should also be considered.

Asthma and COPD may be difficult to distinguish, particularly in older patients and in smokers or ex-smokers. In addition, they may also coexist (e.g., ACO). While the history and pattern of symptoms can help distinguishing the two conditions, the diagnosis is not straightforward in patients with long-standing asthma who have developed fixed airflow limitation. In addition, some bronchodilator reversibility (increase in forced vital capacity, often larger than an increase in FEV₁ of > 12% and > 200 mL) is documented in COPD patients [39, 40]. An accurate diagnosis (and specific treatment) is critical as patients with ACO have worse outcomes than those with asthma or COPD alone [41].

Asthma is more common in obese people, but obesity can cause symptoms that mimic asthma [42]. However, asthma may be both over- and underdiagnosed in obese patients [43].

The accuracy of a diagnosis of asthma made by general practitioners in primary health care is low. Indeed, in this setting, a large minority of patients (25–35%) with a diagnosis of asthma are not confirmed as having asthma when appropriate testing is performed [44-47]. Respiratory symptoms associated with obesity can mimic asthma, thus representing a frequent cause of overdiagnosis, although nonobese patients are as likely as obese patients to be overdiagnosed with asthma [44]. However, obese patients may be either over- or underdiagnosed with asthma [43]. Confirming the diagnosis of asthma may be particularly challenging in patients on controller medications.

Assessment of asthma includes the assessment of symptom control and future risk of adverse outcomes, treatment issues and comorbidities. In order to assess symptom control, frequency of symptoms (days per week), night awakening or limitation of activity, and frequency of rescue medication use in the preceding 4 weeks should be considered [48]. A number of symptom control tools are available, including screening tools, and categorical numerical asthma control tools such as Asthma Control Questionnaire and Asthma Control Test [49-51]. Poor symptom control is a well-established risk factor for future asthma exacerbations [52]. However, additional risk factors for exacerbations and adverse outcomes include a history of ≥1 severe exacerbations in the previous year, poor adherence to treatment, incorrect inhaler technique, comorbidities, low FEV₁, smoking and sputum or blood eosinophilia [53]. Once the diagnosis of asthma has been made, lung function, particularly FEV₁, is an independent risk factor for exacerbation. Indeed, a low FEV₁ percent predicted, particularly if < 60%, is a risk factor for both asthma exacerbations [54] and lung function decline [55], independent of symptom level. Indeed, lung function does not correlate strongly with asthma symptoms [56, 57]. Short-term PEF monitoring may be useful for assessing response to treatment and exposure to triggers for worsening symptoms, whereas long-term PEF monitoring is recommended only for patients with severe asthma or those with impaired perception of airway limitation [58]. There is growing evidence that measurement of the fractional concentration of exhaled nitric oxide (FENO) may be useful for monitoring both response and adherence to anti-inflammatory treatment in patients with eosinophilic asthma [59]. In fact, FENO values reflect airway inflammation, although it cannot be used interchangeably with sputum eosinophilia [60]. Notably, FENO is also increased in nonasthma conditions (e.g., eosinophilic bronchitis, atopy, and allergic rhinitis); therefore, it is of limited value in making a diagnosis of asthma.

The concept of asthma control refers to the level of symptoms (daytime symptoms, night symptoms, activity limitation, reliever medication use) and the risk of poor outcomes and reduced lung function, despite therapy (adequate inhaler technique and adherence are key issues).

The concept of asthma severity refers to the level of treatment required to control symptoms and exacerbations [61]. Therefore, asthma severity should be assessed once the patient is on the minimum effective level of treatment for several months, although it may change over months or years.

Mild asthma is asthma that is well controlled with step 1 or step 2 treatment, i.e., as-needed reliever medication alone, or low-intensity controller medication.

Moderate asthma is asthma that is well controlled with step 3 treatment, i.e., low-dose inhaled ICS/long-acting β₂-agonists (LABA) (Table 2).

