Asthma and its guideline-based management

Asthma is a chronic inflammatory disease of the airways. Its management under the 2007 guidelines of the US National Asthma Education and Prevention Program rests on what the disease does to the airway, how severity differs from control, what each class of medicine is for, and how therapy is stepped up and down against control. Patient education and environmental control are components of that management, and a biologic add-on extends the options for severe disease.

Definition, signs and burden

Asthma is a chronic inflammatory disorder of the airways associated with tremendous morbidity and mortality. Its signs include wheeze, cough, shortness of breath, chest pain and diurnal variation, and wheeze, high-pitched whistling sounds when breathing in and out, is the most common sign in young children. ¹ It is a chronic lung disease caused by the interaction of genetic and environmental factors, which makes the airways narrow, swell and produce mucus; its main symptoms are coughing, wheezing and shortness of breath, and severe attacks can lead to hospitalisation. ² Exacerbations are acute or subacute episodes of progressively worsening shortness of breath, cough, wheezing and chest tightness, or some combination of these, and they can occur regardless of severity or of perceived control. ^{3, 4}

In 2008 the disease affected more than 20 million Americans, and its prevalence rose 75% between 1980 and 1994. Each year it accounted for 13.6 million physician office visits, 1 million outpatient department visits and a quarter of all emergency department visits, and for 5,000 deaths in the United States. It accounted for more than $11.5 billion in direct health care costs, $4.6 billion in indirect costs such as work missed because of a child's asthma, and $5 billion in prescription drug costs. ¹

Although it affects adults too, asthma has long been recognised as a paediatric health problem. By 2008 nine million US children had been diagnosed with asthma, and the prevalence may have been increasing; the rate in children under five years old rose by more than 160% between 1980 and 1994. ¹

Asthma in medical communication

With so many people affected by asthma, effective medical communication about the disease has become imperative. ⁵ More clinicians are seeing asthma in family practice and other non-specialist settings, so medical writers who work in continuing medical education and on manuscripts need to understand how the disease works and how it is commonly treated in clinical practice in order to convey safe, accurate and timely information. ⁵ Communicators who write for lay audiences also need to understand the disease and its treatment, because patients with asthma, and the parents of children with it, need clearly articulated, up-to-date information about both. ⁵ Asthma and other respiratory problems have received increased media attention in the wake of the air pollution created by the September 11 attacks, suggested links between inner-city living and asthma, and increasing carbon dioxide emissions and ozone alert days. ⁵

Reversible and irreversible airway changes

Asthma impairs lung function by causing the airway smooth muscle to constrict. Airway remodeling is the term widely used for the irreversible lung damage asthma causes, such as smooth muscle and mucous gland hypertrophy and hyperplasia, airway wall thickening and narrowing, loss of tethering and airway closure, hypervascularity and neural proliferation, all of which may have some irreversible characteristics. Appropriate treatment can reverse some characteristics of asthma, such as bronchoconstriction, excess mucus secretion, tissue oedema, inflammatory infiltrate and exudates, airway lining damage, and bronchial hyperresponsiveness. ⁶

Airway hyperresponsiveness, an exaggerated bronchoconstrictor response to a wide variety of stimuli, is a major feature of asthma, though not necessarily unique to it. Its degree, defined by contractile responses to methacholine challenge, correlates with clinical severity. Its mechanisms are multiple, including inflammation, dysfunctional neuroregulation and structural changes, and inflammation appears to be a major factor in its degree; treatment directed at reducing inflammation can reduce hyperresponsiveness and improve control. In some people airflow limitation may be only partially reversible, and permanent structural changes can occur in the airway that are associated with a progressive loss of lung function. ⁷

Risk factors and diagnosis

Risk factors include age, environmental stressors such as allergens, microbes and pollutants, biologic and genetic factors, airway injury and aberrant repair. In practice asthma is diagnosed when a cough or wheeze becomes recurrent, other coughing and wheezing conditions have been excluded, risk factors are present, and the person responds to asthma therapy. It is generally assessed by a detailed medical history, a physical examination focused on the upper respiratory tract, chest and skin, spirometry to demonstrate obstruction and determine reversibility, and additional studies such as a chest x-ray as necessary. ⁶

