The classification of severity is different according to the moment at which asthma is evaluated: at the onset, at the time of diagnosis or thereafter once control of the disease has been achieved. In the first case, the level of severity depends on the frequency and intensity of symptoms (number of attacks and between-attack status: mainly exercise tolerance and nighttime symptoms), the need for a rescue bronchodilator and the values of respiratory function tests. In small children in whom lung function testing is not feasible, severity is only classified according to symptomatology.

Some children with asthma present symptoms intermittently, episodically, more or less frequently, while others suffer from more persistent symptoms. The type of moderate or severe asthma is determined by the frequency and intensity of the symptoms. In any case, the classification of severity is established once treatment is started, based on the medication necessary to keep the child well-controlled.

In this way, the patient who requires step 5 or 6 treatment will have severe asthma, the one who needs step 3 or 4, a moderate asthma, the one who requires step 1 or 2, a mild asthma.

Childhood asthma varies substantially over time, even during a single year, which makes its classification difficult. Most young children experience asthma symptoms during viral infections only; they may experience, therefore, moderate or severe asthma in the winter and remain asymptomatic in spring and summer seasons. In order to typify correctly a case of asthma in children, it is necessary to specify, in addition to severity, the triggering factors in the individual patient and the degree of control of asthma.

El Asthma control is defined by the extent to which clinical manifestations have declined or disappeared with the treatment prescribed.209 It includes two components: current symptom control and future risk (future consequences of such control).113

The current control of symptoms is evaluated by the presence and frequency of symptoms, both at daytime and nighttime, the need of rescue medication and the presence of some limitation for daily life activities. The criteria established to define the degree of control vary from one guideline to another, but generally it is classified as good or poorly controlled asthma, although some guidelines also introduce the concept of partially controlled.113

To facilitate symptom control evaluation, there are available specific Spanish validated questionnaires. One of these questionnaires is the Asthma Control Questionnaire in Children (CAN) (Control de Asma en Niños), with a version for 9-14 year-old children and another version for parents (2-8 year-old children). This instrument evaluates 9 questions about clinical manifestations within the last 4 weeks and is scored between 0 (good control) and 36 (poor control). A patient is considered to be poorly controlled when scores are equal to or higher than 8210 (table 20). Also available is the Childhood Asthma Control Test (c-ACT),211 validated in Spanish212,213 for 4-11 year-old children, which includes 7 questions (4 for the child

and 3 for the parents/caregivers). A patient is considered to be poorly controlled when the score is lower than 20 (table 21).

Table 21.

Pediatric Asthma Control Test (ACT) questionnaire validated in Spanish.212,213

The future risk evaluates the presence of risk factors for exacerbations (table 22), to develop a fixed airflow limitation (undertreatment with ICS, prematurity,214 environmental exposure to tobacco smoke, low FEV1, severe asthma, previous hospitalizations) and for suffering treatment-related side effects (frequent courses of oral glucocorticoids, high doses of ICS).113,215

In addition to the control of clinical symptoms and pulmonary function, measurement of FENO has been advocated as an approach to assess the control of inflammation. Although potentially useful in some patients, FENO measurement does not seem to add relevant benefits to the aforementioned follow-up and treatment strategies.215

Treatment of asthma should follow an overall plan, established by consensus of the physician and the patient (and eventually by the patient's family), in which the goals, the interventions to achieve them, and the criteria for schedule modification or adaptation according to changing disease circumstances must be made clear. Distinguishing between the current control domain and the future risk domain in the control of the disease is relevant, because it has been documented that these domains may respond differently to treatment224,225. For example, some patients may have a good daily control of asthma symptoms and yet experience exacerbations, and vice versa.

Treatment should be adjusted continuously, so that the patient remains always in a well-controlled status. This cyclic treatment adjustment means that asthma control should be objectively assessed (chapter 2.6), that the patient is being treated to achieve control, and that treatment is periodically checked to maintain asthma control (fig. 6). That is, if the patient is not well controlled, treatment must be stepped up as needed in order to regain control, always taking into account the role of non-pharmacological measures, treatment adherence and risk factors susceptible to be modified.

Figure 6.

Cyclic treatment adjustment according to periodic assessment of control of asthma.

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If asthma has been controlled for at least 3 months, maintenance therapy may be gradually decreased in order to determine the minimum treatment needs that are required to maintain control226. A simple scoring system (FEOS scale) that combines data of different clinical (ACT, previous exacerbations) and functional (spirometric values) variables has been developed, to determine the risk after stepping down treatment in patients with controlled asthma227.

Drugs used to treat asthma are classified as controller or maintenance medications and reliever medications, also called “rescue” medications. Controller or maintenance medications should be administered continuously during prolonged periods of time, and include inhaled glucocorticoids (ICS) or systemic glucocorticoids, leukotriene receptor antagonists (LTRA), long-acting ß2-adrenergic agonists (LABA), tiotropium and monoclonal antibodies (omalizumab, mepolizumab, reslizumab, benralizumab, and dupilumab). Chromones and sustained-release theophylline have fallen into disuse because of their lower efficacy.

Reliever medications are used on-demand for rapid treatment or prevention of bronchoconstriction, and include inhaled short-acting ß2-adrenergic agonists (SABA) (table 24) and inhaled short-acting anticholinergics (ipratropium bromide). The use on-demand of the combinations budesonide/formoterol, beclomethasone/formoterol or beclomethasone/salbutamol can also be considered reliever medications.

The six treatment steps (fig. 7) aimed at achieving asthma control are the following:

Figure 7.

Therapeutic steps for maintenance treatment in adult asthma.

ICS: Inhaled glucocorticoid; LABA: Long-acting β2- adrenergic agonist; LTRA: Leukotriene receptor antagonist; SABA: Short-acting β-adrenergic agonist.

aAfter confirmation of adequate treatment adherence and use of the inhaler (s). bLAMA: tiotropium or glycopyrronium. cWithout maintenance treatment. dOn-demand ICS+formoterol can be used when this maintenance combination is also used.

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Inhaled therapy is the preferred administration route for the treatment of asthma as it acts directly on the lungs, delivers a greater amount of drug into the airways, elicits a rapid response and is associated with few or no systemic effects.222,319–323

The main disadvantage of this route is the difficulty of the inhalation technique of the different devices.216,324–326

Currently available inhalation devices include: the conventional pressurized inhaler (pMDI) and the Modulite® system, which can be used with or without a spacer, the breath actuated inhaler (BAI) k-haler® and Easy-breathe®, the soft mist inhaler (SMI) Respimat®, the dry powder inhalers (DPI) (Accuhaler®, Aerolizer®, Breezhaler®, Easyhaler®, Ellipta®, Forspiro®, Genuair®, Handihaler®, Nexthaler®, Spiromax®,

Turbuhaler®, Twisthaler® and Zonda®) and the nebulizers (jet, ultrasonic or vibrating mesh). Each of them has their own technical characteristics that should be considered when prescribed (table 26).324

All inhaler devices if correctly used provide en efficient deposition of the drug in the lung.320

The use of spacers is recommended for pMDI. Spacers circumvent coordination issues, improve the distribution and the amount of drug reaching the bronchial tree, reduce the deposition of drug particles in the oropharynx, decrease cough and the possibility of oral candidiasis (that may be associated with the use of ICS), decrease systemic bioavailability and, hence, the risk of systemic effects.327–330

Healthcare professionals involved in the care of patients with asthma should know the inhalation techniques of each of the devices; knowledge, however, is still insufficient.331,332

Given that the proper use of inhalers is a crucial aspect in the treatment of patients with asthma, all healthcare professionals involved, doctors, nurses and pharmacists especially those from the community due to their accessibility, should be involved in the instruction and review of the inhalation technique.333–340

The patient should be periodically trained and controlled in the use of the prescribed inhaler device, explaining its characteristics, the appropriate technique, demonstrating how it is used, then asking the patient to perform the maneuvers (with a placebo device) and correcting the possible mistakes.323,341–343

Whenever pharmacologically possible, a single type of inhaler device should be used.344,345

After the instruction in the use of the device, the patient should be given a brochure with description of the technique and receive information on how to find demonstration videos showing the correct inhalation technique.321,322,216,342,343

It is important to take advantage of control visits, performance of pulmonary function tests and admissions to the hospital to check the patient's inhalation technique.342

Hydrofluorocarbon (HFC) propellants in current pressurized cartridge inhalers (pMDIs) contribute to global warming as greenhouse gases.346,347 New less polluting HFC propellants are being investigated. Until these are available, the use of dry powder or mist devices may be preferable in new patients >6 years or with inspiratory flow >30 L/min. Changing the inhaler, for non-clinical reasons, could pose a risk of disease deterioration and/or promote low therapeutic adherence (including poor inhalation technique with the new device). Replaced inhalers and cartridges will be deposited at the convenient point of the integrated packaging management and collection system (SIGRE) of pharmacies for correct recycling.