Severe asthma is asthma that requires step 4 or step 5 treatment, i.e., high-dose ICS/ LABA, in order to prevent it to become “uncontrolled,” or asthma that remains “uncontrolled” despite this treatment strategy. This description of asthma severity is used in clinical practice and differs from that used in epidemiological studies and clinical trials. Severe asthma should be distinguished from “uncontrolled” asthma (respectively difficult-to-control asthma) in which disease control is often not achieved due to poor inhaler technique, poor medication adherence, comorbidities and complications as well as persistent exposures to sensitizing or irritant agents [62]. Uncontrolled asthma is a more common cause for persistent symptoms and exacerbations, and may be more easily improved.

The long-term goals of asthma management are to achieve good symptom control and to minimize future risk of exacerbations, fixed airflow limitation and side effects of treatment. To this end, establishing a partnership between the patient and health care provider is crucial, and a shared-care approach – in which patients play an active role in the management of their asthma – is associated with improved outcomes [63]. Similarly, “control-based” management strategies, in which treatment is adjusted based on the patient’s response in terms of both symptom control and future risk of exacerbations and side effects, have been shown to improve asthma outcomes [64].

The pharmacological options for long-term treatment of asthma include: controller medications, which reduce airway inflammation, control symptoms, and reduce future risks of exacerbations and decline in lung function; reliever/rescue medications, which are provided to all patients for as-needed relief of symptoms; and add-on therapies, which are considered in patients with persistent symptoms despite high-dose controller medications and treatment of modifiable risk factors. Regular treatment with controller medication (usually, low-dose ICS or low-dose ICS/LABA depending on the presenting symptoms) should be initiated soon after the diagnosis of asthma has been made, as early controller treatment has been associated with greater improvement in lung function and reduced long-term decline in lung function following severe exacerbations [65-67]. Once treatment has been initiated and a cycle of assessment, adjustment of treatment, and review of the response has been completed, controller medication is adjusted up or down in order to achieve good asthma control. Once good disease control has been maintained for 2–3 months, treatment may be stepped down to the patient’s minimum effective dose. Conversely, in the presence of persistent symptoms or exacerbations despite 2–3 months of controller treatment, common problems such as incorrect inhaler technique, poor adherence, persistent allergen exposure and comorbidities should be excluded before stepping up treatment.

Short-acting β₂-agonists (SABAs) are the preferred option for rapid relief of asthma symptoms (evidence A; Table 3). Treatment of asthma with SABA alone should be limited to patients with occasional daytime symptoms of short duration, with no night waking and normal lung function. LABA monotherapy (without ICS) should not be used for relief [68]. The newest GINA update recommends the evaluation of low-dose ICS even in step 1.

Regular low-dose ICS plus as-needed SABA represent the preferred option. Indeed, regular use of low-dose ICS reduces asthma symptoms, increases lung function, improves quality of life, and reduces the risk of exacerbations and asthma-related hospitalizations or death (evidence A) [69-71]. Leukotriene receptor antagonists, though less effective [72], represent a valid alternative to ICS in patients unwilling to use ICS, those experiencing intolerable side effects from ICS, or in patients with concomitant allergic rhinitis [73, 74] (evidence B).

At this step, the options differ depending on age. For adults and adolescents, there are two preferred options: combination of low-dose ICS/LABA as maintenance treatment with as-needed SABA as reliever, or low-dose ICS/formoterol as both maintenance and reliever treatment. Adding LABA to the same dose of ICS provides additional improvements in symptoms and lung function and reduces the risk of exacerbations [75] (evidence A). In children aged 6–11 years, the preferred option is to increase ICS to medium dose [76].

For adults and adolescent patients with ≥1 exacerbations in the previous year, combination of low-dose ICS/formoterol as both maintenance and reliever treatment is the preferred option as it is more effective in reducing exacerbations than the same dose of maintenance ICS/LABA or a higher dose of ICS (evidence A) [77]. Conversely, increasing the ICS dose (e.g., combination high-dose ICS/LABA) provides little additional benefit (evidence A) [78, 79] and increases the risk of side effects. Soft mist tiotropium (5 μg/day), a long-acting muscarinic antagonist, may be used as add-on therapy for adult or adolescent patients with a history of exacerbations (evidence A) [80].

