At the conclusion of this exercise, the learner will be prepared to:
- Apply the appropriate terms and definitions related to asthma care
- Formulate an understanding of the pathophysiology of asthma and its various phenotypes
- Identify the various asthma risk factors and methods for prevention
- Reference the appropriate tests and evaluations used to diagnose asthma
- Establish a basic understanding of the various management components and medications used to treat asthma on a daily/chronic as well as an urgent/emergent basis
Asthma is a chronic inflammatory airway disorder characterized by airway hyperresponsiveness and recurrent episodes of acute symptoms such as wheezing, coughing, chest tightness, and/or shortness of breath (SOB) that affects between 235 and 300 million people worldwide (Lynne & Kushto-Reese, 2015; World Health Organization, 2017). According to the Centers for Disease Control and Prevention (CDC), asthma effects more than 24 million Americans and is responsible for over 430,000 hospitalizations, 1.6 million emergency department (ED) visits, and over 10 million office visits to medical providers annually. Asthma costs more than $62 billion annually to treat and causes over 13 million missed school days and 14 million missed work days in the United States alone. Amongst patients diagnosed with asthma, roughly half of adults and 40% of pediatric patients are not well controlled (Hsu, Sircar, Herman & Garbe, 2018). When discussing asthma, the term control refers to the presence of symptoms, any limitations in daily activities, and general quality of life. This should be regularly assessed using an established tool such as the asthma control questionnaire (ACQ), asthma control test (ACT), or similar (Bostantzoglou et al., 2015). These tools are covered in greater detail in the “Treatment and Management” section.
Chronic asthma symptoms are related to a combination of inflammation and airway hyperresponsiveness (Bostantzoglou et al., 2015). While the exact cause of asthma is unknown, most attribute the development of asthma to a combination of atopy (a genetic tendency towards an IgE-mediated over-reaction to external triggers), a familial tendency, and exposure to certain childhood upper respiratory infection(s) and/or allergens or triggers. The hygiene hypothesis suggests that the rise in asthma cases in the US in recent decades is due to western civilization being “too clean”, reducing the number of environmental exposures and infections and thus altering our immune systems (NHLBI, n.d.). The bronchiolar inflammation and airway constriction lead to resistance and the hallmark symptoms of cough, wheezing, and SOB. The inflammation may exist without obvious symptoms, and can affect the trachea, the bronchi and/or the smaller bronchioles. The source for the inflammation is still being studied, but the current understanding is that airway capillaries dilate and leak, causing microvascular leakage. In addition, expansion of mucus-secreting glands and an increase in mucus-secreting cells cause increased mucus production and decreased mucus clearance. The enzymes typically responsible for breaking down the inflammatory mediators are decreased in asthma patients, causing this process to persist longer and occur more frequently. The inflammation causes damage to the epithelium, and eventually a phenomenon known as epithelial peeling, which leads to the airway hyperresponsiveness. If left untreated, over time this chronic damage to the epithelial layer of the respiratory tract causes airway remodeling secondary to permanent fibrotic damage which decreases lung function as well as responsiveness to treatment. Bronchospasms are caused by sharp contractions of the smooth muscles that line the bronchi (Lynne & Kushto-Reese, 2015).
Figure 1. Airway anatomy and Asthma Pathophysiology
Different subtypes of asthma have emerged in the last couple decades, called phenotypes. Early-onset atopic asthma typically present during childhood and is characterized by reports of wheezing and associated allergies, or triggers from external environmental factors such as dust mites, animal fur/dander, pollen. The pathophysiology of this phenotype is largely driven by T-helper 2 cells, which then produce the chemical cytokines interleukin 4 (IL-4), interleukin 5 (IL-5), and interleukin 13 (IL-13). IL-4 effects airway epithelium production of chemokines as well as promoting B-cell isotype switching and T-helper 2 cell development. IL-5 plays a role in the maturation, migration, and survival of eosinophils while IL-13 contributes to airway inflammation and hyperresponsiveness via increased mucus production, subepithelial fibrosis, and eotaxin production (deGroot, ten Brinke, & Bell, 2015). Future exposures to certain allergens or triggers cause an excessive release of IgE by then-activated B-lymphocytes leading to release of inflammatory mediators, chemokines, nitric oxide, prostaglandin D2, histamine, and leukotrienes (Lynne & Kushto-Reese, 2015).
About 5-10% of asthma patients fall into the non-atopic, late-onset eosinophilic phenotype. This phenotype has a much later onset of asthma, few to no allergies, more severe disease, and a poorer prognosis. This phenotype was first described in 1999 by Wenzel et al. Symptoms typically include reports of dyspnea on exertion (DOE) and chronic rhinosinusitis. Further examination and testing typically reveals fixed airflow obstruction and decreased forced vital capacity on lung function testing (LFTs), increased residual volume (“air trapping” or dynamic hyperinflation), and nasal polyposis. The definitive diagnosis for this particular phenotype is a finding of positive eosinophilia in a bronchial biopsy or induced sputum sample, but due to the invasiveness, cost, and difficulty of obtaining those tests, this phenotype may be often estimated using a peripheral blood sample showing positive eosinophilia. This phenotype is largely believed to be driven by innate lymphoid cells, which when activated produce IL-5 and IL-13 (deGroot et al., 2015). Further differentiation can be made amongst asthma patients based on the presence or absence of eosinophilia, the age of onset (as above), the presence or absence of allergic rhinitis, the resistance to or response to certain medications (such as inhaled corticosteroids [ICS] or leukotriene receptor antagonists [LTRA]), the presence of chronic obstructive pulmonary disease (COPD) as a comorbidity, and the presence of obesity, especially in female adult patients. These clinical and historical features will help categorize asthma patients into various evolving phenotypes, and as this science continues to progress, also help assist with selecting the most appropriate treatment (Hirose & Horiguchi, 2017). The Global INitiative for Asthma (GINA), a collaborative report between the World Health Organization (WHO) and the US Department of Health and Human Services National Heart, Lung, and Blood Institute (NHLBI) was last updated and published in 2018. This most recent update recognized the existence of these various phenotypes, but did not feel that these phenotypes correlated strongly enough with specific pathological processes or treatment responses to warrant any phenotype-specific treatment algorithms (GINA, 2018).
Risk Factors and Prevention
According to the National Institutes of Health (NIH), risk factors for the development of asthma include the presence of environmental or food allergies, eczema, frequent childhood respiratory infections, parents with asthma, and occupational exposure to certain airborne irritants or chemicals. Statistics regarding asthma prevalence indicate that it is more common in boys than girls, but in adulthood is more commonly found in women than men. It is more common in Black Americans or Puerto Ricans, as well as those that are low income (Hsu, Sircar, Herman & Garbe, 2018; NHLBI, n.d.). There is also some evidence that obesity is a risk factor as well (Lynne & Kushto-Reese, 2015). Prevention for asthma is not well understood, although a recently published randomized, double-blind, placebo-controlled trial assess the effect of high-dose vitamin D supplementation in high risk pregnant women to determine if this would decrease the rate of asthma. The trial enrolled almost 900 high-risk (defined as the mother or father of the baby having a positive history of asthma, allergic rhinitis or eczema) pregnant women between 10-18 weeks gestation. They all received a prenatal multivitamin daily with 400 iu of vitamin D and were randomized to either receive an additional 4000 iu vitamin D supplement or placebo. Adherence was tracked using electronic medication bottles. A total of 806 infants were born and evaluated. The primary endpoint was a diagnosis of asthma or recurrent wheeze by three years. 98 of 405 (24%) children had been diagnosed with asthma/wheeze in the high-dose group by the completion of the study, while 120 of 401 (30%) had been diagnosed in the low-dose group. This difference was not statistically significant. However, a statistically significant higher number of women in the high-dose group (289 of 386 or 75%) were found to have a normal vitamin D level > 30 ng/mL during the third trimester versus the low-dose group (133 of 391 or 34%) (Litonjua et al., 2016). Similarly, while the GINA report found that low vitamin D levels in asthma patients is positively associated with worsening lung function and increased exacerbation frequency, they found that studies of vitamin D supplementation have not yet been shown to improve asthma control (GINA, 2018).
The diagnosing of asthma can be difficult and complicated due to its widely variable presentations, as discussed above. Patients may present with high levels of eosinophilic inflammation and few symptoms, severe symptoms and lower levels of eosinophilia and inflammation, or a classic presentation of eosinophilia and inflammation that seem to positively correspond with the level of symptoms. In a study published in JAMA in 2017 by Aaron et al., 613 adult patients across ten cities in Canada were evaluated between 2012 and 2016. These patients had all been diagnosed as having asthma by another physician. They were given instructions and equipment to perform peak flow monitoring at home and asked to maintain a symptom diary. In the testing lab, patients were tested using spirometry before and after administration of a rapid-acting bronchodilator and serial bronchial challenge tests with methacholine. In patients with normal pulmonary function testing, medications were gradually tapered to assess for any underlying symptoms. Of the 613 study patients, asthma was ruled out initially in 203 of them, 71 of which had been on controller medication daily for asthma prior to the study and 179 of which had been diagnosed without the appropriate pulmonary function testing. In those 203 patients, medications were gradually weaned and after one year only 6 of those patients had a recurrence of their symptoms and a positive bronchial challenge test and required their medications be restarted. Of these 203 patients, 54 were diagnosed with allergic rhinitis, and 12 were found to have serious cardiorespiratory conditions that had been misdiagnosed. The conclusion of this study was to recommend to all providers evaluating potential asthma to diagnose the disease not solely based on symptoms and physical exam findings, but also on objective pulmonary function testing such as spirometry, ideally prior to and following administration of a bronchodilator medication to assess reversibility, serial peak flow measurements, and/or bronchial challenge tests (Aaron et al., 2017).
The clinical signs, symptoms, and features of asthma that providers should be watchful for include a history of recurrent or chronic dry cough, wheezing, difficulty breathing, SOB, or chest tightness. Symptoms are typically worse at night, often causing nighttime awakenings, or with exertion. Commonly referred to as triggers, symptoms may also increase in the context of viral upper respiratory infections, exposure to allergens or irritants, changes in the weather, laughing or crying spells, high stress, or other triggers (NHLBI, 2012). The Asthma and Allergy Foundation of America (AAFA) also includes smoke and air pollution as potential triggers, and list potential allergens to include dust mites, cockroaches, mold, pet fur/dander, mice, and pollen (AAFA, 2015). Additional triggers for specific patients may include medication (such as aspirin or other nonsteroidal anti-inflammatory drugs [NSAIDs] or non-selective ß-blockers), grasses, flowers, or sulfites (NHLBI, n.d.). A recent study in Pennsylvania found a positive association between local natural gas development activity and local asthma exacerbations. The association was especially strong when they reviewed the number of mild exacerbations (asthma exacerbations requiring an oral systemic steroid course, but not an emergency department [ED] visit or inpatient hospital admission) on or immediately after days of high stimulation (hydraulic fracturing) or production activity (Rasmussen et al., 2016). NIH provides more information to asthma patients regarding possible triggers and how best to avoid them (see below.)