Smokers with asthma have more severe symptoms, a poorer response to ICS treatment, even in patients with mild asthma,348 and an accelerated loss of pulmonary function,349,350 so that a step-up in treatment is often required.351 The proportion of asthmatic smokers is high and similar to that in the general population. Moreover, since longitudinal studies have found a relationship between tobacco use and asthma in both adults and adolescents,352 the primary objective in environmental control is getting the patient to stop smoking. To this purpose, smokers should receive full information of the most appropriate quitting methods.353 Exposure to both environmental contaminants and passive smoking aggravates the course of asthma and constitute a risk factor for asthma development in childhood.354 Administrative regulations banning smoking in public spaces are being having a highly positive impact.355,356 Also, passive exposure to smoke of electronic cigarettes has been related with a higher risk for exacerbations and asthma symptoms,357,358 and active exposure to severe effects of respiratory health,359 so that vaping cannot be recommended as a method to quit.

Some asthma patients, particularly those with sinonasal polyposis, may experience exacerbations when administered acetylsalicylic acid or other non-steroidal anti-inflammatory drugs (NSAID). Many of these reactions are serious or even fatal,360 so that it is necessary that patients are correctly diagnosed based on evident data in the medical history (several reactions to different NSAIDs) or by means of an oral challenge test which, in severe cases, can be replaced with bronchial or nasal inhalation challenge testing.361,362 This issue is more comprehensively explained in chapter 8.5 (acetylsalicylic acid-exacerbated respiratory disease). These patients, however, among their environmental measures, should avoid the use of analgesic or anti-inflammatory treatments with drugs of the NSAID therapeutic class.

Specific recommendations should be considered in allergic asthma, once sensitizations to different allergens had been confirmed in each patient. The most effective measures are those enabling a dramatic decrease of exposure levels, such as those applicable to many patients with occupational asthma (job change) or asthma due to animal dander (removal of animals from the patient's home) or cockroach allergy (wise use of pesticides).363–368

Isolated individual interventions, such as the use of mattress covers or acaricides have not shown to be effective, not even in reducing exposure levels.369–371

However, in a recent randomized study, the use of impermeable bed covers was effective for preventing exacerbations in children and adolescents with allergic asthma triggered by dust mites.372

The use of combined specific measures has been associated with a significant reduction in the level of allergen exposure and, in consequence, of benefits in clinical efficacy.363,373,374 In a randomized trial of 937 patients with uncontrolled moderate to severe asthma and sensitization to at least one domestic allergen, in which combined measures were applied (impermeable covers, vacuum cleaners and air purifiers in the bedroom both with HEPA filters, cockroach disinsection plans), associated with a general education program, for one year, obtained a significant reduction in symptoms and unscheduled medical visits.363

Finally, the two more recent systematic reviews of the effect of combined interventions showed favorable outcomes.367,375

Subcutaneous immunotherapy with allergen extracts is an effective treatment in well-controlled allergic asthma with low or medium treatment levels (therapeutic steps 2 to 4), provided that a clinically relevant IgE-mediated sensitization against common aeroallergens has been demonstrated and well-characterized and standardized allergen extracts are used,376,377 avoiding complex mixtures.378,379 However, many patients with mild intermittent asthma (step1) suffer from moderate or severe allergic rhinitis concomitantly, which would justify the prescription of immunotherapy.380 Subcutaneous immunotherapy should not be prescribed to patients with uncontrolled severe asthma, because its efficacy is not well documented and a high risk of serious, even fatal, adverse reactions.379,381 For this reason, subcutaneous immunotherapy should only be prescribed by specialist physicians with experience in this type of treatment and administered in centers equipped with the basic resources for the immediate treatment of a possible adverse reaction.

The search for safer and more convenient alternatives for the patient has led to investigate the efficacy of sublingual immunotherapy. Some systematic reviews conclude that oral immunotherapy with capsules or lyophilized extracts can significantly reduce clinical manifestations and the use of rescue medication in children, adolescents and adults with allergic asthma.377,382–384

Most clinical trials showing clinical efficacy were performed with well-characterized extracts and at much higher doses than those usually prescribed for subcutaneous immunotherapy. The tolerability profile of sublingual immunotherapy is optimal and fatal reactions have not been reported.377,384

Sublingual immunotherapy with an oral lyophilized mite extract when added to regular pharmacological maintenance treatment is able to reduce the number of moderate to severe exacerbations385 and to improve the control of the disease, with a very favorable safety profile. Therefore, its use is recommendable for adult patients with moderately controlled or partially controlled asthma.380

When there are several immunotherapy alternatives available, priority should be given to the use of those that are considered registered drugs with well-established efficacy, safety, and quality data.

At the moment, no comparative studies on the cost-effectiveness of immunotherapy versus conventional pharmacotherapy are yet available, and they are not likely to be performed since their complex design makes them still unfeasible.

However, immunotherapy is not only useful in controlling disease manifestations, but it also offers additional advantages over pharmacotherapy, such as the maintenance of clinical benefits for several years after treatment discontinuation,386,387 a decrease in the risk of developing asthma in patients with allergic rhinitis,387,388 or the occurrence of new sensitizations in monosensitive patients.389 Finally, immunotherapy has been found to be cost-effective in comparison with pharmacotherapy alone in patients with the coexistence of allergic rhinoconjunctivitis and asthma.390,391

Influenza392,393 and pneumococcal394,395 vaccines have not been shown to be effective in preventing asthma exacerbations.

However, since it is a cost-effective approach, and due to the high risk of complications in patients with chronic diseases396,397 and a higher risk of therapeutic failure in children,398 annual influenza vaccination should be considered in patients with moderate and severe asthma, both in adults and children. Similarly, and given that asthma population have a high risk of invasive pneumococcal disease,399,400 different international401 and national402 consensus documents as well as the National Healthcare System403 recommend the administration of pneumococcal vaccine in patients with severe asthma.

Education of asthma patients is an essential component of treatment, because reduces the risk of exacerbations, improves quality of life and decreases healthcare costs,262,404 thus becoming an indispensable part of the overall management of the disease.228,404–410 The main goal of education is to provide patients with the knowledge and skills they need to improve self-care and treatment compliance. This results in a better adherence to treatment and, in consequence, in an optimal control of the disease. In addition, education promotes patient's self-control of asthma. Self-control is the situation in which the patient monitors their symptoms and applies self-management following a plan agreed with his/her doctor. Self-control supported by a healthcare professional reduces the number of consultations and exacerbations, and improves quality of life without increasing costs.411,412

From a practical point of view,413 education should consider two major aspects: transmission of knowledge and acquisition of skills and competences (table 27). Regarding the information that the patient should receive about asthma, their needs, previous knowledge, beliefs,414 age, severity of asthma, and the degree of involvement necessary in his/her self-control and treatment should be considered.

These interventions should include:415 self-management of symptoms or PEF monitoring, written action plans, and regular assessments of asthma control, asthma treatment and abilities of the healthcare personnel.411

Interventions without written action plans are less effective415,416 Actions that are exclusively informative are ineffective.408,416 Regarding the skills to be developed, patients will be trained in taking the prescribed medication, particularly in the technique of their inhalation devices,321,322,324,325,417 in the recognition of exacerbations and how to act early, and in the avoidance of allergenic triggers.418,419

Minimal educational interventions reduced to the essentials (mini-action plan, avoidance behaviors and revision of inhalation technique) have shown efficacy if they are administered repeatedly at follow-up visits.420

The education program should include establishing an action plan, which consists of a set of individualized written instructions in which asthma severity, disease control and the usually prescribed treatment are taken into account. The main objective of the action plan is the early detection of asthma worsening and the rapid adoption of measures to achieve quick remission. Depending on the patient's and the physician's preferences,421–423 the level of control on which the action plan should be based can be assessed in terms of severity and frequency of asthma symptoms, as well as through daily home recording of PEF. This plan should include two basic components:424–426 the usual treatment in situation of clinical stability of the disease and actions to be implemented in case of asthma worsening (table 28). This action plan will be reviewed at every clinical visit, either scheduled or unscheduled, as well as the time of hospital admissions or visits to the emergency department.

Table 28.

Asthma action plan.