In patients with persistent symptoms or exacerbations despite step 4 treatment, the following therapeutic options that may be considered include: add-on omaliz-umab (anti-IgE treatment) for patients with moderate to severe allergic asthma (evidence A) [81], add-on soft mist tiotropium (5 μg/day) in patients aged ≥12 years with a history of exacerbations (evidence B) [80], add-on anti-IL-5 treatment such as mepolizumab for patients aged ≥12 years with severe eosinophilic asthma (evidence B) [82, 83], add-on low-dose OCS (evidence D) [61] and, in highly selected patients, bronchial thermoplasty (BT; evidence B) [61]. For patients with overlap eosinophilic and allergic asthma, the best therapeutic option (omalizumab or anti-IL-5/anti-IL-5R) is currently unknown.

Asthmatic patients should be reviewed on a regular basis (ideally, 1–3 months after starting treatment and every 3–12 months thereafter) to monitor asthma control and response to treatment, which, in severe and chronically undertreated disease, may take several months [84]. Stepping up adjustments, either sustained (e.g., for at least 2–3 months) or short-term (for 1–2 weeks), should be made only once symptoms are confirmed to be due to asthma, inhaler technique and adherence have been assessed, and modifiable risk factors (e.g., smoking) addressed. Once asthma symptoms have been well controlled and lung function has been stable for 3 months or more, stepping down of treatment can be considered to find the patient’s lowest dose that controls both symptoms and exacerbations. However, the response to any step-down treatment should be carefully monitored as too low or too quick dose reductions (evidence B) [85] as well as complete withdraw of ICS (evidence A) [86] increase the risk of exacerbations. In patients experiencing exacerbations despite maximal doses of treatment, modifiable risk factors (e.g., smoking, obesity, exposure to allergens, major psychological or socioeconomic problems) should be searched for and addressed.

Allergen-specific immunotherapy may be considered if allergy plays a prominent role (e.g., in asthmatic patients with allergic rhinoconjunctivitis). There are currently two approaches: subcutaneous immunotherapy and sublingual immunotherapy. Immunotherapy is associated with reduced symptom scores and medication usage, and improved allergen-specific and nonspecific AHR [87], although most studies have been in mild asthma, and only few studies have compared immunotherapy with pharmacological therapy. Moreover, potential benefits of allergen immunotherapy must be weighed against the risk of adverse effects and the cost of treatment [88] (evidence D).

Mite allergen avoidance is not recommended as a general strategy in asthma (evidence A). In patients with mite-sensitive asthma, physical (mattress encasings) and chemical measures aimed at reducing exposure to house dust mite allergens do not appear to improve asthma symptom or reduce drug usage [89]. However, the quality of the studies in the meta-analysis was low. Allergologists still advocate a measure to reduce the mite concentration at home [90]. Conversely, dampness or mold removal in homes reduces asthma symptoms and medication use in adults (evidence A).

Patients with moderate-severe asthma are advised to receive influenza vaccination yearly (evidence D), although vaccination does not reduce the frequency or severity of asthma exacerbations (evidence A) [91]. Likewise, there is insufficient evidence to recommend routine pneumococcal vaccination in asthma patients (evidence D), although people with asthma, particularly children and the elderly, are at higher risk of pneumococcal disease [92].

BT is a potential therapeutic option at step 5 in highly selected adult patients whose asthma remains uncontrolled despite optimized treatment (evidence B). Compared with sham-controlled patients, BT is associated with a sustained reduction in asthma exacerbations, but no beneficial effect on lung function or asthma symptoms [93, 94]. Quite recently, BT was found to lead to a persistent reduction in severe exacerbations (compared to sham-treated patients) up to 5 years with a 48% average decrease over 5 years in severe exacerbation event rates (events per patient per year) in BT-treated patients compared with the 12 months prior to BT treatment. The decrease in severe exacerbations in the BT-treated patients included a substantial reduction in the use of systemic corticosteroids associated with those exacerbations [95]. The effectiveness of this technique has been confirmed in randomized controlled trials and is now endorsed by several international guidelines, including the Global Initiative for Asthma (GINA) guideline [3]. Up to now, BT may be an option in severe uncontrolled asthma, particularly in those without evidence of blood eosinophilia or perennial allergy or who failed to respond to the therapy with omalizumab or anti-IL-5 antibodies or anti-IL-5R antibodies. We recommend that this treatment modality should only be offered in highly specialized asthma centers preferably within clinical studies/registries.