Figure 2: Common Asthma Triggers
The most recent GINA report stated that diagnosis of asthma should be based on history, as well as evidence of variable airflow limitation via spirometry testing or peak flow measurements with reversibility test. For further details regarding GINA’s diagnostic criteria, see below (GINA, 2018).
Table 1: GINA Diagnostic Criteria, Age 6+
|Diagnostic Feature||Criteria for Making the Diagnosis of Asthma|
|1. History of variable respiratory systems|
|Wheeze, shortness of breath, chest tightness and cough|
Descriptions may vary between cultures and by age, e.g. children may be described as having heavy breathing
|2. Confirmed variable expiratory airflow limitation|
|Documented excessive variability in lung function* (one or more of the tests below)|
AND documented airflow limitation*
|The greater the variations, or the more occasions excess variation is seen, the more confident the diagnosis|
At least once during diagnostic process (e.g. when FEV1 is low) confirm that FEV1/FVC is reduced
(normally >0.75-0.80 in adults, >0.90 in children)
|Positive bronchodilator (BD) reversibility test* (more likely to be positive if BD medication is withheld before test:|
SABA ≥4 hours, LABA ≥15 hours)
|Adults: increase in FEV1 of >12% and >200 mL from baseline, 10-15 minutes after 200-400 mcg albuterol or equivalent (greater confidence if increase is >15% and >400 mL)|
Children: increase in FEV1 of >12% predicted
|Excessive variability in twice-daily PEF over 2 weeks*||Adults: average daily diurnal PEF variability >10%**|
Children: average daily diurnal PEF variability >13%**
|Significant increase in lung function after 4 weeks of anti-inflammatory treatment||Adults: increase in FEV1 by >12% and >200 mL (or PEF† by >20%) from baseline after 4 weeks of treatment, outside respiratory infections|
|Positive exercise challenge test*||Adults: fall in FEV1 of >10% and >200 mL from baseline|
Children: fall in FEV1 of >12% predicted, or PEF >15%
|Positive bronchial challenge test|
(usually only performed on adults)
|Fall in FEV1 from baseline of ≥20% with standard doses of methacholine or histamine, or ≥15% with standardized hyperventilation, hypertonic saline, or mannitol challenge|
|Excessive variation in lung function between visits* (less reliable)||Adults: variation in FEV1 of >12% and >200 mL between visits, outside of respiratory infections|
Children: variation in FEV1 of >12% or >15% in PEF† between visits (may include respiratory infections)
BD: bronchodilator (short-acting SABA or rapid-acting LABA); FEV1: forced expiratory volume in 1 second; LABA: long-acting beta2-agonist; PEF: peak expiratory flow (highest of three readings); SABA: short-acting beta2-agonist.
*These tests can be repeated during symptoms or in the early morning
**Daily diurnal PEF variability is calculated from twice daily PEF as ([day's highest - day's lowest] / mean of day's highest and lowest), and averaged over one week.
†For PEF, use the same meter each time, as PEF may vary by up to 20% between different meters. BD reversibility may be lost during severe exacerbations or viral infections.
10If bronchodilator reversibility is not present at initial presentation, the next step depends on the availability of other tests and the urgency of the need for treatment. In a situation of clinical urgency, asthma treatment may be commenced and diagnostic testing arranged within the next few weeks, but other conditions that can mimic asthma should be considered, and the diagnosis of asthma confirmed as soon as possible.
The National Asthma Education and Prevention Program (NAEPP) last published guidelines, called the Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma (EPR-3), in 2007. This report recommended that patients over the age of five suspected of having asthma be tested using spirometry, both before and after a dose of short-acting ß agonist (SABA) medication (NHLBI, 2012). Spirometry testing (see Figure 3 below) involves having the patient breathe into and out of a mouthpiece that is connected to a machine or an equipped laptop, with a nose clip in place to ensure all airflow is being limited to the mouth for proper reading. The patient is instructed to take in a deep breath, and then to breathe out into the mouthpiece as hard and as fast as possible. The machine is then able to produce two primary numbers using these results: the forced vital capacity (FVC) which is roughly the total lung capacity or volume of air exhaled in liters, and the forced expiratory volume in one second (FEV1) which is the volume exhaled in the first second. A third number is then calculated using these two primary numbers, the FEV1/FVC ratio, or percentage of total lung capacity that the patient is able to exhale in the first second. These numbers are often compared to the expected capacity/ability based on the patient’s size. The patient is tested once, then given a SABA medication to act as a bronchodilator, and the test is then repeated several minutes later to assess for reversibility. An improvement of 12% or 200mL in the patient’s FEV1 is often considered diagnostic for an asthmatic with variable or reversible airflow obstruction (AAFA, 2017; Lynne & Kushto-Reese, 2015). Potential barriers to the use of spirometry to diagnose asthma regularly by primary care and pediatric providers include the time required to perform the test, the training required to correctly administer and then interpret the results, the availability of the necessary equipment, and the misconception that young children cannot properly perform the test. Spirometry can be especially helpful in ruling out differential diagnosis such as vocal cord dysfunction, functional dyspnea, anatomic obstruction, and restrictive pulmonary defects. There are specific products designed to make spirometry testing easier in children, such as the EasyOne Air, The Micro, and Pneumotrac to name a few (Stickle, 2018). Spirometry should be repeated at least every one to two years in most asthmatics, or more frequently in those that are not well controlled (NHLBI, 2012).
Figure 3: Spirometry
A peak flow meter (see Figure 4 below) is a small handheld device that asthma patients should be given to monitor themselves at home. Patients should be instructed to stand, take a deep breath, make sure the indicator is at the bottom of the device, and blow into the device as hard and fast as possible to obtain a score, or peak flow number. This can be repeated immediately two times, using the highest score out of three. This should be done at a consistent time, typically first thing in the morning before they take their medications. Initially after diagnosis, the patient should do this twice daily (in the morning and around lunchtime) and record the numbers for two to three weeks. The highest number out of the 28 readings they record will become their personal best (PB). The patient’s PB then serves as a benchmark moving forward to indicate a concerning change, or drop, in lung function. The same procedure may be repeated during any two to three week period to reassess and update the patient’s PB. Their asthma action plan (AAP), which is a written instruction sheet or road map for asthma patients to adjust medications and manage their asthma symptoms at home, is based on this PB number. A patient’s peak flow number will often start to decrease before the patient even identifies any appreciable symptoms prior to an exacerbation. In patients that are unable to successfully perform spirometry, a record of highly variable peak flow readings, as well as reversibility 10-15 minutes after taking a SABA inhaler, may be used as a diagnostic test for asthma if necessary (AAFA, 2017; NHLBI, n.d.). GINA recommends that patients also check their peak flow following an exacerbation to monitor recovery, following any medication changes, if they feel an increase in their symptoms, to help identify and pinpoint domestic or occupational triggers. They recommend regular peak flow monitoring in patients with poor perception of airflow limitation, a history of sudden and severe exacerbation(s), or with severe and/or difficult to control asthma (GINA, 2018).
Figure 4: Peak Flow Meter
A bronchial challenge test involves attempting to provoke or trigger symptoms by testing spirometry first then exposing the patient to a chemical irritant (methacholine, smoke, perfume, etc), and then retesting with spirometry. The purpose is to determine if exposure causes a decrease in the patient’s FEV1. A bronchial challenge is considered positive if the FEV1 decreases by 15-20% after exposure (although this may take several exposures of progressively increasing doses). Methacholine commonly causes wheezing and SOB in asthmatics. Histamine will cause increased mucus production and bronchoconstriction. Mannitol, which is an inhaled substance used during bronchial challenge testing in other countries, causes airway constriction via mast cell granulation and inflammation. It is approved by the FDA for this purpose but is not currently used in this country (AAFA, 2017; Lynne & Kushto-Reese, 2015). Additionally, a bronchial challenge test, or bronchoprovocation test, may also be done in patients suspected of having exercised induced bronchospasms (EIB) to assess the effect exercise (typically running on a treadmill) has on the patient’s spirometry results (NHLBI, n.d.). Similarly, the most recent practice parameter suggests a diagnosis be made based on a standardized exercise challenge or eucapnic voluntary hyperpnea (EVH) (Weiler et al., 2016). All of these tests are done to help the patient identify which particular triggers to avoid, or to prove the existence of hyperreactivity in the airway in the case of normal spirometry results.
Fractional exhaled nitric oxide (FeNO) is a newer technology that tests the fractional concentration of exhaled nitric oxide. According to GINA (2018), it has not yet been established to rule in or rule out asthma. FeNO is typically increased in patients with T-helper 2 inflammation, but also increased in eosinophilic bronchitis, atopy, allergic rhinitis, and eczema. FeNO results may vary up or down in neutrophilic asthma patients or in the context of viral upper respiratory infection. FeNO results are often decreased in smokers, during bronchoconstriction or early phases of an allergic response. The hope is that eventually FeNO may serve as both a diagnostic test for asthma, as well as a method for assessing and predicting response to certain therapies. Studies thus far have shown that when FeNO results are used in conjunction with clinical management guidelines in children and young adults with asthma, they show a decreased risk for exacerbations. Studies utilizing FeNO in non-smoking adults showed no significant clinical impact. For this reason, while FeNO continues to be a focus of much interest and research, GINA 2018 and the joint statement on severe asthma published by the European Respiratory Society (ERS) and the American Thoracic Society (ATS) both recommend against using FeNO to diagnose or guide asthma treatment in the general population at this point (Chung et al., 2014; GINA, 2018). In preparation for their upcoming update to EPR-3, the NAEPP conducted a systematic review of the evidence regarding the utility of FeNO in the diagnosis and management of asthma. They found that the diagnostic utility of FeNO varies by patient, and is more helpful in nonsmokers, pediatrics, and steroid-naive patients. The sensitivity and specificity varied based on the diagnostic cutoff used. For example, in patients age 5 and up, if a cutoff score of 20 parts per billion (ppb) or less was used, the sensitivity was 0.79 and specificity was 0.72; if a cutoff score of 40ppb or greater was used the sensitivity decreased to 0.41 and specificity increased to 0.94. There was insufficient evidence regarding FeNO’s utility to predict asthma in patient age 0-4 with chronic wheezing. Regarding utility during asthma management, they found only a weak association between FeNO results and control, or risk of asthma exacerbation, but this association was admittedly stronger in patients with atopy. They found no association between FeNO results and asthma severity. Overall, the results were found to be poorly reproducible. They found that studies showed the use of management algorithms that incorporate FeNO results reduced the risk of exacerbations, but had no effect on the risk of hospitalization, quality of life (QOL), asthma control or FEV1. They did find evidence that FeNO results may help identify asthma patients that are more likely to respond to ICS and may help predict impending exacerbations in patients undergoing ICS reduction or withdrawal, but not as a stand-alone test. The clinical context clues improve this predictive ability. FeNO results can be altered by medications. Specifically, FeNO results are often lower in patients taking ICS, LTRA, or omalizumab, but not in patients taking long-acting ß agonists (LABAs) (Wang et al., 2017). A meta-analysis of over 13,000 patients found FeNO to be “moderately” accurate in patients 5 and older, but again results were more reliable in nonsmokers, ages 5-18, and those not currently on steroids. It was consistently increased in patients with eosinophilic-type asthma and was recently included as a measure of “eosinophilic inflammation” in guidelines published and utilized in the UK (Pruitt, 2018).