Action plans improve the patient's quality of life, but a systematic review did not find other beneficial or detrimental effects with the use of a written action plan.427

Patient's adherence to treatment is a critical factor for achieving and maintaining disease control. It is estimated that adherence in asthma patients is lower than 50%.428–430

Low adherence is associated with increased morbimortality as well as with a greater use of healthcare resources.431,432

Three types of patients with low adherence or non-adherence have been described: erratic (due to forgetfulness to take medication), deliberated (or intentionally non-adherence where the patient decides not to take medications) and involuntary or unwitting (due to failure in understanding the disease and/or its treatment).433,434

Treatment adherence should be evaluated at each medical visit using a reasonably validated method, such as the Test of Adherence to Inhalers (TAI) and pharmacy dispending medication or the combination of both.435–437

The education program should include the assessment of the level of adherence, promoting the appropriate corrective measures in case of low adherence and adapting them to the patient's pattern of non-adherence.

Participation of the patient in the choice of the inhaler provides greater therapeutic adherence and control of the disease. Therefore, patients should be involved in the selection of the inhaler device.330,332,344,345,438–441

Non-adherence to control medication in severe asthma can be detected by the FENO suppression test.442

For education to be effective, a confidence relationship between the healthcare team and the patients should be established, so that patients can raise their doubts, concerns and fears. The healthcare provider should use a simple and understandable language towards both the patients and their relatives, ensuring that all concepts have been understood and encourage the patients to put forward their doubts and queries. Also, common objectives with the patient should be established, always based on written and individualized plans.

An appropriate agreement between the patient's opinions and expectations and his/her physician is one of the factors related to asthma control.443

Patients and their families should be encouraged to raise doubts and queries regarding the information received or emerging as a result of the medical visits, allowing sufficient time to be solved on the next visit.228

Since education is a continuous process and not an isolated event, each visit should give the opportunity to review, strengthen and increase the patients’ knowledge and skills; hence, it is indispensable that education should be agreed on and accepted by the whole healthcare team.408

Table 29 describes the educational tasks that should be undertaken at each visit. Once properly trained, the nursing and pharmacy staff should actively participate in the organization and management of education programs.334,444–446

Individualized discharge programs assisted by trained nursing personnel prevent readmissions due to exacerbations.447

Educational interventions carried out in the Primary Care setting reduce unscheduled visits and the inappropriate use of drugs, such as antibiotics.448

In the interventions to potentiate self-care, patients’ sociocultural differences should be considered.414

Educational interventions cannot exclusively be developed in the clinical setting. Interventions of self-care in schools or by other patients with asthma provide a better control, a reduction of exacerbations and an improvement of quality of life. Also, they can positively influence on adolescents to quit smoking.449,450

The use of telemedicine improved adherence to treatment431 through inhaler monitoring devices451 or reminder alarms.452 It also improves symptoms and decreases the use of medical care.453 Teleconsultation improves asthma control and quality of life454 (see section 9.4).

The efficacy of the patient's self-control in asthma is very positive. For interventions on the patient's self-management to be effective, it is necessary to combine the active participation of the patient, with training and motivation of professionals integrated into a healthcare system that values the self-control in asthma patients.455

Educational workshops are a useful tool as a complement to individualized care, being more profitable when performed during the periods of time when patients present more symptoms.456

The community pharmacist, due to its accessibility and frequent use by the patient, can identify poorly controlled patients especially those who abuse SABA agents or have low adherence to anti-inflammatory maintenance treatment. The community pharmacist can offer health education improving adherence, asthma control and obtaining better clinical and economic outcomes. If necessary, he/she can refer the patient to medical consultation.340,457–460

In clinical practice, it is difficult to differentiate a mild exacerbation from a transient loss of asthma control, since changes observed will be close to the normal range of variation for a given patient.461

Milder attacks can be managed at home by the patient him/herself or in primary care centers, provided a correct clinical and respiratory function assessment has been carried out and treatment response can safely be achieved within the first 2hours.

Asthma patients who have been provided with written action plans, including home PEF monitoring and how to act in case of loss of control, have an excellent and readily usable tool for managing mild exacerbations.477 In order to quickly implement the adequate measures, patients should be trained in identifying the early indicators of exacerbations and be ready to act immediately according to their assigned action plan, which should include the actions to be implemented according to the response to treatment.

The treatment schedule to be followed does not depend on the setting where the patient is being cared for. The therapeutic regimen should include the administration of short-acting ß2-agonists (SABA), such as salbutamol or terbutaline, and inhaled (ICS) or oral glucocorticoids. The addition of ipratropium bromide is not necessary for mild attacks, and antibiotics should not be routinely prescribed.

Inhaled SABA are the most effective and rapidly acting bronchodilators for treating asthma exacerbations. Salbutamol at doses of 200 to 400μg (2 to 4 puffs) with spacer is used.478,479

Treatment with salbutamol at doses of 2 puffs every 3-4hours can be continued until remission of the exacerbation episode.

If a favorable outcome is observed within the first 2hours of treatment (symptom resolution, PEF over 80% predicted or personal best value) and if this clinical response is maintained for 3-4hours, no more treatments are necessary.

The lack of response requires referral of the patient to a hospital emergency department.

The use of systemic glucocorticoids accelerates resolution of exacerbations and prevents relapses.480 Except for very mild attacks, systemic glucocorticoids should always be administered as early as possible,481,482 particularly in the following cases:

• •

  Pulmonary obstruction cannot be reversed with inhaled SABA.

• •

  The patient is already taken oral glucocorticoids.

• •

  The patient has treated him/herself a previous loss of asthma control with other therapeutic options without success.

• •

  There is a history of previous exacerbations requiring oral glucocorticoids.

The daily dose of prednisone is 0.5-1mg/kg of the ideal body weight (or equivalent doses of other steroids), up to 50mg; this dose should be maintained for 5 to 7 days, and may be discontinued without down-titration in order to achieve a quick improvement and prevent early relapses.482,483

The administration of glucocorticoids by the oral, intramuscular or intravenous route provides similar biological results, but the oral route is less invasive and cheaper.482,484–486

If response to inhaled bronchodilator treatment within the first hours is satisfactory, no hospital referral is required. Patients should be instructed on the need for adequate adherence to the treatment prescribed, their maintenance treatment plan should be reviewed, and a minimal asthma education intervention should be provided.487,488

The first measure consists of immediate oxygen administration, with a flow providing a saturation over 90% (95% in pregnant women or in patients with concomitant heart disease).489

In severe exacerbations with greater airflow obstruction and risk of hypercapnia, the use of oxygen with controlled FiO2 to obtain saturations around 93-95% is preferable than the use of high-flow oxygen therapy with which saturations around 100% can be achieved.489,490

In patients with severe exacerbations, the use of capnography to assess the trend to hypercapnia can be considered.491

Inhaled short-acting ß2-adrenergic agonists (SABA) are the first-line bronchodilator treatment. Both the dose and the dosing intervals should be individualized according to the choice of the administration system and the therapeutic response.

There is evidence that the use of a pressurized inhaler with spacer is the most cost-effective system;492 however, cost-effectiveness is lower in patients with very severe exacerbations.

It has been shown that the administration of SABA using a nebulizer or a pMDI inhaler with spacer has a similar clinical efficacy in terms of pulmonary function, length of stay in an emergency department, and risk of hospitalization. However, the dose when using a pMDI inhaler is lower.492–496

There is some debate as to whether nebulized treatment should be administered continuous or intermittently.497,498 A practical approach may include an initial continuous nebulization therapy to stabilize the patient followed by intermittent therapy.

There is no evidence to support the use of a route other than inhalation for the administration of bronchodilator medication.499 The intravenous route, with a very slow continuous infusion, should be used when there is no response to inhalation therapy in patients under mechanical ventilation and monitored in an ICU.

Similarly, no beneficial effects have been demonstrated when adding intravenous medication to the inhaled therapy.499

The use of parenteral epinephrine (subcutaneous or intravenous) is not indicated for treating exacerbations, except when these occur in a patient with anaphylaxis. In this case, the intramuscular administration is the route of choice because higher and more quickly plasma concentrations are obtained as compared with the subcutaneous route, as well as there is a greater safety margin.500–502

When administered in aerosol form, doses higher than 2mg, equivalent to 5mg salbutamol are required as lower doses are ineffective.503

The intravenous administration of epinephrine would only be indicated in case of cardiac arrest or in hypotensive patients who do not respond to intravenous volume replacement and multiple doses of intramuscular epinephrine.504,505

The use of ipratropium bromide during the initial phase of moderate or severe exacerbations concomitantly with a SABA is associated with a greater increase in pulmonary function (estimated by FEV1 or PEF) and a decrease in hospitalizations as compared to the use of a SABA alone.506,507

Systemic glucocorticoids accelerate the resolution of asthma attacks and prevent relapses.482,506,508 They should be prescribed early, within the first hour of treatment in the emergency room, since their effect starts 4-6hours after administration. They are especially indicated if no improvement is seen after the first dose of SABA, if the patient was already receiving them or if previous exacerbation episodes requiring these systemic glucocorticoids had occurred.