A number of nonpharmacological strategies and interventions can also be considered to assist with symptom control and risk reduction. They include: smoking cessation; physical activity; avoidance of occupational exposures; and avoidance of medications that may worsen asthma, although with varying levels of evidence.

Providing patients with education and inhaler skills, encouraging adherence to medication, and providing training in asthma self-management are essential steps of disease management. These are best achieved through a partnership between the patient and their health care providers [96].

Poor inhaler technique leads to poor asthma control and increases risk of exacerbations and adverse effects [97]. Yet, up to 70–80% of patients are unable to use their inhaler correctly and most of them are unaware of their problem using the inhaler device. Strategies to ensure effective use of devices include: choosing the most appropriate device based on available options, patient skills and cost; showing the patient how to use the device correctly; and checking (and eventually correcting) inhaler technique, and re-check it regularly (evidence A).

Poor adherence to medications occurs in approximately 50% of asthmatic patients on long-term therapy [98]. Factors contributing to poor adherence include: medication/regimen factors (e.g., difficulties using the device), unintentional poor adherence (e.g., misunderstanding about instructions), perception that treatment is not necessary, or concerns about side effects. Interventions such as shared decision-making and prescription of once-daily (vs. twice-daily) medications have been shown to improve treatment adherence in asthma [99]. Providing patients, their family, and other carers with asthma information is similarly important and the GINA website (www.ginasthma.org) contains educational materials as well as links to several asthma websites. Guided self-management (either “patient-directed” or “doctor-directed”) is effective in controlling symptoms and minimizing the risk of exacerbations and need for health care utilization (evidence A) [100]. However, most effective self-management education requires three components: self-monitoring of symptoms and/or PEF; a written asthma action plan, which shows patients how to make short-term changes to their treatment in response to changes in their symptoms and/or PEF, and describes when to access medical care; and regular follow-up consultations with a health care provider to assess asthma control and treatment issues (evidence A) [101]. In patients with severe disease at high risk of hospitalization, follow-up by telehealthcare may be beneficial [102].

A number of comorbidities are commonly present in patients with asthma, particularly those with difficult-to-treat or severe asthma. Recognition and active management of comorbidities is important because they may contribute to symptoms, impaired quality of life, and poor asthma control [103].

Asthma is more difficult to control in obese patients [104, 105], and this may be due to a different type of airway inflammation, concomitant obstructive sleep apnea and GER, or mechanical factors. However, because of other potential causes of dyspnea and wheezing in obese patients, the diagnosis of asthma should be carefully reviewed. Similar to other asthmatic patients, ICSs are the mainstay of treatment, although their response may be reduced [105]. Weight loss is an essential part of the treatment plan in obese patients (evidence B) [106, 107].

Symptoms and/or diagnosis of GER disease are more common in asthmatic patients compared with the general population [103]. However, asymptomatic GER is an unlikely cause of poorly controlled asthma, and there is no value in screening patients with uncontrolled asthma for GER (evidence A). Patients with poorly controlled asthma should be treated with anti-reflux medication (e.g., proton pump inhibitors or motility agents) only if they have also symptomatic reflux (evidence A) [108].

Depressive and anxiety disorders are more prevalent among asthmatic patients, and are associated with poor asthma control and treatment adherence, increased exacerbations, and worse quality of life [109, 110]. A number of studies have evaluated the effectiveness of psychological interventions in adults with asthma, but the results are inconsistent [111].

Food allergy is a rare trigger for asthma symptoms (< 2% of asthmatics). However, in patients with confirmed food-induced reactions (particularly to peanuts and tree nuts), co-existing asthma is a strong risk factor for more severe and even fatal reactions [112]. Appropriate food avoidance and asthma control is the mainstay of treatment.