The GINA and NAEPP guidelines

Treating asthma has always been a challenge for physicians, and since the early 1990s two sets of guidelines have been available to help them diagnose, manage and treat it. ⁸ The Global Initiative for Asthma (GINA) released its first report in 1993, and the National Heart, Lung, and Blood Institute and the National Institutes of Health released the first expert panel report of the National Asthma Education and Prevention Program (NAEPP), the more relevant to US practitioners, in 1991. ^{8, 1} GINA is a joint programme involving international stakeholders, determined to improve asthma treatment, and its reports provide physicians with an up-to-date review of the literature and evidence-based strategies that can be easily implemented in clinical practice. ⁹ Both first reports provided management guidance for children and adults built around education, environmental control and pharmacotherapy chosen according to disease severity: intermittent, mild, moderate or severe. ⁷ The expert panel report was updated in 1997 and 2002, largely to account for changes in the medicines available, and the basic focus of treatment remained the same. ⁷ It has been widely regarded as a tool for clinicians who treat people with asthma. ¹

GINA in late 2006 and NAEPP in the third quarter of 2007 released new guidelines that recognise asthma as a heterogeneous disease requiring management tailored to the individual. ^{7, 1} Both emphasise asthma control, and the NAEPP guidelines shift the focus of treatment from disease severity to impairment and risk. ^{7, 1} The new NAEPP guidelines still suggest that asthma be managed through patient education, environmental control and appropriate pharmacotherapy using a stepwise approach. ¹ The NAEPP guidelines are the more widely used in the United States, but medical writers who work on asthma-related projects should take the time to familiarise themselves with both sets. ⁷ The 2007 NAEPP guidelines give medical communicators an important starting point for understanding asthma. ⁵

The NAEPP guidelines organise management into four components: measures of assessment and monitoring, obtained by objective tests, physical examination, patient history and patient report, with the goal of diagnosing and assessing the characteristics and severity of asthma and monitoring whether control is achieved and maintained; education for a partnership in asthma care; control of environmental factors and of comorbid conditions that affect asthma; and pharmacologic therapy. ⁷

Severity at initial assessment

The NAEPP guidelines still recommend classifying severity at the initial assessment, but only as a means of initiating therapy using a stepwise approach. After that first visit, patients should be evaluated as well-controlled, not well-controlled or very poorly controlled regardless of their initial severity, and control should be evaluated through routine monitoring so that therapy can be adjusted as appropriate. ⁷

The severity tables are given separately for three age bands, birth to 4 years, 5 to 11 years, and 12 years and over, and they define the normal ratio of forced expiratory volume in one second (FEV₁) to forced vital capacity by age: above 85% at 5 to 11 years, 85% at 8 to 19, 80% at 20 to 39, 75% at 40 to 59 and 70% at 60 to 80, with FEV₁ not assessable below 5 years. The four initial categories are intermittent, mild persistent, moderate persistent and severe persistent. For example, a 16-year-old with mild persistent asthma at initial assessment would have symptoms more than two days a week but not daily, nighttime awakenings three or four times a month, short-acting beta-agonist use for symptom control more than two days a week but not daily, minor interference with activities of daily living, and an FEV₁ above 80% of predicted with a normal ratio. ⁷

For people aged 12 and over, the severity table runs five impairment components across the four categories. ^{4, 10} Symptoms go from no more than two days a week, through more than two days a week but not daily and daily, to throughout the day. Nighttime awakenings go from no more than twice a month, through three or four times a month and more than once a week but not nightly, to seven times a week. Short-acting beta-agonist use for symptom control, excluding prevention of exercise-induced bronchospasm, runs from no more than two days a week to several times a day. Interference with normal activity runs from none through minor and some limitation to extreme limitation. Lung function runs from a normal FEV₁ between exacerbations, through FEV₁ above 80% of predicted with a normal ratio and FEV₁ above 60% but below 80% of predicted with the ratio reduced by 5%, to FEV₁ below 60% of predicted with the ratio reduced by more than 5%. Exacerbations requiring oral systemic corticosteroids separate intermittent asthma, at none or one a year, from every persistent category, at two or more a year. ¹⁰

Severity is also assessed in terms of risk, not only impairment. For anyone with persistent asthma, whatever the severity, attention should be paid to two or more exacerbations requiring oral systemic corticosteroids in the past year. ⁴ In every case severity and the interval since the last exacerbation are to be considered. ^{4, 10} Frequency and severity may fluctuate over time for patients in any severity category, and the relative annual risk of exacerbations may be related to FEV₁. ¹⁰ NAEPP also encourages clinicians to assess for long-term loss of lung function and for treatment-related adverse effects. ⁴