The preferred administration route of glucocorticoids is the oral route, as it is as effective as the intravenous administration,509 less invasive and cheaper.484,485 The intravenous route is limited to patients with severe dyspnea preventing swallowing and patients with vomiting or under mechanical ventilation.

The daily dose is 50mg of prednisone, as a single morning dose481 for 5-7 days, with no down-titration being necessary.510,511

Early use of high doses of ICS within the first hour of treatment reduces the need for hospital admission as in the case with systemic administration of glucocorticoids.508

The use of ICS together with systemic glucocorticoids provides even a higher reduction in the number of hospital admissions.508

Theophylline drugs should not be used in exacerbation episodes because of their lower efficacy and safety as compared with salbutamol.512

Routine administration of magnesium sulfate is not indicated, although in selected patients experiencing severe obstruction (FEV1 25-30% of predicted) or persistent hypoxemia, a single dose of 2g administered by infusion reduces the need for hospitalization.513–515

A systematic review of patients with severe exacerbations treated with intravenous magnesium sulfate showed a mild improvement of pulmonary function only.516

However, a more recent systematic review showed beneficial effects of inhaled magnesium sulfate added to SABA or SABA plus ipratropium bromide, reducing hospital admissions, in addition to a mild improvement of pulmonary function.517

Heliox, a mixture of helium and oxygen, in 80/20 70/30 proportion, has no place in the routine management of exacerbations due to the lack of consistent data regarding the efficacy of this compound. However, it may be considered in patients who do not respond to the usual treatment,518,519 particularly to nebulizing SABA.520

Regarding leukotriene antagonists, no data supporting their use either orally or intravenously are available. There is no evidence supporting the use of antibiotics, except in the presence of a clearly symptomatic respiratory infection.

The use of non-invasive mechanical ventilation may be an option in severe exacerbations resistant to treatment. It allows improvement of the respiratory rate, dyspnea, and, in particular, airflow obstruction due to a direct effect of positive pressure, or indirectly contributing to a better distribution of aerosols.521

Close monitoring is necessary so as not to delay the use of invasive mechanical ventilation in patients with an imminent life-threatening compromise.

Inhaled corticosteroids (ICS). ICS are the first-line of treatment. In children older than 3 years of age, the efficacy of daily ICS has been conclusively established, with improvement of clinical, parameters and bronchial inflammation parameters, better quality of life, and decrease in the risk of both exacerbations and hospitalizations.549,550

Infants and preschool children treated with daily ICS experience fewer recurrent asthma/wheezing episodes,551,542 with a better treatment response being obtained by those showing risk factors of developing persistent asthma (Asthma Predictive Index [API]),552,553 while viral-induced episodic wheezing shows limited response.554 A treatment trial followed by evaluation of response is recommended.555

Treatment with ICS, either continuously or intermittently, does not modify the natural history of the disease.556,557

In preschool and children, the use of controller drugs (ICS or montelukast) at regular doses or intermittently at the onset of symptoms is not recommended.558–560

Early intermittent therapy with ICS at high doses given to infants and preschool children with moderate-severe episodic wheezing and risk factors (API+) at the onset of symptoms have shown to be effective in reducing the severity and duration of exacerbations,550,561,562 but further safety studies are needed to establish a generalized recommendation of this therapy. It could be an option in highly selected cases in which education and acceptance by families are guaranteed.563,564

When administered at usual doses, ICS are safe drugs for the management of childhood asthma. There is usually a decrease in the growth rate at the beginning of treatment (1-3 years), although this is a transient effect and does not influence final growth or final height. However, the final height of children treated with ICS over prolonged periods is lower, an effect proved to be dose-dependent.565,566

It is difficult to establish the equivalent doses of ICSs mostly used in pediatric age.567 Comparable doses of ICS drugs for use in the pediatric age group are tentatively shown in table 39., taking into account that the lowest dose that maintains patient's control must be sought.

Leukotriene receptor antagonists (LTRA). In preschool children with virus-induced asthma/weezing episodes, LTRA are associated with a modest reduction of symptoms and the need of oral glucocorticoids as compared with placebo.559,568,569 Although a definite beneficial effect remains unclear, a clinical trial to assess response to LTRA may be conducted, which could be stopped if the expected response is not obtained.568 More evidence is needed to determine whether there is a responder phenotype to montelukast.570

If asthma symptom cannot be controlled with ICS at low doses, increasing ICS at medium doses is more effective than the association with montelukast.571

Association of long-acting ß2-adrenergic agonists and ICS. It has been approved for use in children over 4 years of age. The use of a LABA when administered with an ICSs is safe, but should never be used as monotherapy.572,573

One study showed a decrease in exacerbations and the need for systemic glucocorticoids in children aged 4-11 years with formoterol/budesonide administered in a single inhaler, both as maintenance treatment and as reliever (MART strategy),574 although some authors consider that the evidence in this age group is limited.575

En In children aged between 6 and 11 years with uncontrolled persistent asthma with low doses of ICS, doubling the ICS dose has a similar effect on clinical control and lung function than adding a LABA.576 However, the clinical phenotype and the heterogeneity of the individual response to ICS, LTRA and LABA should be assessed,539,577 therefore, it is necessary to closely monitor the response to treatment in children with uncontrolled asthma using ICS.

Tiotropium. It is a long-acting muscarinic antagonist. It can be used in children from 6 years of age with poorly controlled severe asthma treated with ICS at high doses plus a LABA. The dose is 5μg once a day.578 A study in children aged 1 to 5 years concluded that tolerability of tiotropium is good in preschool children and that this agent can reduce the number of exacerbations.579

Biologics. Biologics are drugs indicated in severe uncontrolled asthma that are aimed at treating the underlying inflammation by blocking different mediators. In the pediatric field, there are currently three biological agents available, all of them being monoclonal antibodies that are administered subcutaneously. Omalizumab targets IgE, mepolizumab blocks IL-5, and dupilumab targets IL-4 and IL-13. They have shown efficacy and safety and are recommended for children aged 6 and above.580,581 Their characteristics, indications, doses, and modes of administration are indicated in section 7.5 (Severe uncontrolled asthma in children).

Immunotherapy (IT). When biologically standardized extracts are used and appropriately selected in sensitized patients, immunotherapy has been shown to provide a beneficial effect by reducing symptoms, the need of reliever and maintenance medication, and decreasing bronchial hyperresponsiveness (both specific and non-specific).582

Also, IT prevents the development of new sensitizations and asthma in children with rhinitis.583,584

Considering that the main objective is to achieve control with the least possible medication, the treatment should be continuously adjusted, escalating or de-escalating the therapeutic step based on the level of control, always considering non-pharmacological measures, therapeutic adherence, and modifiable risk factors (Figure 10).

Figure 10.

Stepwise treatment of asthma in the pediatric age according to the level of

ICS: inhaled glucocorticoids; LTRA: leukotriene receptor antagonists; LABA: long-acting β2-adrenergic agonist; GC: glucocorticoid. *From 6 years of age. **Off-label.

(0.37MB).

The maintenance treatment will be initiated based on the initial severity level (recurrence or intensity of symptoms). Subsequently and retrospectively, the severity will be classified according to the level of treatment necessary to maintain symptom control.

• •

  Step 1. Children who have occasional asthma symptoms, without nighttime symptoms, and without risk factors for exacerbation, should only use bronchodilators on-demand. In the case of infrequent asthma symptoms but with risk factor(s) for exacerbation (table 19), the corresponding treatment for step 2 should be initiated. It is important to perform a careful evaluation, ensuring that the symptoms are truly intermittent and not persistent. From the age of 12, the use of formoterol associated with ICS could be considered.

• •

  Step 2. Children who require treatment with SABA two or more times per month, without symptoms between episodes and with normal lung function, should initiate treatment with low doses of ICS or consider montelukast as an alternative.

• •

  Step 3-4. Children with more than 6-8 asthma episodes per year, symptoms between episodes, asthma-related awakenings once a week, and/or impaired pulmonary function should adjust their treatment to step 3 or 4. In this step, there are three options: ICS at medium doses, adding a LABA to ICS at low dose (step 3), or association of a LABA with ICS at medium doses (step 4), and in children under 4 years of age, montelukast associated with low doses of ICS.

• •

  Step 5-6. In children with persistent symptoms, the need for short courses of oral corticosteroids, wheezing with minimal exertion, and impaired pulmonary function, treatment should be initiated at step 5 (ICS at high doses/LABA). Once control is achieved, the treatment should be stepped down to the lowest effective dose.585

If control is not achieved in children less than 4 years of age, it is necessary to consider adding one or more of the following drugs: LABA (off-label use), tiotropium (off-label use in children under 6 years), macrolides, or even oral glucocorticoids. In children of more than 6 years of age, options include tiotropium, monoclonal antibodies, or oral glucocorticoids (see chapter 3, “Severe Asthma”).