Most patients with asthma, either allergic or nonallergic, have concurrent rhinitis, and 10–40% of patients with allergic rhinitis have asthma [113]. Chronic rhinosinusitis is associated with more severe asthma, especially in patients with nasal polyps [114]. Current guidelines (Allergic Rhinitis in Asthma, ARIA) recommend intranasal corticosteroids for treatment of both allergic rhinitis and chronic rhinosinusitis [115]. Up to 40% of patients with eosinophilic asthma, chronic hyperplastic eosinophilic sinusitis, and nasal polyps present intolerance to aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) (Samter trias, morbus widal) [116]. Following ingestion of aspirin or NSAIDs, an acute attack of sinus and asthma symptoms develops within minutes to 1–2 h. Aspirin-exacerbated respiratory disease should be suspected in patients with a history of asthma exacerbation following ingestion of Aspirin or other NSAIDs. Bronchial challenge with Aspirin is the diagnostic gold standard, but this should be performed in highly specialized centers because of the high risk of severe reactions [117, 118]. Avoidance of Aspirin and NSAID-containing products is a critical part of Aspirin-exacerbated respiratory disease management. If an NSAID is indicated for other medical conditions, a cyclooxygenase-2 inhibitor can be considered with appropriate medical surveillance [119]. Corticosteroids (either inhaled or oral) are the mainstay of treatment. Desensitization to aspirin can reduce formation of nasal polyps and improve nasal and asthma scores [120].

Athletes, particularly those competing at high level, have an increased prevalence of various respiratory conditions, including asthma. In these patients, asthma is characterized by less correlation between symptoms and pulmonary function, higher lung volumes and expiratory flows, and more difficulty in controlling symptoms. Exposure to air pollutants and training in extreme cold should be avoided. ICSs are the treatment of choice, while minimizing the use of β₂-agonists will avoid the development of tolerance [33].

During pregnancy, asthma control often changes due to a number of factors, including mechanical or hormonal changes, or reduction or cessation of asthma medications [121]. In addition, exacerbations are common, particularly in the second trimester [122]. Poor symptom control and asthma exacerbations are associated with worse outcomes for both the baby (e.g., preterm delivery and low birth weight) and the mother (pre-eclampsia) [122]. Despite general concern, the use during pregnancy of medications to achieve good symptom control and prevent exacerbations is justified (and recommended) as the benefit of actively treating asthma greatly outweighs the risk related to medications (evidence A) [123]. ICSs prevent asthma exacerbations during pregnancy [124] and cessation of ICS during pregnancy is a risk factor for exacerbations (evidence A) [122]. In addition, the use of ICSs as well as β₂-agonists or montelukast does not increase the risk for fetal abnormalities [125]. Acute exacerbations occurring during pregnancy should be treated aggressively with SABA, oxygen and systemic corticosteroids in order to avoid fetal hypoxia.

In this setting, the development of asthma is often preceded by rhinitis. Identification and elimination of occupational sensitizers along with avoidance of any further exposure are critical aspects of disease management (evidence A). Given the economic and legal implications of the diagnosis of occupational asthma, suspected cases should be referred for expert evaluation and advice (evidence A).

Older patients may attribute asthma symptoms to aging or concomitant conditions (e.g., cardiovascular disease). Economic burden of asthma in this patient population may be higher due higher hospitalization rates and medication costs [126]. Decisions about treatment in elderly patients with asthma need to take into account not only the usual goals of symptom control and risk minimization but also the impact of poor self-management skills, comorbidities, and concomitant medications (e.g., potential drug interactions). In addition, side effects of β₂-agonists and corticosteroids are more common in the elderly than in younger adults [127]. Complex medication regimens and prescription of multiple inhaler devices should be avoided, if possible.

There is no evidence of increased perioperative risk for the general asthmatic population [128]. However, perioperative bronchospasm in asthmatic patients may be life-threatening [129]. Therefore, careful attention should be paid preoperatively to achieve good asthma control.