Additional areas of future interest include forced oscillation technique (FOT) or impulse oscillometry (IOS). This test attempts to assess for resistance in small airways (under 2 mm) and is potentially easier for children and those patients that may struggle with the forced expiratory efforts required in spirometry testing. The patient applies low volume sound waves through a mouthpiece instead (Pruitt, 2018). The ERS/ATS guidelines suggest that sputum samples tested for eosinophil counts should be combined with clinical diagnostic criteria in adults only at centers experienced in this technique (Chung et al., 2014). In patients that fit the clinical picture of eosinophilic asthma of late onset, sputum analysis may be beneficial. However, the high level of difficulty and limited access to capable labs are obvious barriers to this being used on a widespread basis. An alternative is to utilize a blood eosinophil count in combination with FeNO results, which have been shown to have better diagnostic accuracy when used together (de Groot et al., 2015). Sputum eosinophil counts are not widely available at this time, but GINA points out that they have been shown to decrease the risk of exacerbations when used in conjunction with clinical management guidelines. For this reason, GINA does not recommend that sputum sample eosinophil counts be utilized in the management of the general population with asthma but do recommend it in adults with moderate to severe asthma who have access to a center experienced in this diagnostic technique (GINA, 2018).
Assessing for differential diagnosis is extremely important in asthma, as many respiratory and even cardiac condition often mimic the symptoms of asthma. For example, COPD in patients over the age of 65 and asthma of late onset may be very difficult to differentiate, as they will often both respond to certain medications. Clues that the patient may actually be developing COPD instead of asthma include a history of smoking and/or occupational exposure, while clues that it is more likely asthma including the presence of nasal polyps and/or steroid dependency (de Groot et al., 2015). The most important resource in the case of uncertainty regarding diagnosis is a referral to a specialist for confirmation (GINA, 2018).
Table 2: Differential diagnoses of asthma with common presenting symptoms by age
Allergic Rhinitis (nasal congestion, chronic dry cough)
Bronchiectasis (Recurrent infections, productive cough)
Chronic upper airway cough syndrome (Sneezing, itching, blocked nose, throat-clearing)
Congenital heart disease (Cardiac murmurs)
Cystic fibrosis (Excessive productive cough and mucus production)
Gastroesophageal Reflux Disease (chronic cough)
Inhaled foreign body (Sudden onset of symptoms)
Hyperventilation, dysfunctional breathing (Dizziness, paresthesia, sighing)
Paroxysmal Nocturnal Dyspnea (PND) (shortness of breath, worse at night)
Vocal cord dysfunction (Dyspnea, inspiratory wheezing [stridor])
Bronchopulmonary dysplasia (Premature delivery, symptoms since birth)
Chronic upper airway cough syndrome (Sneezing, itching, blocked nose, throat-clearing)
Primary ciliary dyskinesia (Recurrent infections, productive cough, sinusitis)
Alpha1-antitrypsin deficiency (Shortness of breath, family history of early emphysema)
Central airway obstruction (Dyspnea, unresponsive to bronchodilators)
COPD* (Cough, sputum, dyspnea on exertion, smoking or noxious exposure)
Cardiac failure (Dyspnea with exertion, nocturnal symptoms)
Ischemic heart disease (Dyspnea with exertion, SOB, chest tightness)
Medication-related cough (Treatment with angiotensin converting enzyme [ACE] inhibitor)
Parenchymal lung disease (Dyspnea with exertion, non-productive cough, finger clubbing)
Pulmonary embolism (Sudden onset of dyspnea, chest pain)
Treatment and Management of Asthma
Treatment and management of asthma has three components: non-pharmacological treatment as well as two types of pharmacological treatment, reliever medications and control medications. Finally, we will discuss newer treatments being explored and what may be on the horizon soon. We will begin with a discussion of non-pharmacological treatments available as these apply to all asthma patients regardless of severity, age, or phenotype and are often primarily implemented by nurses helping to educate the patients and their families. The GINA guidelines (2018) emphasize a reasonable and comprehensive list of treatments that asthma patients should be educated on. They recommend quitting smoking (if the patient smokes) or avoiding any exposure to secondhand smoke (if they live with a smoker). They recommend regular physical activity, regardless of whether or not the patient has exercise-induced symptoms. They suggest asthma patients avoid exposure to any known triggers when possible, especially if these are occupational, indoor allergens, or air pollution. Although asthma patients may not feel comfortable making extreme decisions such as changing their profession or moving to a rural area that has less smog and air pollution in the environment, they can at least engage in a program to reduce exposure to indoor allergens in their own homes and schools (GINA, 2018). An evidence summary conducted in preparation for the next update to the EPR-3 found that there is a paucity of high-quality studies looking at the effectiveness of managing indoor allergen exposure and its effect on asthma morbidity and control. Consistently, studies that incorporate the use of high-efficiency particulate air filter (HEPA) vacuums appear to decrease the rate of exacerbations and increase patient’s report of QOL. Mattress covers designed to reduce allergens improved non-validated measures of respiratory symptoms when used in combination with other interventions but had no clinical effect when tested on their own. Consistent pest control service reduced the number of asthma exacerbations (Leas et al., 2018). For pediatric patients who spend a large portion of their waking hours in a school environment, JAMA published a study in 2017 regarding the impact of indoor allergens found in schools and the students’ asthma morbidity. They followed 284 patients between the ages of 4 and 13 in 37 different urban schools in the northeastern US. They collected samples from the students’ school and home environments to see how the allergen exposure differed in the two environments. They found a higher percentage of school samples contained mouse allergen than home samples, and at a higher concentration. The students exposed to a higher than average amount of mouse allergen were statistically more likely to report an “asthma symptom day” and showed a significant decrease in lung function based on FEV1. In this study, the other allergens found in most samples, including rat, cockroach, cat, dog, and dust mite allergens, did not seem to have the same correlation with asthma symptoms or lung function (Sheehan et al., 2017). Certain medications could cause worsening asthma symptoms, such as the non-selective ß-blockers and NSAIDs mentioned above, as well as angiotensin-converting-enzyme (ACE) inhibitors, non-potassium-sparing diuretics, and cholinergic drugs, and these should be avoided in asthma patients, or stopped if a decline in function or increase in symptoms is seen after starting a trial of these medications (Lynne & Kushto-Reese, 2015). Patients should be educated on the importance of a balanced, healthy diet to maintain a healthy weight, or a weight loss plan if needed, as obesity has been shown to negatively impact asthma patients’ lung function. Breathing exercises are also recommended (GINA, 2018). The American Lung Association has helpful patient education videos on their website regarding pursed lip breathing (which involves breathing in through the nose, and then out very slowly through pursed lips, making sure that exhale is at least twice as long as the time spent inhaling) and diaphragmatic breathing (also known as belly breathing, where again the patient breathes in through the nose, but places their hands or another object on their belly to reinforce filling the lungs by pulling down and out with the diaphragm into the abdomen, and then slowly exhaling, again taking at least twice the time on exhale as the time spent on inhale) (American Lung Association, 2018). Decreasing stress has been shown to beneficially affect asthma control and lung function, and asthma patients should be educated on whichever stress-relief activity or program fits best with their lifestyle and personality. Finally, GINA and the AAFA both recommend that all asthma patients pay very close attention to their vaccination record and ensure that all recommended vaccinations are up to date, especially the influenza and pneumococcal vaccinations (AAFA, 2015; GINA, 2018). Regarding specifically the treatment of EIB, the practice parameter published in 2016 suggests that a warm-up period prior to high-intensity exercise has been shown to decrease severity of EIB (Weiler et al., 2016).
Immunotherapy for the treatment of allergic asthma has become more commonplace and better studied in recent years. GINA lists this particular treatment amongst the recommended non-pharmacological treatments that should be considered with asthma patients. Specifically, they recommend sublingual allergen immunotherapy (SLIT) in patients that have allergic rhinitis related to a proven allergy to house dust mites along with an FEV1>70% of predicted and persistent exacerbations despite treatment with ICS. They also list nasal spray corticosteroid as an alternative in these patients in lieu of ICS (GINA, 2018). In 2016, a promising study was published in JAMA regarding the use of SLIT. It enrolled 834 adults in Europe with asthma and a proven house dust mite allergy based on positive serum IgE test and/or skin prick test. Of note, severe asthma patients (with a hospitalization in the last three months or an FEV1 less than 70% of predicted) were excluded from this study. The study design started with all enrolled patients on oral budesonide inhaler as well as a PRN SABA from 7-12 months. Two doses of immunotherapy were tested against an equal group of patients given placebo. After 3 months of the SLIT therapy, patients’ budesonide dose was cut in half, and if no reported exacerbations, was stopped altogether at the six-month mark. They found that both groups of patients given the sublingual dose of allergen had a significantly lower risk of moderate or severe exacerbation versus placebo, although no significant effect on asthma control or QOL was seen. The most frequent adverse events that were reported was oral pruritus, mouth edema, and throat irritation (Virchow et al., 2016). In preparation for the upcoming revision of EPR-3, an evidence summary was completed by the Effective Health Care Program. This evidence summary looked at two versions of immunotherapy: sublingual (SLIT) as well as subcutaneous immunotherapy (SCIT). Almost all studies were conducted on house dust mite-allergic patients. They found moderate strength of evidence that SCIT decreased the need for asthma patients to take their long-term control medication such as ICS. SCIT may (low strength of evidence) also increase QOL, decrease the need for reliever or rescue medication use, decrease systemic steroid use, and increase FEV1 amongst asthma patients. They found insufficient evidence regarding SCIT’s effect on symptom control, health care utility, or use in pediatric asthma patients. They found local reactions were common, and even systemic reactions were common but mild. There were no reported events of anaphylaxis or death in 462 pediatric patients, but they found insufficient evidence regarding anaphylaxis and death risk associated with SCIT in adults (61 cases of anaphylaxis reported out of 1,037 patients, 1 death reported). Regarding SLIT, they concluded that there exists high strength of evidence of improvement in asthma symptoms, moderate strength of evidence that it improves FEV1 and decreases use of long-term ICS, and low strength of evidence that it may decrease use of reliever medications and improve QOL. They found insufficient evidence regarding SLIT’s use in pediatric patients or its effect on systemic steroid use or health care utilization. Regarding the safety of SLIT, they found local reactions to SLIT were common, systemic reactions were frequent, but with only a few (3) reports of anaphylaxis and no reports of death. The conclusion of the reporting committee was that while further studies are needed, such as studies on severe asthma, on pediatric patients, and on multi-allergen regimens, the current evidence points towards immunotherapy being a safe and effective option for allergic asthma patients (Lin et al., 2018). It remains to be seen what the newest final recommendation will be when EPR-4 is published, including this additional research, as the 2007 version recommended SCIT as a consideration for asthma patients with persistent allergic asthma with sensitivities to dust mites, animal dander, and/or pollen (NHLBI, 2012).