In children older than 12 years, it is possible to apply the so-called MART therapy, that is, ICS/formoterol, both as maintenance and rescue treatment.

The following factors should be considered: time course of the exacerbation episode, pharmacological treatment administered, presence of associated diseases, and possible risk factors (previous intubation or ICU admission, hospitalizations in the previous year, frequent need of admission to the emergency department in the previous year and/or use of oral glucocorticoids, and excessive use of SABA in the preceding weeks).

Severity assessment is mainly based on clinical criteria (respiratory rate, presence of wheezing and sternocleidomastoid retractions). Although no clinical scale is considered to be well validated586,587 the Pulmonary Score (table 40)588 has been found to be useful and applicable to all ages. The combination of symptoms and arterial oxygen saturation (SaO2) allows completing an estimation of the severity of the exacerbation episode (table 41).

Inhaled short-acting ß2-adrenergic agonists (SABA). These agents constitute the first-line treatment due to their higher effectiveness and lower incidence of side effects.589 They should preferably be administered via a pressurized inhaler with a spacer chamber, since this way of administration is as effective as nebulizers for treating an acute asthma episode.590–593

The recommended doses and dosing intervals depend on the severity of the exacerbation episode and the response to the initial doses.594 The most commonly used drug is salbutamol, which is available as a solution for use with a nebulizer and a pressurized inhaler. The latter must be administered in sequences of 2-10 puffs of 100μg until response is obtained. In mild exacerbations, a series of 2-4 puffs may be sufficient, although up to 10 puffs may be necessary for severe exacerbations.

Nebulized SABA should be restricted to those cases in which the patient requires oxygen supply for SaO2 normalization, although a recent randomized clinical trial (RCT) showed that even in severe exacerbations, the administration of salbutamol and ipratropium bromide with spacer chamber and facial mask with oxygen by means of a nasal cannula was more effective than using a nebulizer.595

Continuous nebulization does not offer greater advantages compared to intermittent nebulization when the same total doses are administered.596,597

Ipratropium bromide. The use of frequent doses, every 20minutes, of ipratropium bromide for the first 2hours in case of severe asthma exacerbations or moderate exacerbations not responding to initial treatment with SABA, has been shown to be effective and safe.588,598 The nebulized dose is 250μg for children weighing less than 30kg y 500μg for those weighing more than 30kg. The dose for inhaled use with a spacer chamber is 40-80μg (2-4 puffs). The maximum effect, which tends to decrease gradually, is observed with the first doses, so that inhalations beyond the first 24-48hours should not be maintained.599

In infants, the use of ipratropium combined with inhaled SABA has been shown to be effective in the treatment of the most severe exacerbations.600 The effect of this association administered by an inhaler seems to be higher as compared to that administered by nebulization.595

Systemic glucocorticoids. The efficacy of systemic glucocorticoids in preschool children with mild to moderate acute episodes of wheezing induced by viral infections has been questioned; hence, its use should be restricted to more severe exacerbations (1-2mg/kg/day).569,601,602 In children over 5 years of age, these agents have shown benefit after early use,603 with the oral route being preferred over the intravenous or intramuscular routes, except for circumstances in which oral intake is not feasible.604,605 Systemic glucocorticoids should be administered in moderate-severe exacerbations, and may be considered for mild exacerbations when sufficient improvement with bronchodilators has not been achieved or the child has a history of severe attacks (in this case, early administration). Prednisolone at doses of 1-2mg/kg/day (maximum 40mg) for 3 to 5 days or until resolution of the asthma attack is the most commonly used drug.606,607

Dexamethasone is being used as an alternative. The effect of administering a single dose of dexamethasone orally (at 0.3-0.6mg/kg) is not inferior to that of administering prednisolone orally (at 1mg/kg/day) during 3 days of treatment.608–611

Inhaled glucocorticoids. There is insufficient evidence to recommend the use of ICS as an alternative612 or additional treatment to systemic glucocorticoids613,614 in the management of asthma exacerbations. Larger studies are needed, with better methodological quality and cost-effectiveness analysis,615 as well as safety studies.612

Magnesium sulfate. It can be used in severe exacerbations with unsuccessful response to the initial treatment,616,617 but its use does not prevent hospitalizations.618 The drug is administered intravenously as a single dose of 40mg/kg (up to 2g) over 20minutes.

Nebulized magnesium sulfate together with a ß2-adrenergic agonist in the treatment of an asthma exacerbation seems to have benefits in the improvement of pulmonary function.619,620

Treatment of an asthma exacerbation episode depends on its severity and follows the flow chart shown in Figure 11. Doses of drugs and duration of administration should be modified according to the severity of the exacerbation and the response to treatment.

Figure 11.

Treatment of asthma exacerbation in children.

SaO2: oxyhemoglobin saturation; max: maximum. SABA: short-acting β2-adrenergic gonist.

(0.4MB).

When SaO2 is below 94%, oxygen therapy is required to maintain SaO2 between 94-98%.621,622 An SaO2 <92% after initial treatment with inhaled bronchodilators can be used as a marker to select the most severely ill patients who should be hospitalized for starting intensive treatment.621,622

During the first 2 hour of treatment and in children with moderate/severe exacerbation unresponsive to first-line therapy, the use of a high-flow nasal cannula seems to be superior to conventional oxygen therapy to reduce breathing difficulty.623,624 However, more studies are needed to demonstrate the general efficacy of this approach in the management of asthma and respiratory insufficiency in the emergency setting.625

Regarding non-invasive ventilation (NIV), the current available evidence does not allow to confirm or exclude its use in exacerbation episodes refractory to the usual treatment.626

Mild and moderate exacerbations can be treated in the primary healthcare setting.

In the presence of severe exacerbation or suspicion of complications, history of high-risk exacerbations or lack of response to treatment, patients should be referred to the hospital in a medicalized ambulance.

Follow-up. It is necessary to evaluate the degree of the control of symptoms in the previous weeks, the presence of risk factors, possible triggering factors, and previous treatment. Also, it is important to assess the level of therapeutic adherence and to supervise that the inhalation technique is correct. A written action plan must be reviewed or provided and a follow-up visit arranged.544

It has been estimated that between 12% and 30% of patients with suspected SUA do not have asthma.726,745–747

It should be confirmed that the diagnosis of asthma has been made correctly and, in case of doubt, studies aimed to demonstrate objectively the presence of airflow obstruction, variability and/or bronchial hyperresponsiveness (see chapter 2.2) should be performed. If diagnosis cannot be confirmed, other diseases mimicking asthma should be excluded through the rational and progressive use of work-up studies summarized in table 47.

It is necessary to identify and evaluate some factors unrelated to the disease, the presence of which can contribute to poor control of asthma. These factors can be grouped into the following categories:

• •

  Factors directly related to the patient: treatment adherence and inhalation technique. Up to 50% to 80% of cases of SUA are caused by inadequate adherence or by a deficient inhalation technique.732,745,748

  Therefore, adherence should always be evaluated (preferably using validated questionnaires or information on dispensing prescriptions in the the community pharmacy) and the inhalation technique (direct observation) (see chapter 3.4).

• •

  Factors related with comorbidities and aggravating conditions. Different diseases or processes when present concomitantly with asthma can contribute to an insufficient control of the disease. It has been shown that 92% of patients with SUA suffer from at least one of these conditions, which in turn are more prevalent than in patients without SUA.730

  Table 48 summarizes the most commonly cited comorbidities and their corresponding tests for evaluation, diagnostic confirmation, and treatment approach.738,740,741,749,750

  Table 48.

  Common comorbidities and aggravating factors of asthma with their corresponding diagnostic tests and treatment.