The term “difficult-to-treat” refers to asthma in which factors such as comorbidities, poor adherence or allergen exposure interfere with achieving disease control. Conversely, “refractory” or “treatment-resistant” refers to patients whose disease remains poorly controlled despite optimal treatment and management of comorbidities. “Severe asthma” includes patients with refractory asthma and those with incomplete response to treatment of comorbidities [61]. Confirmation of the diagnosis is crucial because 12–50% of cases are erroneously labelled as “severe asthma” [130]. Patients with severe or difficult-to-treat asthma report frequent or persistent symptoms, frequent exacerbations and impaired quality of life [131], and should be referred to specialized centers for further evaluation and management.

Exacerbations of asthma are episodes of acute or subacute worsening in symptoms and lung function [132]. They usually occur in patients with a pre-existing diagnosis of asthma, including patients with mild or well-controlled asthma [133, 134], but may occasionally represent the first manifestation of the disease. Exacerbations may also occur when the controller medication is reduced below an individual threshold. Risk factors include exposure to external agents (e.g., viral infections or pollution), but asthma exacerbations are not necessarily preceded by exposure to known risk factors [135]. Patients at higher risk of asthma-related death (e.g., those reporting history of near-fatal asthma requiring intubation and mechanical ventilation, hospitalization or emergency care visit for asthma in the previous year, or overuse of SABA) [136, 137] should be promptly identified and flagged for more frequent review.

The management of worsening asthma and exacerbations is part of a continuum, from self-management by the patient with a written asthma action plan to management of more severe symptoms in primary care, emergency department, and hospital.

All patients should be provided with a written asthma action plan in order to recognize and respond appropriately (e.g., changes to medication or access to medical care) to worsening asthma. Repeated dosing with inhaled SABA provides prompt but temporary relief, and should be associated with increased controller treatment as higher ICS doses have an equivalent effect to a short course of OCS in preventing worsening asthma progressing to a severe exacerbation (evidence A) [138]. The combination of rapid-onset LABA (formoterol) and low-dose ICS (budesonide or beclometasone) in a single inhaler is effective in reducing exacerbations requiring OCS and hospitalizations in at-risk patients (evidence A) [139-141]. A short course of OCS (e.g., 40–50 mg/day for 5–7 days; evidence B) [138] is generally used for patients who fail to respond to increased doses of medication or deteriorate rapidly. Patients should go to an acute care facility or see their doctor immediately if their asthma continues to deteriorate despite following their action plan.

The severity of the exacerbation should be promptly assessed (based on severity of symptoms, lung function, and vital signs), while initiating treatment with SABA, oxygen supplementation, and systemic corticosteroids. Initial response to treatment (e.g., symptoms, oxygen saturation and lung function) should be reviewed after 1 h. For mild to moderate exacerbations, repeated administration of inhaled SABA (up to 4–10 puffs every 20 min for the first hour) is the most effective way to rapidly reverse airflow limitation (evidence A) [142]. The most cost-effective route of delivery is pMDI and spacer (evidence A) [143]. Oxygen therapy should be titrated to maintain oxygen saturation at 93–95%. OCS should be given promptly, especially if the patient is deteriorating, at a recommended dose of 1 mg prednisolone/kg/day or equivalent (up to a maximum of 50 mg/day) for adults, and 1–2 mg/kg/day (up to a maximum of 40 mg/day) for children 6–11 years, and continued for 5–7 days (evidence B) [144, 145]. Antibiotics should not be prescribed unless there is clear evidence of chest infection. Patients who present with signs of severe or life-threatening exacerbation (e.g., respiratory rate > 30/min, pulse rate > 120 bpm, use of accessory muscles, or oxygen saturation < 90%) or fail to respond to treatment should be immediately transferred to an acute care facility. Discharge medication should include as-needed reliever medication, OCS and regular controller treatment, which can generally be resumed at previous levels 2–4 weeks after the exacerbation.

Lung function (either PEF or FEV₁) and oxygen saturation (preferably by pulse oximetry) should be closely monitored until a clear response to treatment has occurred. Saturation levels < 92% breathing room air signal the need for aggressive therapy. Arterial blood gas measurements should be considered for patients with a PEF or FEV₁ < 50% predicted, SpO₂ < 92% or those who do not respond to initial treatment. Chest X-ray is not routinely performed, and should be considered if a complicating or alternative process is suspected or for patients not responding to treatment.