The extensive pharmacology available to asthma patients can be overwhelming for providers. Options include control medications, which are typically taken daily on a scheduled basis regardless of symptoms. This may include ICS, LABA, LTRA, long-acting muscarinic antagonists (LAMA), theophylline (bronchodilator in pill form), cromolyn (previously Intal, a mast cell stabilizer) and a host of newer biologics that work by diminishing or blocking the effects of various different steps in the inflammatory cascade such as omalizumab (Xolair, an antibody that binds IgE), dupilumab (Dupixent, an antibody to IL-4), mepolizumab (Nucala, an antibody to IL-5), benralizumab (Fasenra, an antibody to IL-5) and others. Reliever, quick-relief or rescue medications work quickly to diminish symptoms, but most have a much shorter duration. These include SABAs like albuterol (ProAir or Ventolin) and terbutaline (not currently available as an inhaler in the US) or short-acting muscarinic antagonists (SAMA) such as ipratropium bromide (Atrovent). Formoterol is longer-acting but rapid-onset LABA that is also utilized as a reliever. Finally, some medications can only be given via nebulizer, such as cromolyn, or are given in pill form (theophylline), or via injection, as with most of the biologics, but the vast majority are inhaled with a metered dose or dry powder inhaler. We will also mention briefly the use of magnesium sulfate (MgSO4) as an acute exacerbation therapy. As a guide, the EPR-3 published a useful algorithm regarding the assessment of asthma severity at initial diagnosis (see below) based on frequency of symptoms, nighttime awakenings, SABA use, and exacerbations in combination with everyday impairment and spirometry results broken down by age group (NHLBI, 2012).
Table 3: EPR-3 Asthma Severity Classification by Age
These levels of severity, once assessed, then correspond with EPR-3’s stepwise treatment algorithm that assists providers in determining the best medication regimen for their individual patient, broken down again by age group (see Table 4 below).
Table 4: EPR-3 Asthma Treatment Algorithm
The key to utilizing this step-wise approach is the accurate and consistent assessment of symptom control at each follow-up visit (see Table 5 below). The patient should be asked about nighttime awakenings and daytime symptoms. Medication adherence should be discussed with non-judgemental and open-ended statements and questions. Inhaler technique should be assessed at each visit, and the presence of an Asthma Action Plan (AAP) that is up to date and appropriate should be confirmed. These follow-up visits should occur every 2-6 weeks while the patient is gaining control, every 1-6 months to monitor if well-controlled, or every 3 months if a step-down in therapy is anticipated or being carried out. This follow-up should include spirometry on all patients over the age of four at least every one to two years, as well as use of validated symptom control tools in all patients over the age of 11. The definition of good control is a combination of decreased impairment in function as well as a decreased risk of future exacerbation or damage (NHLBI, 2012). Bostantzoglou et al. (2015) defines control as the significant reduction or elimination of symptoms and limitations in daily life and an increase in QOL. GINA guidelines point out that persistent bronchodilator reversibility of >12% or >200 mL in a patient on a long-term control medication or who was given a dose of SABA within the last four hours or LABA within the last 12 hours indicates uncontrolled asthma. Similarly, excessive variability in a patient’s peak flow readings indicates suboptimal control and an increased risk for exacerbations in the future (GINA, 2018).
Table 5: EPR-3 Follow-up Assessment of Asthma Control
According to GINA recommendations, follow-up visits to assess control should occur 1-3 months after initial diagnosis, then every 3-12 months depending on the level of control. A follow-up is also recommended within one week of an exacerbation and 2-3 months after any medication change. FEV1 should be reassessed 3-6 months after starting long-term control treatment to establish personal best (PB), and periodically after that, but at least every one to two years in asthma patients over the age of four. The gradual, progressive decline in spirometry results seen in some asthma patients over their lifetime is referred to as fixed airflow limitation and is usually incomplete and reversible with appropriate treatment (GINA, 2018). An FEV1 that is less than 60% predicted was found to be an independent predictor for future risk of exacerbation and accelerated decrease in lung function (Bostantzoglou et al., 2015). This means that if there is a discordant patient with a decreased FEV1 but minimal complaints of symptoms, the provider needs to consider whether the patient is significantly limiting their lifestyle in order to avoid symptom provocation or has a poor perception of airflow limitation secondary to untreated airway inflammation. Conversely, if a patient presents with increased complaints of symptoms, but good or acceptable spirometry results, the provider must consider differential diagnoses such as undetected gastroesophageal reflux disease (GERD), cardiac disease, cough related to post-nasal drip, or other. According to both EPR-3 and GINA, asthma symptom control should be assessed with a validated tool. The GINA symptom control tool is a simple, four question tool that asks about daytime symptoms and/or use of reliever medication more than twice per week, nighttime awakenings, and any activity limitation in the last four weeks (GINA, 2018). Other asthma symptom control tools that have been well-validated and tested include:
- Royal College of Physicians’ Three Question Tool - a categorical tool that asks about activity limitation, daytime/daily symptoms, and difficulty sleeping in the last 30 days
- Asthma Control Questionnaire (ACQ) - a numerical self-assessment of morning symptoms, limitation in activity, nighttime awakenings, SOB, wheezing, use of reliever medication (in ACQ-6), and pre-bronchodilator FEV1 (in ACQ-7); final score ranges 0-6, <0.75 is well controlled, 0.75-1.5 yellow/grey zone, >1.5 is poorly controlled; may be used in adults and pediatrics
- Asthma Control Test (ACT)- a numerical test that includes patient report of level of control, limitation in activity, nighttime awakenings, SOB, and use of reliever medication; scores range from 5-25, 20-25 is well controlled, 16-19 not well controlled, <16 very poor control; childhood ACT (c-ACT) is available
- Asthma Control Scoring System- a numerical tool that includes daytime/daily symptoms, limitation in activity, nighttime awakenings, use of reliever medication, PEF% predicted, FEV1% predicted, change in PEF% predicted, and sputum eosinophilia (optional)
- 30-second Asthma Test- a self-report of symptoms based on five yes/no questions
- Test for Respiratory and Asthma Control in Kids (TRACK) - for use in pediatrics, includes recent history of exacerbations
- Composite Asthma Severity Index (CASI)- for use in pediatrics, includes recent history of exacerbations (Bostantzoglou et al., 2015; GINA, 2018; NHLBI, 2012)
Similar to EPR-3, GINA 2018 also included a stepwise treatment algorithm in their 2018 update that is very similar to EPR-3’s (see Table 6 below). The primary difference between the two is that GINA’s algorithm includes just 5 steps and lacks the age-group breakdown (their algorithm is applicable to all patients age six and up), although they do specify dosage differences based on age (see Table 7 below). Both groups recommend stepping down treatment after 3 months of good control or stepping up treatment in the case of continued symptoms/exacerbations. They both point out the importance of confirming correct inhaler technique and medication adherence, as well as treating comorbidities such as GERD, obesity or smoking prior to stepping up treatment, as all of these conditions may worsen or mask asthma symptoms and lead to inappropriate treatment (GINA, 2018; NHLBI, 2012).
Table 6: GINA Treatment Algorithm
Table 7: Low, Medium, and High Doses of Inhaled Corticosteroids by Age per GINA
|Adults and adolescents (12 years and older)|
|Drug||Daily dose (mcg)|
|Beclometasone dipropionate (CFC)*||200-500||>500-1000||>1000|
|Beclometasone dipropionate (HFA)||100-200||>200-400||>400|
|Fluticasone furoate (DPI)||100||n/a||200|
|Fluticasone propionate (DPI)||100-250||>250-500||>500|
|Fluticasone propionate (HFA)||100-250||>250-500||>500|
|Children 6-11 years|
|Beclometasone dipropionate (CFC)*||100-200||>200-400||>400|
|Beclometasone dipropionate (HFA)||50-100||>100-200||>200|
|Fluticasone furoate (DPI)||n/a||n/a||n/a|
|Fluticasone propionate (DPI)||100-200||>200-400||>400|
|Fluticasone propionate (HFA)||100-200||>200-500||>500|
|Mometasone furoate||110||≥220- <440||≥440|
CFC: chlorofluorocarbon propellant; DPI: dry powder inhaler; HFA: hydrofluoroalkane propellant
*Beclometasone dipropionate CFC is included for comparison with older literature
ICS is the primary controller medication used in both algorithms. They function by reducing bronchial inflammation, preventing exacerbations, and often relieve cough. (Bostantzoglou et al., 2015). They were first developed in 1973 due to the significant side effects seen with systemic steroids (de Groot et al., 2015). A common side effect of ICS can be thrush, but the risk of this can be reduced significantly with the use of a spacer or chamber (which also helps with medication delivery when using a metered dose inhaler [MDI]) as well as diligent oral hygiene after medication administration (NHLBI, n.d.). In older patients ICS may also increase rate of bone mineral loss and cause skin thinning, bruising, and adrenal suppression (Bostantzoglou et al., 2015). ICS has also been shown to slow growth rates in children by an average of 1 cm, although this is both non-progressive yet not entirely predictable (NHLBI, 2012). GINA guidelines recommend a lower dose of ICS earlier, as opposed to a higher dose, with greater side effects, later. They indicate that an increase in FEV1 should be seen within days of starting ICS and usually plateaus in roughly two months, while peak flow readings usually increase to PB level after about two weeks of treatment, with variability diminishing after three months of treatment (GINA, 2018). Eosinophilic asthmatics typically require a higher dose of ICS for inflammation management, regardless of what may seem like acceptable symptom control (Bostantzoglou et al., 2015). In some patients, because inflammation can affect the entire respiratory tract, ICS may be insufficient, and systemic steroids carry with them significantly greater adverse effects (de Groot et al., 2015). An area of research that is potentially upcoming, Dunican and Fahy (2017) discussed the development of a six gene expression biomarker signature to predict steroid responsiveness in asthma patients. This biomarker is able to select patients with airway inflammation secondary to T helper 2 cells that respond better to corticosteroid treatment with more accuracy than sputum or blood eosinophil counts (Dunican & Fahy, 2017).