  Comorbidity	Diagnostic tests	Treatment
  Sinonasal disease	Rhinoscopy/nasal endoscopy	Intranasal glucocorticoids
  	Sinus imaging studies (CT/MR)	Nasal Iavages/antileukotrienes
  		Endonasal surgery
  Gastroesophageal reflux	pH-metry/esophageal manometry	Hygienic-dietetic counselling
  	Treatment test with PPI	Proton pump inhibitors
  	Upper digestive endoscopy	Surgical repair
  Obesity	BMI	Weight loss
  		Bariatric surgery
  Sleep apnea syndrome (SAS)	Polysomnography	CPAP
  		Weight loss if necessary
  Psychopathology (anxiety, depression)	Psychologist/psychiatrist evaluation	Psychotherapy/specific treatment
  Fibromyalgia	Rheumatological evaluation
  Functional dyspnea	Specific questionnaires (Nijmegen questionnaire)	Psychotherapy
  		Respiratory re-education
  Inducible laryngeal obstruction (ILO)	Laryngoscopy in exacerbation or methacholine/exercise challenge	Logophoniatric rehabilitation
  		Treatment of comorbidities: reflux
  Drugs: NSAID, non-selective β-blockers, ACE inhibitors	Clinical history	Substitution
  Tobacco and other inhalation toxics	Questioning	Cessation/quit

  NSAID: non-steroidal anti-inflammatory; ACE: angiotensin-converting enzyme; CT: computed tomography; MR: magnetic resonance; PPI: proton pump inhibitors; BMI: body mass index; CPAP: continuous positive airway pressure.
• •

  Factors related to triggers of exacerbations. It is necessary to identify whether exposure to triggers of exacerbations are present (see table 4), particularly active and passive smoking, e-cigarettes, cannabis inhalation, allergen exposure (mites, pollens, fungi, dander, cockroaches, etc.), indoor and outdoor air contamination, occupational agents, molds and harmful chemical products, drugs such as non-cardioselective ß-blockers, non-steroidal anti-inflammatory drugs (NSAID), and angiotensin-converting enzyme (ACE) inhibitors.738,740

  Moreover, lack of response due to SABA abuse (by downregulation of ß2 receptors and increase of bronchial hyperresponsiveness [BHR]) has been reported.751,752

Classification into phenotypes aims to identify specific patients who are candidates for a particular treatment739,753 (see section 7.3). Currently, specific biomarkers for each phenotype/endotype are not available.754

The minimum follow-up period, by a specialist or a specialized asthma unit, to accept the diagnosis of SUA is 6 months.728,738,741

Allergic asthma accounts for 40-50% of severe cases of asthma, and has an atopic underlying mechanism mediated by the activation of type-2 helper T lymphocytes (Th2), the production of interleukin (IL) 4, IL-5 and IL-13, and an isotype shift within B lymphocytes towards IgE production. Allergic bronchopulmonary aspergillosis (ABPA) is a particularly severe variety of allergic asthma that shows a pure eosinophilic or mixed (eosinophilia and neutrophilia) inflammatory pattern in sputum. Periostin (an IL-13-induced cell matrix protein), which can be measured in blood and bronchial secretions, and the fractional exhaled nitric oxide (FENO) are good biomarkers of the “increased” T2 variant.771–774 The diagnosis requires the demonstration of sensitization to an allergen and the triggering of symptoms with exposure to such allergen.

It accounts for more than 25% of severe asthma cases and is characterized by the presence of eosinophils in bronchial biopsies and sputum samples despite treatment with glucocorticoids at high doses. Chronic rhinosinusitis and nasal polyps may also occur. A subset of patients develops AERD. Although eosinophilic asthma is associated with a lower prevalence of atopy, IgE and FENO may be increased. Alterations of the arachidonic acid metabolism are involved in the pathogenesis of this phenotype of asthma. A high production of IL-5 may explain the eosinophilic inflammation in the absence of the traditional allergy-mediated T2 mechanism.775–778

This phenotype of asthma occurs without eosinophilia, neither in the peripheral blood, nor in sputum. It frequently shows a paucigranulocytic profile, neutrophilia, scarce local eosinophilia, low FENO levels, and a poor response to glucocorticoids. It can be accompanied by chronic airflow limitation with important air trapping and, frequently, history of smoking is present.779,780 It should be taken into account that inflammatory biomarkers of type T2 phenotype (peripheral blood eosinophils, sputum eosinophils, and FENO) are frequently suppressed by oral glucocorticoids. In our opinion, analysis of peripheral blood eosinophils and FENO should be repeated up to three times (e.g. when asthma worsens, before the administration of oral glucocorticoids), before assuming that asthma does not belong to the T2 phenotype.

In the GINA 2019, the possibility of type 2 refractory inflammation is considered, in the presence of any of the following findings in a patient taking ICS at high doses or daily oral glucocorticoids:740

• -

  Peripheral blood eosinophils ≥ 150/μl, and/or FENO ≥ 20 ppb, and/or

• -

  Sputum eosinophils ≥ 2%, and/or

• -

  Asthma is clinically induced by allergens.

Asthma education. Asthma education activities are not different from that usually recommended for the remaining asthma population (see chapter 3.5). However, approaches such as maximizing avoidance measures and smoking cessation should be implemented, with special emphasis to confirm objectively that adherence to treatment and the inhalation technique are both correct. At present, there are different devices for remotely adherence monitoring.781,782

Background pharmacological treatment. According to the inclusion criteria defining SUA, in patients on maintenance therapy with a combination of ICS/LABA at high doses it is advisable to add, at least, a third controller drug, usually tiotropium783,784 (see chapter 3.2).

Treatment of comorbidities. If either an associated comorbid condition or an aggravating factor has been identified, the appropriate therapeutic measures should be initiated (table 48).738,740,749,750

Patients with SUA according to the pathophysiological underlying mechanism (T2 or non-T2 asthma) and the presence or absence of different inflammatory markers are classified into the aforementioned phenotypes (see section 7.3).

Inflammation markers of T2 phenotype may be suppressed by treatment with oral glucocorticoids (OCS); therefore, they should be preferably measured before starting treatment with OCS or at the lowest possible dose, and at least on three occasions (e.g. during an exacerbation), prior to assume that a patient presents a non-T2 phenotype. In corticosteroid-dependent patients, it is important to check their historical values.

A phenotype-directed treatment algorithm is proposed in the present guideline (fig. 16 and table 50); the different monoclonal antibodies available for treating SUA are shown together with their main characteristics.

Figure 16.

Treatment of SUA according to phenotype.

SUA: severe uncontrolled asthma; ICS: inhaled glucocorticoids; LABA: long-acting β2-adrenergic agonists; LAMA: long-acting cholinergic agonists; CRSwNP: chronic rhinosinusitis with nasal polyposis; HES: hypereosinophilic syndrome; EGPA: eosinophilic granulomatosis with polyangiitis; PMN: polymorphonuclear neutrophils; ACT: Asthma Control Test; ACQ: Asthma Control Questionnaire; SNOT-22: Sinonasal Outcome Test; VAS: visual analogue scale; FENO: fractional exhaled nitric oxide; EOS: eosinophils; aSensitivity to allergens and presence of compatible clinical features, and total IgE ≥ 75 IU; bOmalizumab if IgE ≥ 75 U/l and EOS <150μl; cDupilumab if EOS ≥300μl and/or FENO ≥50 ppb and between 150-300 EOS and FENO ≥25 ppb. Not recommended if EOS ≥1,500μl. dTezepelumab if FENO ≥25 ppb; eMepolizumab if current EOS ≥150μl and ≥300μl in the previous 12 months. fBenralizumab if current EOS ≥150μl and nasal polyposis or ≥3 severe exacerbations in the previous year or FCV <60%; gReslizumab if EOS ≥400μl.

Notes

Definitions

SUA: asthma requiring treatment with 5-6 therapeutic steps according to GEMA and presents ≥1 of the following criteria:

• –

  ACT <20 or ACQ ≥1.5.

• –

  ≥2 courses of oral corticoids (OCS) during ≥3 days

• –

  in the previous year.

• –

  ≥1 hospital admission due to asthma exacerbation in the previous year.

• –

  FEV1 ≤ 80% predicted.

Type 2 refractory inflammation: ≥1 of the following criteria in a patient using inhaled glucocorticoids (ICS) at high doses or daily OCS:

• –

  ≥150 eosinophils per microliter in blood

• –

  FENO ≥25 ppb/ul (American Thoracic Society Committee).

• –

  ≥2% eosinophils in sputum.

• –

  Asthma is clinically induced by allergens.

Patients requiring maintenance treatment with oral glucocorticoids can also have an underlying type 2 inflammation. However, OCS often suppress type 2 inflammation biomarkers (blood and sputum eosinophils and FENO). Therefore, when possible, these tests should be performed before starting a short course or maintenance treatment with OCS, or when the patient receives the lowest possible dose of OCS.

Thresholds of peripheral blood eosinophilia: At least one analytical result of more than 300 Eos/μl in the last year. Low values of eosinophils may appear in patients recently treated or on chronic treatment with systemic glucorticoids. In this case, it can be useful to review the patient's historical values.

Thresholds of FENO. The cutoff value is established at 25 ppb. However, it should be considered that results of FENO measurement can altered by the recent use of systemic glucocorticoids and total dose of inhaled glucocorticoids, age. and current smoking (lower values in smokers). In the presence of high FENO levels, it is necessary to confirm that self-administration inhaled medication is correct (treatment adherence and inhalation technique).

Response to a biological drug. It is defined by:

• –

  ACT score equal or higher than 20 or a significant change as compared with baseline score (≥3 points).

• –

  Absence of hospital admissions or visits to the emergency room.

• –

  More than 50% reduction of exacerbations.