Titrated low flow oxygen therapy should be administered by nasal cannulae or mask to achieve oxygen saturation of 93–95%. Inhaled SABA should be administered frequently, and the most cost-effective delivery is by pMDI with a spacer (evidence A) [142, 143], although in Switzerland, SABA are more likely to be administered via a nebulizer system. On the other hand, the routine use of intravenous β₂-agonists in this setting is not recommended (evidence A) [144]. Systemic corticosteroids (oral prednisone 40–50 mg for 5–7 days or intravenous equivalent methylprednisolone) speed resolution of exacerbations and prevent relapse, and should be used in all but the mildest exacerbations (evidence A) [145, 146]. Their use is particularly important if initial SABA treatment fails to produce durable improvement in symptoms or if the exacerbations developed while the patient was taking OCS. A 5- to 7-day course in adults and a 3- to 5-day course in children are usually sufficient (evidence B) [147, 148]. Early administration of high-dose ICS (e.g., within the first hour after presentation) reduces the need for hospitalization in patients not receiving systemic corticosteroids (evidence A) [149]. On discharge home, the majority of patients should be prescribed regular ICS treatment as ICS-containing medications reduce the risk of asthma-related death or hospitalization (evidence A) [61]. Ipratropium bromide (a short-acting anticholinergic) and SABA are associated with fewer hospitalizations and greater improvement in PEF and FEV₁ compared with SABA alone [150]. In patients with FEV₁ < 25–30% predicted at presentation and those who fail to respond to initial treatment and have persistent hypoxia, intravenous magnesium sulfate (2 g infusion over 20 min) should be considered (evidence A) [151, 152]. The evidence regarding the role of noninvasive ventilation is weak and no specific recommendation has been made in this regard.

Prior to discharge from the emergency department or hospital to home, a follow-up appointment within 1 week should be arranged, and strategies to improve asthma management (e.g., medications, inhaler techniques, and written action plan) should be addressed [153]. Patients who have been hospitalized for asthma, or who repeatedly present to an acute care setting, should be referred to a pulmonologist.

A significant proportion of patients with symptoms of chronic airway disease have features of both asthma and COPD [154-156]. While at present there is no general consensus on definition or defining features for this subgroup of patients, there is broad agreement that they experience frequent exacerbations [154], have poor quality of life, more rapid decline in lung function and higher mortality than patients with asthma or COPD alone [154, 157]. Prevalence rates between 15 and 55% have been reported [157, 158].

ACO is characterized by persistent airflow limitation along with features associated with both asthma and COPD.

Initial evaluation (clinical history, physical examination, and other investigations) aims at confirming the presence of chronic airway disease and excluding other causes of respiratory symptoms [159-162]. A number of features (e.g., age, symptoms, smoking history, occupational exposure, previous treatment, and response to treatment) may favor a diagnosis of asthma or COPD. When a patient has a similar number of features of both asthma and COPD, a diagnosis of ACO should be considered. Spirometry is an essential component of the evaluation of individuals with suspected chronic airway disease; yet, it is of limited value in distinguishing between asthma with fixed airflow obstruction, COPD, and ACO. If the favored diagnosis is asthma or ACO (or if there is uncertainty about the diagnosis of COPD), patients should receive adequate controller therapy (e.g., ICS or ICS/LABA, as appropriate) but not LABA monotherapy. Conversely, if the favored diagnosis is COPD, patients should receive appropriate symptomatic treatment with bronchodilators or combination therapy but not ICS monotherapy [162]. Patients with ACO should also be advised about smoking cessation, pulmonary rehabilitation, vaccinations, and treatment of comorbidities. Expert advice and further diagnostic evaluation should be sought for patients with persistent symptoms and/or exacerbations despite treatment, patients with comorbidities that may interfere with the assessment and management of their disease, or if an alternative/complicating pulmonary diagnosis is suspected.

Thomas Rothe and Paolo Spagnolo contributed equally to this article.