Asthma control

Control is assessed on an impairment side and a risk side. The impairment side is symptoms, nighttime awakenings, interference with normal activity, short-acting beta-agonist use for symptom control, FEV₁ or peak flow, and validated questionnaires. The risk side is exacerbations requiring oral systemic corticosteroids, progressive loss of lung function and treatment-related adverse effects. ¹¹

Several validated measures can be used to assess control, among them the Asthma Control Questionnaire, the Asthma Therapy Assessment Questionnaire, the Asthma Control Test and the Asthma Control Score. NAEPP recommends that clinicians discuss control with patients so that they better understand their disease, and clinicians and patients can together develop a written asthma action plan, updated as needed, that can include education, environmental controls and pharmacotherapy. ⁴

For people aged 12 and over, each of the three control categories has its own thresholds. ¹² Well-controlled means symptoms and rescue use on no more than two days a week, nighttime awakenings no more than twice a month, no limitation of activity, lung function above 80% of predicted or personal best, and none or one exacerbation a year requiring oral systemic corticosteroids. Not well-controlled means symptoms and rescue use on more than two days a week, awakenings one to three times a week, some limitation, and lung function at 60% to 80%. Very poorly controlled means symptoms throughout the day, awakenings four or more times a week, extreme limitation, rescue use several times a day, and lung function below 60%. Two or more exacerbations a year requiring oral systemic corticosteroids mean asthma that is not well-controlled or very poorly controlled. ^{13, 12} On the validated questionnaires, well-controlled corresponds to an Asthma Therapy Assessment Questionnaire score of 0, an Asthma Control Questionnaire score of 0.75 or less and an Asthma Control Test score of 20 or more. Not well-controlled corresponds to scores of 1 to 2, 1.5 or more and 16 to 19, and very poorly controlled to scores of 3 to 4 and 15 or less, the Asthma Control Questionnaire not being applicable. Asthma Control Questionnaire values of 0.76 to 1.4 are indeterminate regarding well-controlled asthma. ^{13, 12} Evaluation requires long-term follow-up care. ¹³

Each category carries its own recommended action. ^{13, 12} For well-controlled asthma, the current step is maintained, follow-up visits are regular every one to six months, and stepping down is to be considered once control has held for at least three months. ^{13, 14} For asthma that is not well-controlled, therapy is stepped up one step and re-evaluated in two to six weeks, and alternative treatment options are to be considered for side effects. ¹³ For very poorly controlled asthma, a short course of oral systemic corticosteroids is to be considered, therapy is stepped up one or two steps and re-evaluated in two weeks, and alternatives are again to be considered for side effects. ¹² Medication side effects can vary in intensity from none to very troublesome and worrisome; their intensity does not correlate with specific levels of control but should be considered in the overall assessment of risk. ¹³

Patient education

Asthma education should be included in all aspects of care and reinforced as often as possible, beginning at diagnosis and continuing through follow-up visits. NAEPP names four key components of asthma management through education: involving all members of the health care team; having the principal clinician introduce the key educational messages and negotiate agreements about treatment goals, specific medications and the actions the patient will take to reach them; reinforcing and expanding those messages, such as the patient's level of control, inhaler technique, self-monitoring and use of the written action plan, through all members of the team; and implementing education at all points of care where health professionals meet people with asthma, including clinics, medical offices, emergency departments and hospitals, pharmacies, homes, and community sites such as schools and community centres. ⁴

Clinician assessment and patient self-assessment are the primary methods for monitoring asthma, hence the importance of patient education in the 2007 NAEPP guidelines. ¹⁵ To reduce impairment and risk, NAEPP recommends assessing patients at one- to six-month intervals. ¹⁵ Evidence suggests that education programmes based in the emergency department, the pharmacy, the home and the school may be effective, along with computer-based programmes. ¹⁵