• –

  Suppression of the use of oral glucocorticoids or significant decrease of doses (≥50%).

Choice among monoclonals

The order in which biologics appear in the scheme when they coincide for the same indication only takes into account the time since each drug has been commercialized.

In the choice of biologics should be considered: blood eosinophil count, pulmonary function, use of maintenance treatment with oral glucocorticoids, presence of comorbidities: nasal polyposis/AERD, chronic urticaria, atopic dermatitis and asthma-associated diseases (eosinophilic granulomatosis with polyangiitis, eosinophilic pneumonia, allergic bronchopulmonary aspergillosis, eosinophilic esophagitis).

• –

  Benralizumab (higher efficacy ≥300 eosinophils/μl): patients with poor pulmonary function, polyposis, maintenance with oral glucocorticoids and difficult access to asthma unit living far away [long distances]).

• –

  Reslizumab (higher efficacy ≥400 eosinophils/μl): improves pulmonary function. Not effective for reducing OCS doses. Intravenous administration.

• –

  Mepolizumab (indication from 150 eosinophils/μl but higher efficacy ≥500 eosinophils/μl): indicated in patients with ≥150 eosinophils/μl if there are historical values of ≥300 eosinophils/μl. It has been shown that allows reduction of withdrawal of OCS.

• –

  Dupilumab (higher efficacy ≥300 eosinophils/μl and/or FENO ≥50 ppb): improves pulmonary function, nasal polyposis and severe dermatitis. It has been shown that allows reduction of withdrawal or OCS and increases eosinophil values. Administration every 15 days.

To choose between drugs with potential efficacy in a given patient, criteria of posology, patient's preferences, and costs should be also considered.

Thermoplasty is indicated in patients neither with emphysema/bronchiectasis/atelectasis nor with important comorbidities, without treatment with anticoagulants or immunosuppressants, and who do no present recurrent infections. FEV1 should be greater than 40% and any contraindication for fiberoptic bronchoscopy with sedation should be absent.

(0.38MB).

4.5.1.6Systemic glucocorticoids

In some patients with SUA suffering from an exacerbation episode, treatment with OCS is necessary. Patients requiring OCS courses may present adverse effects, the risk of which increase with the use of ≥ 4 courses of OCS in a year or >30 days a year.849,850

The use of OCS at the minimum necessary dose and for the shortest time possible should be reserved as one of the last alternative for patients in whom control is not achieved with other therapeutic options.851 In these circumstances, preventive or treatment measures for possible adverse effects will be considered.

Some studies with not very robust designs, carried out in small samples of patients showed that intramuscular triamcinolone depot (glucocorticoid with the addition of a fluorine group), in patients with corticosteroid-dependent asthma, compared to the usual OCSs, provided a significant reduction of exacerbations, an increase in pulmonary function, and fewer side effects.852,853 However, they are not free of adverse effects and the pharmacokinetic profile is unknown.

4.5.1.6.1Recommendations for taperingl of oral glucocorticoids

Some studies have shown that the use of OCS is not uncommon.854,855

A significant dose-response relationship between chronic use of OCS and the risk of complications has been observed.856

Every patient undergoing treatment with OCS should undergo proper monitoring and management of possible side effects. A protocol to this purpose is shown in table 51.

Table 51.

Protocol of monitoring side effects of systemic glucocorticoids.

Osteoporosis	Annual height measurement.Evaluation of the risk of fractures.Bone densitometry before treatment with SGC and at one year:• If low BMD, repeat at one year.• If normal BMD, repeat at 2-3 years.
Adrenal insufficiency	If the use of SGC exceeds 2 consecutive weeks continuously or 3 cumulative weeks in the previous 6 months:• Evaluation of symptoms.• Baseline cortisol assay (8-9 a.m).
Ophthalmological	Annual ophthalmological examination.Early referral for ophthalmological examination (in the presence of cataracts and/or risk factors for glaucoma).
Cardiovascular	Calculate the risk according to the Framingham index.Lipid profile after one month of starting treatment with SGC, repeat every 6-12 months.
Hyperglycemia	Glycemia every 3-6 months on the first year, and then annually.
Infections/pneumonias	Alert the patients to seek medical care in the presence of fever and/or symptoms of infection.Microbiological surveillance. Serial sputum cultures.

BMD: bone mineral density; SGC: systemic glucocorticoids.

Modified from Liu et al., 2013857.

In a recent Dephi expert consensus study,858 the authors made a series of recommendations regarding the use of OCS:

• •

  Minimize OCS use as much as possible.

• •

  An annual cumulative dose of 0.5 to 1g would be indicative of poor asthma control.

• •

  Primary care physicians prescribing at least 3 courses of OCSs per year to a patient should consider specialist referral.

• •

  In all patients who have received a cumulative dose of OCS exceeding 2g in the past year, a fasting morning cortisol test (8 a.m.) should be performed when attempting to reduce the OCS dose below 5mg/day.

• •

  When no other alternative is available, a dose of ≤ 5mg/day of prednisone (or equivalent) would be considered acceptable.

Regarding tapering of OCS doses in patients starting treatment with biologics, the following should be considered:

• •

  The initial tapering of high OCS doses (e.g. 20mg/day) can proceed at a faster pace (e.g. 10mg/week or 30-50% reductions every 2-4 weeks). Reduce 2.5 to 5mg every 0.5 to 2 weeks until the physiological dose is achieved (e.g. 5-10mg/day) and then proceed to a lower pace (1-2.5mg every 1-2 weeks).

• •

  When a reduction in the OCS dose by 5mg/week fails, a slower and lower dose reduction of 1mg/week should be attempted.

• •

  If mild symptoms occur, maintain the current dosage; they are likely to resolve as endogenous-axis recovery occurs.

• •

  If intolerable symptoms occur, return to the previous (efficacious) dose and then later consider reattempting tapering at a slower pace.

Although there is no unanimous agreement, a scheme for reducing the dose of OCS in patients starting treatment with biologics has recently been proposed.859

Figure 17 shows the algorithm proposed for the treatment of corticosteroid-dependent severe asthma in adults725 and fig. 18 the algorithm for down-titration doses of OCS.

Figure 17.

Treatment of corticosteroid-dependent severe asthma in adults (based in part on the 2022 SEPAR consensus860 (OCS: oral glucocorticoids; ACT: Asthma Control Test; ACQ: Asthma Control Questionnaire; SNOT: Sinonasal Outcome Test Questionnaire; VAS: visual analogue scale).

(0.32MB).

Figure 18.

Algorithm for the evaluation of adrenal function during down-titration of OCS dosage.

(Modified from Menzies-Gow et al., 2022).859

*It can be directly substituted by hydrocortisone 20mg/day, preferable at breakfast.

**Do not take OCS on the previous night nor in the morning before blood sampling.

(0.32MB).

Severe asthma in childhood is more common from school age863,864 with a prevalence of 2-5%.865,866 It is associated with a high morbidity,867 costs,868 and future risk of chronic obstructive pulmonary disease (COPD).869,870

The clinical presentation and response to treatment vary from infants to adolescents.871,872

In children with severe recurrent exacerbations, and in younger than 5 years of age, with or without symptoms between episodes, a diagnosis of SUA may be considered when despite a correct treatment with ICS at high doses, the following events are present:

• 1)

  ≥ 1 admission to an intensive care unit,

• 2)

  ≥ 2 hospital admissions requiring intravenous therapy or

• 3)

  ≥ 2 courses of OCS in the previous year.873

The definition for children older than 5 years of age coincides with that for adults.726

A cost-effective multidimensional, Multidisciplinary, and stepwise evaluation is necessary necesaria874,875 (fig. 19).

Figure 19.

Severe uncontrolled asthma in children: stepwise evaluation.

(0.19MB).

Up to 50% of patients present potentially avoidable factors and/or associated comorbidities responsible for difficult control of their asthma.726,876

Children with SUA, despite adequate management of associated factors and comorbidities, are candidates for increasing the therapeutic step.

Inhaled glucocorticoids. A few children benefit from doses of fluticasone propionate or equivalent higher than 500μg/day, which in turn are related with adverse effects.879

Oral glucocorticoids. No data are available on the efficacy of OCS in the maintenance treatment of children with asthma treated with ICS at high doses plus LABA and/or montelukast. After the introduction of tiotropium and monoclonal antibodies, they have been relegated to a second step due to their adverse effects. If necessary, they should be used at the lowest dose for the shortest period of time and monitoring their adverse effects.

Triamcinolone. Triamcinolone could be useful in children with SUA, particularly in non-adherent patients to OCS or to determine the sensitivity or response to steroids.883 However, the use of triamcinolone should be very limited because of side effects and unknown pharmacokinetics.