Intermittent ICS dosing is defined as varying in dose, frequency, or duration of administration, such as initiating a temporary course of ICS or temporarily increasing the dose. An executive summary in preparation for the upcoming update to EPR-3 regarding intermittent ICS use and LAMA use was published by Sobieraj et al. (2017) regarding the efficacy of intermittent ICS use by age group. They reviewed 54 randomized controlled trials and 2 observational studies as part of their process. In patients aged 0-4 with recurrent wheezing, they found intermittent ICS use with SABA (vs. SABA alone) reduced the risk of exacerbation requiring oral steroids based on moderate strength of evidence and improved QOL based on low strength of evidence. In these same patients, Intermittent ICS was found to reduce the risk of exacerbation requiring oral steroids, hospitalization, or rescue medication use versus regularly scheduled ICS controller use. There was insufficient evidence regarding intermittent ICS use versus non-pharmacological therapy or no therapy in this age group. In patients age 5-11 with persistent asthma, they found intermittent ICS use did not affect QOL or rescue medication use versus ICS controller use based on low strength of evidence, and there was insufficient evidence to assess the effect on the other outcomes in this age group. In patients with persistent asthma aged 12 and above, they found that the use of intermittent ICS dosing, either alone or with ICS controller dosing, versus ICS controller dosing alone, was found not to affect the risk of exacerbation based on low strength of evidence. However, the use of intermittent and controller ICS versus controller dosing alone was found to decrease the number of asthma-related outpatient visits based on low strength of evidence (Sobieraj et al., 2017).
Typically, the second controller medication introduced in step 3 of both algorithms discussed above is a long-acting ß agonist (LABA) such as salmeterol (Serevent, Advair), vilanterol (Breo Ellipta) or formoterol (Symbicort, Dulera). These work as bronchodilators by relaxing the smooth muscles that surround the airway by selectively stimulating beta-2 adrenergic receptors. Vilanterol’s half-life is 16-21 hours (allowing once daily dosing) with an onset of about 10 minutes, formoterol’s half-life is 10 hours with an onset less than 5 minutes, and salmeterol’s half-life is just 5.5 hours with an onset of about 15 minutes. They should not be used as monotherapy, but always in conjunction with ICS, and (other than formoterol) not for acute symptom relief. EPR-3 recommends a maximum daily dose of 100 mcg of salmeterol or 24 mcg of formoterol. The effect of adding LABA to low-dose ICS in adult asthma patients who are not well-controlled with low-dose ICS alone results in better control than doubling the ICS dose, but the use of LABA alone has been shown to increase the risk of exacerbation and is not recommended. They work especially well in patients with a lot of wheezing, SOB and nocturnal symptoms, or those patients found to be in the non-eosinophilic clinical phenotype characterized by severe symptoms but minimal inflammation (Bostantzoglou et al., 2015; NHLBI, 2012; Lynne & Kushto-Reese, 2015). GINA guidelines recommend increasing to moderate ICS doses in patients age 5-11 in step 3, but in adults suggests adding a LABA to low-dose ICS. ICS/LABA as the initial maintenance controller treatment has been shown to reduce symptoms and improves lung function but does not reduce risk of exacerbation and is more expensive than ICS alone (GINA, 2018). In 2016, the New England Journal of Medicine (NEJM) published two single safety studies conducted by GlaxoSmithKline (GSK) and AstraZeneca mandated by the FDA secondary to safety concerns (increased risk of mortality) that arose after LABAs began to be used on a widespread basis. The first, by GSK, compared a combination of fluticasone and salmeterol (Advair) with fluticasone (Flovent) alone. Over 11,000 patients over the age of eleven were studied. They found a total of 74 serious asthma events (hospitalization or intubation) total, with 36 in the combination group and 38 in the control group. There were no deaths in this study. The risk of a severe exacerbation was 21% lower in the combination group (Stempel et al., 2016). The second, by AstraZeneca, was a comparison of budesonide and formoterol (Symbicort) versus budesonide alone. Based on over 11,000 patients over the age of 11, the study found no increased risk of death or serious event with the use of ICS plus LABA. Patients with a known history of previous life-threatening asthma event were notably excluded from this study (>four exacerbations or >two hospitalizations in the last year, > ten-year pack history of smoking, history of unstable asthma in the last seven days, previous history of intubation or hypercapnia requiring non-invasive ventilatory support). There were between 43 patients with serious events in the combination group, and 40 patients with serious events in the control group. Of note, this study did report two deaths in the combination group. The results showed over 16% decrease in the risk of exacerbation in the combination group versus the control group (Peters et al., 2016). In 2018, the NEJM published a compilation study regarding the safety of LABA based on the four large prospective randomized controlled clinical trials mandated by the FDA. These trials compared ICS with a combination of ICS and LABA in over 36,000 patients. This included the two trials above, as well as Merck’s trial regarding mometasone and formoterol (Dulera) and a similar trial by Novartis (who terminated their study early discontinued their inhaled formoterol product Foradil in 2015, not for safety reasons). The combination of LABA and ICS was not found to increase the risk of hospitalization, intubation or death, but did show a decreased relative risk for exacerbation, similar to the individual studies’ findings. Unfortunately, this decrease in risk was not universal as it was not seen as strongly in adolescents, African Americans or Asian Americans. Despite the lack of clear evidence that this combination is dangerous, there remains a Black Box warning on all ICS-LABA combination products that patients should be made aware of (Busse et al., 2018). Weiler et al. (2016) stated in the practice parameter published regarding the treatment of patients with EIB that while quick-onset SABA or LABA medication were the most effective, tolerance was common if used daily.
You will notice that in the GINA treatment guidelines (2018), low-dose ICS-formoterol is listed below steps 3-5 as an option for reliever medication. This method, they report, has been shown to reduce exacerbations and hospitalizations in patients over the age of 11 (and likewise in patients 4-11, but they remark that this practice is not approved for this age group in many countries) (GINA, 2018). This newer treatment concept that has emerged recently in asthma is termed single maintenance and reliever therapy (SMART) (Sobieraj et al., 2018b). It is also be referred to as maintenance and reliever therapy (MART), dynamic dosing, or adjustable maintenance dosing (AMD) (Dinakar et al., 2014; Tang, Sun, & FizGerald, 2018). The basic concept is as follows: instead of the traditional instructions to asthma patients, which involves one or two inhalers for daily control/maintenance, and a separate reliever medication in another inhaler to be used PRN, the SMART method instructs patients to utilize one inhaler, a combination of ICS and formoterol, which is a rapid-onset LABA, for both maintenance and for PRN symptom control. Dinakar et al. (2014) discussed this concept as a recommended strategy in adult patients with mild to moderate asthma to both avoid and exit from a state of increased asthma symptoms, termed the “yellow zone”. They recommended the use of a single inhaler, containing both ICS and a LABA, as they found this to be the most convenient for the patient as well as the most well-studied. They did not believe this would be advisable in children or severe asthmatics. They also pointed out that currently in the US this method of dosing is considered off-label (Dinakar et al., 2014). Sobieraj et al. (2017) discussed this as part of the executive summary regarding intermittent ICS use and LAMA use. They found in patients age 5-11 with persistent asthma, the use of SMART versus ICS and LABA as controller medication or versus a higher ICS controller dose reduced the risk of exacerbation based on low strength of evidence. In patients with persistent asthma over the age of 11, when compared with regularly-scheduled ICS controller dosing, they found that the use of SMART reduced the risk of exacerbation and improved spirometry results based on moderate strength of evidence, as well as reducing use of rescue medication based on low strength of evidence. When SMART was compared with ICS controller medication at a higher dose, there was still a reduced risk of exacerbation based on low strength of evidence in the SMART group. When SMART was compared with ICS plus LABA as controller medication, they found a reduced risk of exacerbation (based on high strength of evidence), improved asthma control scores (based on moderate strength of evidence), and reduced use of reliever medication (based on low strength of evidence). When SMART was compared with ICS plus LABA as controller medication as a higher ICS dose, they again found a reduced risk of exacerbations in the SMART group based on high strength of evidence. Finally, when they compared to outcomes of patients using SMART versus the conventional best practices of ICS as a controller medication with or without LABA, they found in the SMART group a reduced risk of exacerbation, reduced use of reliever medication, and improved asthma control scores all based on moderate strength of evidence (Sobieraj et al., 2017). The SYGMA studies, published in 2018 in the NEJM, were conducted by AstraZeneca to look at SMART treatment results utilizing their Symbicort inhaler for an entire year. O’Byrne et al. (2018) looked at the PRN use of budesonide-formoterol (Symbicort) in 3,836 patients older than 11 with mild asthma. They compared:
- SMART Group: PRN budesonide-formoterol (Symbicort) and BID placebo
- Control Group 1: PRN terbutaline (not currently available as an inhaler in the US) and BID placebo
- Control Group 2: PRN terbutaline and BID budesonide (Pulmicort)
The results indicated that the SMART Group had an improved number of “well-controlled asthma weeks”, a reduced number of exacerbations as compared to Control Group 1. The SMART Group had a similar number of exacerbations compared to Control Group 2 and was found to be non-inferior based on ACQ-5 scores and FEV1 but with a significant 17% decrease in daily steroid dosage (O’Byrne et al, 2018). The second SYGMA study again reviewed 4,176 patients over the age of 11 with diagnosed mild asthma. They compared PRN budesonide-formoterol (Symbicort) and BID placebo (SMART group) with PRN terbutaline (not currently available as an inhaler in the US) and BID budesonide (Pulmicort) (control group). They found no significant difference in the annual severe asthma exacerbation rate between the groups. They did find that the SMART group utilized 75% less steroids as compared to the control group. They did see slightly better ACQ-5 scores and improved lung function in the control group, but these findings were below the level of clinical relevance (Bateman et al., 2018). Tang et al. (2018) point out that while up to 70% of asthma patients are categorized as mild, between 40-50% of these are uncontrolled and 25% have had a severe exacerbation in the last 12 months. They postulated that this is due to an overreliance on SABA which is likely secondary to a combination of the comfort level of the patient’s first medication and the quick symptom relief it provides. They found that if SMART therapy is utilized in mild asthma patients it leads to reduced rate of exacerbations, as well as reduced number of hospitalizations and ED visits secondary to reduced inflammation (which SABAs do not effect), improved adherence, and overall less exposure to corticosteroids (Tang et al., 2018). Finally, a systematic review and meta-analysis of SMART therapy using budesonide-formoterol in dry powder inhaler (DPI) evaluated 16 randomized clinical trials involving 22,748 patients over the age of four with persistent asthma ranging from mild to severe. All studies included the use of SABA as reliever medication in the control group. Amongst patients over the age of 11 they found a significantly reduced risk of exacerbation compared with ICS-LABA controller use, even when a higher dose of ICS was used in the control group. Similar results were seen when SMART was compared with ICS alone as a controller medication, either at the same or at higher doses. Amongst the 341 patients ages 5-11, they saw the same reduced risk of exacerbation but based on a smaller sample size (Sobieraj et al., 2018b). GINA guidelines (2018) specify a maximum of 72 mg of formoterol in one 24-hour period.