Inhaled short-acting beta-2 agonists have been part of first-line and emergency treatment for fifty years, and doctors and patients appreciate the rapid symptom relief they give. ⁹ Patients then begin to rely on that relief and often discontinue the background inhaled corticosteroid therapy that prevents the underlying inflammation, some because they are anxious about taking cortisone. ⁹ As a result, patients do not always take their asthma medication correctly, and this is leading to unnecessary deaths. ⁹ After diagnosis, patients need education about medication: they need to take it, have good lifestyle habits and avoid behaviours that may worsen their disease, even when they are feeling well. ¹⁶ In asthma, learning to use the inhaler correctly to benefit fully from the medication is important. ¹⁶ Yet in 2020, in the UK alone, almost two-thirds (65%) of people with asthma did not receive primary care from a healthcare professional that includes an annual review and a check that they are using their inhaler correctly. ¹⁶

Environmental control

Because asthma can be precipitated or worsened by exposure to environmental allergens and pollutants, environmental control is a key part of any asthma treatment plan. ⁴ Among the key components of environmental control, NAEPP names these: ⁴

• Determine the patient's exposure to allergens or irritants, as these may precipitate exacerbations.
• Reduce exposure to allergens and irritants as much as possible.
• Avoid exposure to tobacco smoke and other irritants as much as possible.
• Avoid outdoor exertion when pollution levels are high, as on the ozone alert days common in larger metropolitan areas.
• Evaluate and manage comorbid conditions that may affect asthma, such as gastro-oesophageal reflux, obesity, obstructive sleep apnoea, upper respiratory disease and chronic stress or depression.

^{4, 12}

Medication classes

Asthma medication is either controller or quick-relief medication. Controllers are used long-term and daily to achieve and maintain control; quick-relief medication such as albuterol treats acute episodes and, in anyone with persistent asthma, should be used in addition to, rather than in place of, controller therapy. ¹⁷

Inhaled corticosteroids are a controller and remain the preferred asthma therapy, with proven efficacy measured by symptom improvement, quality of life, lung function, and morbidity and mortality. ¹⁷ There are concerns about their side effects, particularly at higher doses, and they do not affect long-term airway remodeling; there had been some hope that they could reverse some of the changes associated with remodeling, but that does not appear to be the case. ¹⁷ Oral corticosteroids are also an option, but because of their numerous side effects they should be used as long-term therapy only for people with the most severe, difficult-to-control disease. ¹⁷

By 2008 leukotriene modifiers had a more prominent role as a controller, particularly for adults, as an alternative to inhaled corticosteroids, and they are most effective for people whose initial diagnosis is mild persistent asthma. ¹⁷ Their safety profile had traditionally been excellent, but in 2008 the US Food and Drug Administration was investigating a possible association between montelukast and behavioural or mood changes, suicidality and suicide. ¹⁷ Long-acting beta-agonists have proven efficacy when used with an appropriate dose of an inhaled corticosteroid, but their package insert carries a black-box warning for an increased risk of asthma-related exacerbations and deaths, so they should not be prescribed as monotherapy. ¹⁷ They are appropriate for people whose disease is not adequately controlled with other medications or is severe enough to warrant starting two maintenance therapies. ^{17, 14}

Cromolyn and nedocromil are also NAEPP alternatives to inhaled corticosteroids, but in 2008 GINA no longer recommended them for treating asthma. ¹⁴ NAEPP has also added immunomodulators as a treatment option, and they should be prescribed with caution and under an asthma specialist's supervision, because they carry a black-box warning for the risk of anaphylaxis. ¹⁴

Stepwise therapy

NAEPP suggests a six-step approach to tailor therapy to the patient, along with appropriate environmental controls. ^{14, 18} Patients with intermittent symptoms should be started on a short-acting beta-agonist at step 1, and daily controller therapy is added to an as-needed short-acting beta-agonist at step 2. ¹⁴ For people aged 12 and over, the steps are:

• Step 1: a short-acting beta-agonist as needed.
• Step 2: preferably a low-dose inhaled corticosteroid; alternatively cromolyn, a leukotriene receptor antagonist, nedocromil or theophylline.
• Step 3: preferably a low-dose inhaled corticosteroid with a long-acting beta-agonist, or a medium-dose inhaled corticosteroid; alternatively a low-dose inhaled corticosteroid with either a leukotriene receptor antagonist, theophylline or zileuton.
• Step 4: preferably a medium-dose inhaled corticosteroid with a long-acting beta-agonist; alternatively a medium-dose inhaled corticosteroid with either a leukotriene receptor antagonist, theophylline or zileuton.
• Step 5: preferably a high-dose inhaled corticosteroid with a long-acting beta-agonist; omalizumab is to be considered for patients who have allergies.
• Step 6: preferably a high-dose inhaled corticosteroid with a long-acting beta-agonist and an oral corticosteroid; omalizumab is to be considered for patients who have allergies.