Tiotropium. Associated with ICS/LABA in children aged 6 years or more is an option for trying to achieve asthma control884,885 prior to the use of monoclonal antibodies.

Omalizumab. It is an anti-IgE monoclonal antibody that has shown efficacy for treating children aged 6 years or more with persistent moderate or severe allergic asthma insufficiently controlled with high doses of ICS and LABA.886,887 It reduces exacerbations, symptoms, doses of ICS, the use of rescue medication, and improves quality of life.789,888

It is administered subcutaneously every 2-4 weeks, with the dose adjusted to total IgE values and body weight. In several studies carried out in routine clinical practice in children with severe allergic asthma, after the fifth month of treatment with omalizumab, improvement in asthma control, reduction in the rates of exacerbations and admissions, and in ICS doses were observed.889

Mepolizumab. It is an anti-IL5 monoclonal antibody, effective in severe eosinophilic asthma.890,891 Currently there is indication for its use after 6 years of age, with safety and efficacy data that support the use of mepolizumab in children with severe eosinophilic asthma, with a similar than adolescents and adults.829,891 The recommended dose is 40mg between 6-11 years and 100mg from 12 years, administered subcutaneously, once every 4 weeks.

Dupilumab. It is a monoclonal antibody that blocks the shared receptor of IL-4 and IL-13, reduces exacerbations, improves pulmonary function, and decreases the need for oral glucocorticoids in severe eosinophilic asthma in adults and adolescents. Its efficacy has also been proven in children from 6 to 11 years of age, with a dose of 100mg every 2 weeks of 300mg every 4 weeks in patients weighing less than 30kg, 200mg every 2 weeks or 300mg every 4 weeks in those weighing between 30 and 60 kf, and 200mg every 2 weeks in those with a body weight greater than 60 kg.892

Macrolides. They have an immunomodulator and antibacterial effect. In highly selected cases, azithromycin may be beneficial for improving some clinical symptoms and pulmonary function in children (< 6 years of age) with persistent uncontrolled asthma,893 as well as the quality of life, without differences between the eosinophilic and non-esoinophilic phenotypes.894

In infants and preschool children the level of evidence of the studies is even lower, although emerging studies are trying to define therapeutic position alternatives.

When symptoms remain uncontrolled despite ICS at high doses combined with montelukast, either LABA (off-label indication),895tiotropium,896 macrolides or even OCS may be added, although the best therapeutic option has not yet been established. The need to stepped-up treatment should be reevaluated at each visit, trying to maintain it during the shortest possible period of time.

Asthma and chronic obstructive pulmonary disease (COPD) are two different chronic respiratory diseases,897 although it is common to find the characteristics of both diseases in a single patient.898

Asthma and smoking,899,900 low pulmonary function in childhood,901 exposure to irritants902 or environmental contamination903 can contribute to the development of associated COPD in adulthood.

The GesEPOC-GEMA consensus defines asthma-COPD overlap syndrome (ACOS) as the presence of persistent chronic airflow limitation (CAL) (crucial for diagnostic confirmation), in a current smoker or ex-smoker patient (main risk factor), who presents characteristics of asthma (clinical, biological or functional).904

Different definitions of ACOS have been proposed,905–912 the most recent of which are based on two types of patients:

• •

  Patients with asthma who smoke and develop chronic airway obstruction.

• •

  Patients with COPD and eosinophilia.904,911,913,914

The prevalence of ACOS varies according to the source considered and criteria used for definition,915–917 with estimates between 1.6% and 4.5% in the general population, and between 15% and 25% in patients with obstructive respiratory disease.907,918–932

Patients with ACOS have more symptoms, poorer quality of life, higher risk of exacerbations, more accelerated loss of pulmonary function, higher incidence of comorbidities and greater consumption of healthcare resources905,906,927,933–937 as compared to patients with asthma or COPD, but a better survival when treated with inhaled glucocorticoids (ICS).907,919,938,939

The mortality of chronic respiratory disease is higher in patients with ACOS or COPD than in those without chronic airway obstruction.940–942

The following sequential diagnostic evaluation is proposed (fig. 20):913,943

• •

  To confirm that the patient meets criteria for COPD (> 35 years, smoker >10 pack-years, post-bronchodilation forced expiratory volume in one second/forced vital capacity [FEV1/FVC] <70% [assessing the lower limit of normal, particularly at extreme ages]).909,944

• •

  If the patient also meets criteria for asthma,909,945 ACOS is confirmed.

Figure 20.

Diagnostic confirmation of asthma and COPD overlap syndrome (ACOS).

*Maintain after treatment with ICS/LABA (6 months). In some cases added after a course of oral steroids (15 days). ACOS: asthma-COPD overlap syndrome; ICS: inhaled glucocorticoids; LABA: long-acting ß2- adrenergic agonist; BDT: bronchodilation test; LNN: lower limit of normal.

(0.17MB).

If the patient does not meet complete criteria for asthma, the presence of a very positive bronchodilation test (FEV1 post-bronchodilation ≥ 15% and 400ml) or blood eosinophilia (≥ 300 eosinophils/μl), confirms the diagnosis of ACOS.

Although the initial treatment does not differ between patients with pure asthma and those with overlap syndrome, in patients with COPD, a diagnosis of ACOS predicts the response to ICS.946,947 There are proposals for the treatment of ACOS according to its treatable features948,949 that should be agreed upon.

Therapeutic recommendations in patients with ACOS

• •

  If the diagnostic evaluation only confirms asthma, it will be treated according to GEMA guidelines,943 avoiding monotherapy with long-acting ß2-adrenergic agonist (LABA).

• •

  If the diagnostic evaluation only confirms COPD, it will be treated according to GesEPOC guidelines944 avoiding monotherapy with ICS.

• •

  If the evaluation confirms ACOS: start with a combination of ICS at low or moderated doses according to symptoms,950 associated with a LABA.951–955

• •

  In case of persistence of exacerbations or relevant symptoms, it is recommended adding a long-acting muscarinic antagonist (LAMA).956,957

• •

  Treatment of comorbidities.

• •

  Treatment with biologics: the role of omalizumab958–963 or anti-leukin-5 (anti-IL-5) (benralizumab964,965 or mepolizumab963,966,967) in ACOS still remains unclear.968

• •

  Other treatments (when necessary): smoking cessation, respiratory rehabilitation, oxygen therapy.

• •

  Patients should be referred to specialized consultation in case of lack of response or partial response to the prescribed treatment.

• •

  Periodic follow-up assessments should be established.

Although the risk is low, pregnant women with asthma may present maternal and fetal complications. Poor asthma control is associated with prematurity, loss of pregnancy, low birthweight, and increased perinatal mortality, whereas in the mother there is an increased risk of pre-eclampsia, placenta previa, and gestational diabetes.973,974 Also, asthma exacerbations during pregnancy are associated with a higher risk of complications during the gestational period, adverse perinatal events, and respiratory conditions during early infancy in their children.975 Prevention of asthma exacerbations is essential for reducing the risk of complications.976

Poor adherence to treatment977 and upper respiratory tract infections are the most common trigger factors for exacerbations.969 Women with other comorbidities, such as rhinitis, obesity, sudden increase of body weight during the first trimester of gestation, and smoking habit have a poorer control of asthma during pregnancy.978,979

Virtually all drugs used in the treatment of asthma cross the placental barrier; however, the advantage of treating asthma during pregnancy outweighs the potential shortcomings of the use of medication.969,972,978,979

The appropriate use of ICS, LABA, montelukast, and theophylline is not associated with an increase of fetal abnormalities.980

ICS prevent asthma exacerbations during pregnancy.981

Budesonide and other ICS are safe drugs.982,983 A study carried out in 2014 in neonates born from mothers treated with inhaled budesonide during pregnancy did not show a higher rate of teratogenesis (3.8%) as compared to the general population (3.5%).984

Although safety studies of ß2-agonists during pregnancy are not totally conclusive, and a recent study revealed a slightly higher risk for the incidence of cleft palate and gastroschisis985 but advice against the use of these compounds has not been established.986

Oral glucocorticoids (OCS) cause teratogenic effects, and their use should be restricted to asthma exacerbations and severe asthma.987 A study carried out in 250 pregnant women with asthma treated with omalizumab did not reveal a high risk of congenital malformations.988 However, starting the administration of omalizumab during pregnancy is not recommended because of the risk of anaphylaxis.988,989

The same algorithms for the treatment of exacerbations in non-pregnant women with asthma should be followed, but ensuring an adequate oxygenation (SaO2 >95%) and monitoring of the fetus.969,972

Control of asthma and prevention of exacerbations can be improved during pregnancy using measurement of FENO, questionnaires such as the Pregnancy Asthma Control Test (p-CAT) or the Asthma Control Questionnaire (ACQ) or telehealth.990–993