EPR-3 (NHLBI, 2012) and GINA (2018) guidelines both list leukotriene modifiers such as montelukast (Singulair), zafirlukast (Accolade), or zileuton (Zyflo) as alternative options for persistent asthma treatment in patients age 5 and above. They are available as once-daily oral tablets and montelukast is also available in a granule packet. They work by blocking the leukotriene portion of the inflammatory cascade (NHLBI, n.d.). GINA specifies that these oral medications may be an appropriate daily controller choice in patients who experience intolerable adverse effects related to ICS or who may have concomitant allergic rhinitis as well as an alternative in EIB. It is an alternative adjunct with ICS but has been shown to be less effective than adding LABA. It can also be considered an optional adjunct therapy in patients with aspirin-sensitive asthma (GINA, 2018). Bostantzoglou et al. (2015) point out that this medication type may be more beneficial in the non-eosinophilic clinical phenotype characterized by severe symptoms but minimal inflammation. EPR-3 (NHLBI, 2012) specifies that montelukast may be used in children as young as one year, while zafirlukast should be not used under 5 and zileuton should not be used in patients under 12. They further specify that both zafirlukast and zileuton require liver function monitoring regularly. Zileuton also has a slightly different mechanism of action, working as a 5-lipoxygenase inhibitor to interfere with leukotriene formation while montelukast and zafirlukast both function as selective leukotriene receptor antagonists (LTRAs). They also suggest LTRAs as an alternative in the treatment of EIB (NHLBI, 2012). In the American Association of Allergy, Asthma and Immunology (AAAAI) practice parameter on EIB, they mention leukotriene modifiers as a reasonable option and suggest they be used intermittently but warn that protection may be incomplete (Weiler et al., 2016).
Tiotropium bromide (Spiriva) was FDA approved in 2014 as the only LAMA for use in asthma patients over the age of 11 in the US (although others are approved for the treatment of COPD). It functions as an antagonist to acetylcholine receptors, causing bronchodilation, with a half-life of 25 hours. GINA states that in adolescent or adult patients with a history of exacerbations not well-controlled on low-dose ICS and LABA, the addition of tiotropium can be considered in step 4. It has been shown to modestly improve lung function and increase time to severe exacerbation (GINA, 2018). Sobieraj et al. (2017) discussed the use of LAMA as part of the executive summary regarding intermittent ICS use and LAMA use in preparation for the forthcoming update to EPR-3. They found that in patients over the age of 11 with uncontrolled persistent asthma, the addition of LAMA to ICS versus placebo decreased the risk of exacerbation and improved spirometry results. They also compared the addition of LAMA to ICS versus doubling the dose of ICS and found no significant effect. They compared adding LAMA to ICS versus adding LABA, and similarly found no significant effect. Finally, they reviewed what they termed “triple treatment”, which included ICS, LABA, and LAMA and found that the addition of LAMA improved FEV1 based on high strength of evidence and improved asthma control scores based on low to moderate strength of evidence but saw no significant effect on risk of exacerbation or hospitalization (Sobieraj et al., 2017). Separately, a systematic review and meta-analysis of LAMA use was published a year later, which included 15 randomized clinical trials and over 7,000 patients over the age of 11, including 789 between the ages of 12-17. They found similarly that the addition of LAMA to ICS versus placebo reduced the risk of exacerbation requiring systemic steroids and improved spirometry results. They found no significant difference between ICS-LABA and ICS-LAMA. Very similar to the results above, when they compared ICS-LABA with triple therapy (ICS-LABA-LAMA) they found an improvement in FEV1 as well as QOL scores but saw no improvement in exacerbation risk (Sobieraj et al, 2018a).
Theophylline is an oral medication that functions by antagonizing adenosine receptors and increasing cyclic adenosine monophosphate (cAMP), thereby causing bronchodilation. It can be especially helpful with nocturnal symptoms (Lynne & Kushto-Reese, 2015). It is limited in its utility by the necessity of checking levels periodically to ensure a therapeutically appropriate serum concentration (NHLBI, n.d.). EPR-3 (NHLBI, 2012) recommends theophylline as an alternative to low-dose ICS in step 2 treatment, an alternative adjunct to ICS or ICS-LABA in step 3, an alternative adjunct to ICS-LABA in steps 4 and 5, or in step 6 in conjunction with ICS-LABA in an attempt to avoid a course of oral corticosteroids. It is available in liquid, capsule, or sustained-release tablet form. It is typically dosed at 10 mg/kg per day initially (NHLBI, 2012). GINA guidelines offer theophylline as an alternative initial controller medication in adolescents and adults with initial presentation of asthma symptoms and/or SABA use more than twice weekly but notes that this is typically less effective than low-dose ICS. They also mention the use of short-acting theophylline as a reliever medication but note that it has a slower onset of action than most other SABAs and a higher risk of adverse effects. It is also listed as an adjunct treatment option with ICS and/or ICS-LABA in adolescents and adults, but is not recommended for use in children. Lastly, they note that the use of theophylline may worsen GERD symptoms via relaxation of the lower esophageal sphincter (GINA, 2018).
Cromolyn sodium (Intal) is an anti-inflammatory medication that is delivered via nebulizer which functions as a mast cell stabilizer and thereby blocking the cellular response to inhaled antigens that can trigger asthma exacerbations. A significant limitation of cromolyn is the need for a nebulizer and the need to be dosed four times daily in order to be effective. It is listed in EPR-3 as an alternative controller medication in step 2, but not recommended in children under two. It is also one of the options that may be used to pre-treat EIB prior to exercise (NHLBI, 2012). Notably, there was no mention of the use of cromolyn or other mast cell stabilizers in GINA (2018).
Reliever or rescue medications are used to treat asthma exacerbations or sudden onset of symptoms on an as needed basis. Albuterol (Pro-Air or Ventolin) and levalbuterol (Xopenex) are bronchodilators that selectively stimulate beta-2 adrenergic receptors, similar to the previously mentioned LABAs, relaxing the airway smooth muscles. Their half-life is 2.7-6 hours. Both are available in inhalers or can be used in nebulizers, and albuterol can also be found in oral tablet form, extended release oral tablet, or liquid syrup. Terbutaline is a SABA that is available in tablet form as well as subcutaneous injection with a half-life of 3-4 hours. It is approved for use in patients over the age of 5 up to three times per day. EPR-3 and GINA guidelines suggest the use of SABAs like albuterol on an as needed basis in patients with mild intermittent asthma. Formoterol, as mentioned above, is a quick-onset but long-acting beta agonist with a 10-hour half-life. Ipratropium bromide (Atrovent) is a short-acting muscarinic antagonist (SAMA) that creates bronchodilation by antagonizing acetylcholine receptors. It has a half-life of 2 hours and is available as a nebulizer solution that can be mixed with albuterol or levalbuterol or a metered dose inhaler that can be used independently. Both guidelines suggest utilizing the patient report of reliever use to help gauge the level of symptom control in asthma patients (GINA, 2018; NHLBI, 2012)
Severe asthma may be difficult to treat. Especially in eosinophilic asthma patients, steroid resistance and steroid-related adverse effects are significant treatment hurdles. Scientists have suggested blocking IL-5 and IL-13 activity in these patients as a way of reducing steroid resistance, improving steroid sensitivity, and improving treatment response (Dunican & Fahy, 2017). There are a number of new treatment options on the horizon for asthma, including new biologics that target cytokines involved in the inflammatory cascade such as IgE, IL-4, IL-5, and IL-13 as well as new a relatively new procedure called bronchial thermoplasty. Omalizumab (Xolair) is an FDA-approved medication that functions as a monoclonal antibody that binds IgE. While it has been shown to reduce exacerbations as well as eosinophil counts, there are patients that do not respond to omalizumab as expected (deGroot et al., 2015). Omalizumab is the only of the newer biologics specifically recommended in EPR-3 treatment guidelines, suggested it be considered in step 5 or 6 for those asthma patients over the age of 12 with allergies. It is delivered as a subcutaneous injection every 2-4 weeks. (NHLBI, 2012). GINA guidelines also mention omalizumab as an optional adjunct treatment in step 5 for patients over the age of 5 with moderate or severe allergic asthma uncontrolled on step 4 treatment (GINA, 2018). The 2014 ERS/ATS guidelines regarding the treatment of severe asthma mentions that omalizumab should be considered and trialed in patients with severe allergic asthma (Chung et al., 2014). Dupilumab (Dupixent) is a monoclonal antibody to the IL-4𝞪 receptor that has been shown to significantly reduce exacerbations and improve lung function and asthma control in moderate to severe eosinophilic asthma patients (deGroot et al., 2015). It is thought to function by blocking IL-4 and IL-13 activity. It is given via subcutaneous injection twice weekly and is currently FDA-approved as an adjunct for asthma patients 12 and older. In a small study featuring 210 patients age 12 and above with severe asthma on systemic steroids in the previous 6 months and at least 500µg daily of fluticasone or equivalent in the last four weeks were dosed with 300 mg dupilumab or placebo subcutaneously every two weeks for 24 weeks. During that time, glucocorticoid doses were reduced every four weeks from week 4-20 and then kept stable from week 20-24. The dupilumab group was able to reduce steroid dosage by ~70% through the course of the study, as compared with ~41% in the placebo group. 80% of those in the treatment group were able to reduce their steroid doses by 50% or greater (versus 50% of the control group), and 69% of those in the treatment group were able to reduce their steroid daily dose to 5mg or less per day versus just 33% of the control group. Finally, 48% of treatment group were able to completely discontinue oral steroids by week 24 versus 25% of the control group. The treatment group had 59% fewer severe exacerbations than the control group and a significantly better FEV1. Injection site reaction and transient blood eosinophilia were the most commonly reported adverse effects (Rabe et al., 2018). In a contemporaneous year-long study of over 1,900 patients with uncontrolled asthma, a dose of 200mg and 300 mg dupilumab was compared to placebo. Both doses showed significant decrease in exacerbation rate and improvement in FEV1 with all patients, and more marked improvement in those with an eosinophil count > 300. The most common adverse effects were injection site reaction and eosinophilia (Castro et al., 2018). Mepolizumab (Nucala) is a humanized monoclonal antibody to IL-5 that is FDA-approved for adjunctive therapy for severe eosinophilic asthma in patients 12 and older. It is a subcutaneous injection given every four weeks. It struggled to show clinical effect in early studies, but in patients with severe eosinophilic asthma it was shown to significantly reduce exacerbations, improve control, reduce the need for steroid use, as well as reduce sputum and blood eosinophilia (deGroot et al., 2015). In a major study regarding mepolizumab published in NEJM in 2014, 539 patients between the ages of 12-82 received either an IV, a SQ, or placebo every four weeks for 32 weeks. The results showed a roughly 50% reduction in exacerbation rate in the study groups, as well as a significant increase in FEV1, improvement in QOL and asthma control scores, and a decrease in eosinophil counts. The most frequently reported adverse effects in this study were nasopharyngitis, and headache (Ortega et al., 2014). Reslizumab (Cinqair) is a humanized monoclonal IgG4 antibody to IL-5 that is FDA-approved for patients over the age of 18 with uncontrolled asthma as adjunctive therapy. It has been shown to reduce exacerbations by as much as 50-60% in phase II trials, as well as improve function and asthma control scores (deGroot et al., 2015). It is dosed as an intravenous (IV) medication every four weeks. Two randomized clinical trials were done, encompassing 953 patients between the ages of 12-75 with diagnosed asthma, at least one exacerbation in the last twelve months, and an eosinophil count of at least 400 cells/µL. The combined results of these two trials showed an over 40% decrease in the annual rate of exacerbations in the treatment group versus the control group (Castro et al., 2015). Benralizumab (Fasenra) is also a humanized monoclonal antibody to the IL-5𝞪 receptor on eosinophils given via subcutaneous injection. It is FDA-approved as an adjunctive therapy for severe eosinophilic asthma patients 12 and older. In a recent study, 220 adult patients with severe asthma on oral steroids for the previous six months and elevated eosinophil blood counts were randomized to receive either placebo or subcutaneous benralizumab 30mg every four or eight weeks for 28 weeks. The treatment groups showed a median reduction of 75% in oral steroid dose by the completion of the study, compared to a 25% reduction seen in the control group. Both treatment groups had a significant reduction in exacerbation rate as well, and a stronger effect was seen in the 8-week dosing group. No significant effect was seen in asthma control scores, QOL, or FEV1 at 28 weeks (Nair et al., 2017). GINA guidelines mention the optional use of mepolizumab, reslizumab, or benralizumab as part of step 5 treatment in severe eosinophilic asthma patients uncontrolled on step 4 treatment (GINA, 2018). EPR-3 guidelines make a general warning for providers prescribing these newer biologics that patients be monitored after administration and providers should prepared to treat an adverse reaction of anaphylaxis should it occur (NHLBI, 2012).