^{19, 14, 18, 20}

Patient education, environmental control and management of comorbidities belong at every step, and subcutaneous allergen immunotherapy is to be considered at steps 2 to 4 for patients with allergic asthma. ¹⁹ An asthma specialist should be consulted if step 4 care or higher is required, and consultation is to be considered at step 3. ²¹

Quick-relief medication is for all patients. A short-acting beta-agonist is used as needed for symptoms, with the intensity of treatment depending on the severity of symptoms: up to three treatments at 20-minute intervals as needed, and a short course of oral systemic corticosteroids may be needed. Use of a short-acting beta-agonist more than two days a week for symptom relief, as distinct from preventing exercise-induced bronchospasm, generally indicates inadequate control and the need to step up treatment. ²²

According to the Rules of Two, maintenance therapy should be started when a patient uses a quick-relief inhaler more than twice a week, wakes because of asthma symptoms more than twice a month, or needs any of a quick-relief inhaler refill, a burst of oral corticosteroids, or unscheduled acute asthma care such as an emergency department visit more than twice a year. ¹⁴

The guidelines recommend assessing control at every visit, even for a patient on a stable regimen. ¹⁴ Where asthma is uncontrolled or partially controlled, they suggest stepping up therapy as necessary, but only after checking adherence to medication, medication technique such as inhaler use, environmental controls and comorbidities. ¹⁴ The guidelines provide a starting point for determining pharmacotherapy, but the choice of treatment should be based on an understanding of the individual's medical history and disease state. ¹⁴ With so many treatment options, determining the appropriate treatment at any given time involves an ongoing assessment of the response to treatment. ¹⁴ The factors to consider in selecting therapy include control and severity, the guidelines, response to therapy, assessed through the medical history where it is available, the natural history of the disease, relationships among disease features and between outcomes, comorbidities, genetic factors and the individual disease, and each patient must be assessed in terms of control, impairment and risk to identify a treatment plan. ¹⁴

Biologic add-on therapy for severe asthma

In 2019 there was no cure for asthma: available treatments either control the symptoms, as relievers, or reduce the frequency and severity of attacks, as controllers. ² Therapeutic options were limited for patients with severe asthma whose symptoms could not be controlled with available treatments such as high-dose inhaled corticosteroids. ² Dupilumab (Dupixent) is a human monoclonal antibody that reduces airway inflammation by inhibiting the signalling of interleukin-4 and interleukin-13, a novel mechanism of action among the therapeutic options in severe asthma. ² At its February 2019 meeting the European Medicines Agency's human medicines committee, the CHMP, adopted an opinion recommending extending its indication to add-on maintenance treatment for adults and adolescents aged 12 and over with severe asthma with type 2 inflammation, characterised by raised blood eosinophils, raised exhaled nitric oxide measured by the FeNO test, or both, that is inadequately controlled by high-dose inhaled corticosteroids plus another asthma medicine. ² In three pivotal trials in a total of 2,888 patients it reduced severe exacerbations and improved lung function, and its most common side effects were infections, eye disorders such as conjunctivitis, and injection-site reactions. ²

Exacerbations and risk of death

NAEPP provides guidance for managing exacerbations by severity, which often takes place in an emergency department or urgent care rather than in the clinician's office. ³ The primary therapies are short-acting beta-agonists, oral corticosteroids and oxygen, but early treatment is the best management strategy, and it is important that health care providers educate their patients about when to seek emergency care. ³ Exacerbations can be fatal. ³

The guidelines identify these risk factors for death from asthma:

• previous severe exacerbations
• two or more hospitalisations in the past year
• three or more emergency department visits or hospitalisations in the past year
• a hospitalisation or emergency department visit in the past month
• using more than two canisters of short-acting beta-agonists a month
• difficulty perceiving the severity of symptoms and exacerbations
• no written asthma plan
• sensitivity to Alternaria
• low socioeconomic status
• inner-city residence
• illicit drug use
• major psychosocial problems
• cardiovascular disease
• other chronic lung disease
• chronic psychiatric disease

³