There are other biologics that are either in development phases of study or not yet approved for use in the US. Lebrikizumab is a humanized monoclonal IgG4 antibody to IL-13. It was shown to improve FEV1 in a subgroup of patients with moderate to severe asthma and elevated periostin levels at baseline but has not performed as well in trials of mild asthma (deGroot et al., 2015). Tralokinumab is also a humanized monoclonal IgG4 antibody to IL-13. In a large trial with patients with moderate to severe asthma, it failed to show significant improvement in asthma control scores (the primary endpoint) but did significantly improve FEV1 as well as reduce the amount of ß-agonist use. In phase III trials, it failed to show consistent and significant reduction in exacerbation rates (deGroot et al., 2015). Pitrakinra is a human recombinant form of IL-4 that inhibits the activity of IL-4 as well as IL-13. In a phase II trial with patients diagnosed with moderate to severe asthma, this inhaled medication was shown to modestly reduce the number of exacerbations in certain subgroups (deGroot et al., 2015).
In those patients with highly symptomatic asthma but less eosinophilic inflammation, in addition to increased amounts of bronchodilators, some have suggested low-dose azithromycin (Bostantzoglou et al., 2015). The AZALEA trial, published in JAMA in 2016, showed disappointing results. This was a randomized, double-blind, placebo-controlled trial conducted in the UK with 199 asthma patients who required urgent or emergent care for an asthma exacerbation requiring systemic corticosteroids. They were discharged with either placebo or azithromycin tablets. The results showed no significant difference in asthma scores, QOL, lung function at follow-up, or time to a 50% reduction in symptoms per patient report between the two groups (Johnston et al., 2016). The ERS/ATS guidelines on severe asthma (Chung et al., 2014) mirrored this sentiment by recommending that macrolide antibiotics not be used for the treatment of asthma.
Bronchial thermoplasty (BT) is another adjunctive therapy mentioned in the GINA guidelines for adult patients with severe asthma not well controlled with step 4 treatments available. They caution that evidence is limited and long-term effects are not well known at this time. The procedure involves three bronchoscopy procedures done subsequently to deliver local radiofrequency pulse. GINA references a large placebo effect, as well as a transient increase in the number of asthma exacerbations during the three-month treatment period, followed by a subsequent reduction in exacerbations following treatment. They cited no effect on lung function or asthma symptoms compared with sham procedures. They suggest longer term follow-up of treated patients and additional studies (GINA, 2018). In 2014, the ERS/ATS guidelines on severe asthma suggested BT only be done within the context of IRB-approved studies (Chung et al., 2014). EPR-3 did not recommend BT as a treatment adjunct, but instead requested a systematic review of the evidence to provide future evidence-based recommendation, presumably in EPR-4. Alair BT is FDA approved in the US for use in adult patients with severe persistent asthma. The systematic review found the basic concept of BT to deliver controlled radiofrequency thermal energy to the proximal airway to reduce exacerbation by decreasing excess smooth muscle tissue. They reviewed 15 studies, including 432 patients and three primary randomized clinical trials. Two of the trials compared BT with medical care, and one with sham procedure. They found a significant reduction in the use of reliever medication but questioned the clinical relevance of this finding. They found that BT combined with standard medical care statistically improved asthma control and QOL compared to medical care alone but found low strength of evidence for this. There was insufficient evidence regarding a reduction in severe exacerbations, although there was low strength of evidence of a reduction in mild exacerbations when BT plus medical care was compared to medical care alone. When compared with sham procedure, BT resulted only in a significant reduction in ED visits (moderate strength of evidence) and exacerbations (low strength of evidence) following the initial treatment period but did not have a significant effect on asthma control scores, hospitalizations, reliever medication use, or pulmonary function test results. QOL results were inconclusive. There were frequent adverse effects reported, including bronchial irritation, chest discomfort, cough, discolored sputum, dyspnea, wheezing, and nighttime awakenings. No deaths were reported, but serious adverse events occurred more frequently in the BT group in all studies. Their final conclusion was that BT should be considered in a very select group of patients and is modestly beneficial (D’Anci et al., 2017).
Treatment of Exacerbations
EPR-3 guidelines suggest first assessing the severity of the exacerbation utilizing a physical exam, as well as patients reports of symptoms, signs of breathlessness or SOB (audible wheezing, retractions, accessory muscle use, etc). In patients over the age of 5, lung function testing such as spirometry or a peak flow meter may also be used to quantify the amount of limitation in lung function if possible. Supplemental oxygen should be used to treat any existing hypoxemia. Continuous or repeated inhaled SABA (+/- inhaled ipratropium bromide if severe) should be used to reduce airflow obstruction caused by bronchoconstriction. Systemic steroids should be started in patients with moderate to severe exacerbations, or with suboptimal response to SABA treatment, in order to treat underlying inflammation. In very severe exacerbations or those that are not responding to the aforementioned treatments, intravenous magnesium sulfate (MgSO4) or helium-oxygen therapy (Heliox) should be considered (NHLBI, 2012). Magnesium sulfate when administered via infusion has a short half-life (2.7 hours) and functions as a bronchodilator by inhibiting the cellular uptake of calcium, mast cell degranulation, and/or acetylcholine release at motor nerve terminals (Rower et al., 2016). Periodically, the initial assessment should be repeated to assess response to treatment. Patients who present to the ED for care or are ultimately hospitalized should be discharged with medications (SABA, oral corticosteroids, +/- ICS), a referral for follow-up, an asthma discharge plan, and any patient education that may apply, such as inhaler use/technique and environmental trigger exposure (NHLBI, 2012). GINA guidelines list some “alarm bells” that providers should look for in patients with asthma exacerbations, which include drowsiness, confusion, and silent chest. They provide the following guidance on admission to the hospital versus discharge home from the ED:
- If pre-treatment FEV1 or PEF is <25% predicted or personal best, or post-treatment FEV1 or PEF is <40% predicted or personal best, hospitalization is recommended
- If post-treatment lung function is 40-60% predicted, discharge may be possible after considering the patient's risk factors and availability of follow-up care
- If post-treatment lung function is >60% predicted or personal best, discharge is recommended after considering risk factors and availability of follow-up care
- Factors associated with increased likelihood of need for admission include:
- Female sex, older age and non-white race
- Use of more than eight beta2-agonist puffs in the previous 24 hours
- Severity of the exacerbation (e.g. need for resuscitation or rapid medical intervention on arrival, respiratory rate >22 breaths/min, oxygen saturation <95%, final PEF <50% predicted)
- Past history of severe exacerbations (e.g. intubations, asthma admissions)
- Previous unscheduled office and emergency department visits requiring use of OCS
Regarding the use of helium-oxygen therapy, GINA guidelines cite a systematic review of studies comparing this to air-oxygen therapy that found no benefit, and state that they see no role for this treatment in routine care but could be considered in patients not responding to convention treatment. Cost and availability are additional barriers. Regarding the use of MgSO4, GINA guidelines point out that randomized trials in mild-moderate asthma patients showed no benefit, but a single 2 gm IV infusion administered over 20 minutes has been shown to reduce hospitalization rates in:
- Adult patients with FEV1 <25-30% predicted at presentation
- Patients with persistent hypoxemia who fail to respond to initial treatment
- Pediatric patients who fail to improve (FEV1 <60% predicted) after one hour of treatment
For use in children, Rower et al (2016) found a dose of 50-75 mg/kg IV MgSO4 generally effective in achieving a therapeutic range of 25-40 mg/dL based on a small retrospective study of 54 pediatric patients based in Utah.
Asthma Action Plan
A crucial component of comprehensive care, an asthma action plan (AAP) serves as a patient’s road map for the management of symptoms at home on a daily basis. In 2014, Dinakar et al. discussed the use of the AAP in the management of acute loss of control, termed the “yellow zone” AAPs utilize a traffic light analogy, and thus the yellow zone is a loss of control that is mild or moderate in nature, and not severe enough to require an ED visit. An AAP helps the patient monitor their symptoms and their lung function to first identify where they are in the plan (green, yellow, or red zone) and the appropriate actions to take based on that self-assessment. They recommend that all asthma patients, regardless of age, be given a written or electronic AAP that is reviewed, and if needed edited or updated, at each follow-up visit. They define the green zone as less than 2 days per week of symptoms (cough, wheeze) or reliever medication use. They define the yellow zone as an increase in symptoms, increased use of reliever medication, a peak flow reading that is decreased 15% from previous reading or < 80% of PB, or the presence or increase in nocturnal symptoms. SABA use should be initiated if the patient finds themselves in the yellow zone at two to four puffs every four to six hours. If this persists longer than twelve hours, the patient should then contact their provider. If the patient is on a low-to-moderate daily dose of ICS, they could also be instructed on the AAP to increase their ICS dose up to 4x per 24 hours. For pediatric patients under the age of 6 with recurrent wheezing and risk factors for subsequent asthma, they recommend considering initiation of high-dose ICS or montelukast (Singulair) at first sign of wheezing illness to reduce the intensity. For patients with mild to moderate asthma, they recommend the symptom-driven use of a combination ICS-LABA inhaler to manage yellow zone symptoms, just as described above with SMART therapy (Dinakar et al., 2014). GINA guidelines state that all adolescent and adult patients should be educated on and given an AAP (GINA, 2018, p.77). See Figure 5 below for a sample plan below from the NIH, recommended by the EPR-3 guidelines:
Figure 5: Sample Asthma Action Plan
Within asthma care, a few special populations warrant some specialized treatment recommendations. The EPR-3 (NHLBI, 2012) recommends that pregnant women with asthma be monitored very closely while pregnant. They note that asthma control may change during pregnancy, either by improving or worsening, depending on the patient, which may warrant medication and treatment changes. In general, most medications used in asthma management are acceptable during pregnancy, but they recommend ICS as the preferred long-term controller medication (NHLBI, 2012). GINA guidelines are a bit more specific, stating that about ⅓ of asthma patients get worse when pregnant, ⅓ improve, and ⅓ do not change much. They warn that exacerbations are more common during pregnancy, especially in the second trimester, and that uncontrolled asthma increases the risk for preeclampsia, preterm delivery, low birth weight, or perinatal mortality. They note that ICS, all ß agonists, montelukast, and theophylline have shown to pose no increased risk of fetal abnormality. They recommend the use of SABA as needed during labor in the instance of SOB (GINA, 2018). Older adults are at a higher risk of medication interactions and should be warned about the risk of osteopenia or osteoporosis with corticosteroid use (NHLBI, n.d.). Older adults also typically see diminishing lung function over time, as well as increased sensitivity to medication adverse effects and decrease medication clearance. GINA guidelines recommend a simple regimen and inhalers that are easy to use. Obesity poses an additional risk for asthma patients as it has been shown to make asthma control more difficult to achieve. ICS is the recommended treatment, but their response may be reduced. Obese patients should be strongly encouraged to attempt a comprehensive weight loss plan. Anxiety and depression are more prevalent amongst asthma patients, leading to worse asthma control, poor adherence, and decrease QOL if not appropriately treated (cognitive behavioral therapy +/- medications but further research in this particular patient population needed). Adolescent patients will see frequent changes in symptoms, control, and therapy needs due to their rapid growth and hormonal changes during this stage. They also recommend seeing all adolescent patients separate from their caregivers at least briefly to ask about smoking. Those diagnosed with EIB should first be trialed on SABA as need prior to exercise, as well as appropriate conditioning and warm-up, or the use of a mask or scarf if cold-induced. Tolerance to ß agonists is a concern, especially if used more than once daily. Alternatives to SABA include LTRAs or chromones (GINA, 2018). LABA is also listed an option for EIB in EPR-3 guidelines, but caution against frequent use. EIB patients should be encouraged to exercise regularly, like all asthma patients, despite symptoms (NHLBI, 2012). Perimenstrual asthma (also called catamenial) effects about 20% of women. Oral contraceptives and/or LTRAs may be helpful. Occupational asthma refers to patients that are triggered by a chemical or environmental exposure that occurs as part of their regular work day. It generally increases in severity over time. The primary goal of treatment is to limit exposure. Asthmatics that are aspirin-exacerbated typically present with nasal congestion and anosmia, which leads to chronic rhinosinusitis with nasal polyps, and eventually asthma. They typically describe acute exacerbations within 60-120 minutes of exposure to aspirin or other NSAIDs along with rhinorrhea, nasal obstruction, conjunctival irritation, and flushing of the head and neck. It can be confirmed with an aspirin challenge test in a well-monitored environment with access to emergency equipment if needed. NSAIDs should be avoided in these patients, but usually COX-2 inhibitors or acetaminophen are well tolerated. Asthma symptoms can be treated with ICS, LTRA, +/- oral corticosteroids and desensitization therapy (GINA, 2018).
Integration of Care
Asthma is best treated in an integrated, multidisciplinary manner. A study in 2017 looked at results of such a model in Cincinnati youth between the ages of 2-17. Hospitalizations, ED visits and the number of readmissions were reduced by over 40%, and the number of primary care visits with well-controlled asthma increased by ~50% during the course of three years of implementing the plan. It incorporated inpatient factors during phase 1, such as discharging patients with a 30-day supply of all medications in hand, an asthma action plan and inhaler training, electronic decision support embedded in the history and physical in the electronic health record, and home health referrals for up to 5 visits from a registered nurse after discharge. Phase 2 targeted outpatient care and included care coordination services, enhanced pre-visit screening, home health referrals when needed, and a web-based patient registry to track ED visits and hospitalizations. Phase 3 targeted community features, which included a partnership between a primary care practice, the health department, and local public schools to train school nurses on ACT administration and written action plans for the children at school as well as read-only access to the electronic health records for the school nurse (Kercsmar et al., 2017). A similar concept, termed a school-based asthma management program (SAMPRO), is designed by the AAAAI. It involves four components:
- Circle of support - this support and communication network includes the child, the provider, the family, the school registered nurse, and the community
- Asthma Management Plan (AMP) - this includes an AAP (medical authorization for self-carry and administration of asthma medications as needed, parental release of information) in combination with a generic asthma emergency treatment plan (AEP) which is an emergency plan for all students in the school, including stock albuterol and a way to administer the medication
- A comprehensive education plan for all the school personnel
- Assessment of the school environment, remediation of any triggers present
They point out that the presence and utilization of an AAP, both at home and at school, has been shown to reduce mortality and ED visits (Lemanske et al., 2016).
Referral to a Specialist
Recognizing when a patient needs to be referred out to a specialist for more advanced care should be of utmost concern to the provider. In patients age 0-4, the EPR-3 guidelines suggest referral with an asthma specialist if step 3 care or higher is required, with consideration at step 2. In older patients, this threshold is step 4 or higher, with consideration in step 3 (NHLBI, 2012). GINA guidelines (GINA, 2018) recommend referral to an asthma specialist at step 5, or in the following circumstances:
- Difficulty confirming or doubts regarding the diagnosis
- Suspected occupational asthma
- Persistent uncontrolled asthma or frequent exacerbations (in children age 6-11, despite moderate dose ICS)
- The presence of any risk factors for asthma-related death, such as ICU admission, mechanical ventilation, anaphylaxis or a confirmed food allergy
- Risk for or evidence of significant treatment adverse effects (in children, growth delay)
- Symptoms suggestive of complications or sun-types of asthma, such as aspirin-exacerbated respiratory disease or allergic bronchopulmonary aspergillosis (GINA, 2018).
When treating patients with severe eosinophilic asthma, it is recommended to refer to an Ear, Nose, and Throat specialist (ENT) to help manage rhinosinusitis and nasal polyposis (de Groot et al., 2015).
Aaron, S. D., Vandemheen, K. L., FitzGerald, J. M., Ainslie, M., Gupta, S., Lemière, C., … Boulet, L.-P. (2017). Reevaluation of Diagnosis in Adults with Physician-Diagnosed Asthma. JAMA, 317(3), 269–279. doi: 10.1001/jama.2016.19627
American Lung Association (2018). Breathing Exercises.Retrieved on February 12, 2019 from https://www.lung.org/lung-health-and-diseases/protecting-your-lungs/breathing-exercises.html
Asthma and Allergy Foundation of America (2015). Allergens and Allergic Asthma.Retrieved from https://www.aafa.org/allergic-asthma/
Asthma and Allergy Foundation of America (2017). Lung Function Tests.Retrieved from https://www.aafa.org/lung-function-tests-diagnose-asthma/
Bateman, E. D., Reddel, H. K., O’Byrne, P. M., Barnes, P. J., Zhong, N., Keen, C., … FitzGerald, J. M. (2018). As-Needed Budesonide–Formoterol versus Maintenance Budesonide in Mild Asthma. New England Journal of Medicine, 378(20), 1877–1887. doi: 10.1056/NEJMoa1715275
Blake, K., & Raissy, H. (2018). Asthma Guidelines from the National Asthma Education and Prevention Program: Where Are We Now? Pediatric Allergy, Immunology, and Pulmonology, 31(1), 37–39. doi: 10.1089/ped.2018.0878
Bostantzoglou, C., Delimpoura, V., Samitas, K., Zervas, E., Kanniess, F., & Gaga, M. (2015). Clinical asthma phenotypes in the real world: opportunities and challenges. Breathe, 11(3), 186–193. doi: 10.1183/20734735.008115
Castro, M., Zangrilli, J., Wechsler, M. E., Bateman, E. D., Brusselle, G. G., Bardin, P., … Korn, S. (2015). Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. The Lancet Respiratory Medicine, 3(5), 355–366. doi: 10.1016/S2213-2600(15)00042-9
Castro, M., Corren, J., Pavord, I. D., Maspero, J., Wenzel, S., Rabe, K. F., … Teper, A. (2018). Dupilumab Efficacy and Safety in Moderate-to-Severe Uncontrolled Asthma. New England Journal of Medicine, 378(26), 2486–2496. doi: 10.1056/NEJMoa1804092
Chung, K. F., Wenzel, S. E., Brozek, J. L., Bush, A., Castro, M., Sterk, P. J., … Teague, W. G. (2014). International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. European Respiratory Journal, 43(2), 343–373. doi: 10.1183/09031936.00202013
D’Anci, K. E., Lynch, M. P., Leas, B. F., Apter, A. J., Bryant-Stephens, T., Kaczmarek, J. L., … Schoelles, K. (2017). Effectiveness and Safety of Bronchial Thermoplasty in Management of Asthma. Agency for Healthcare Research and Quality (AHRQ). doi: 10.23970/AHRQEPCCER202
de Groot, J. C., ten Brinke, A., & Bel, E. H. D. (2015). Management of the patient with eosinophilic asthma: a new era begins. ERJ Open Research, 1(1), 00024–02015. doi: 10.1183/23120541.00024-2015
Dinakar, C., Oppenheimer, J., Portnoy, J., Bacharier, L. B., Li, J., Kercsmar, C. M., … Wallace, D. (2014). Management of acute loss of asthma control in the yellow zone: a practice parameter. Annals of Allergy, Asthma & Immunology, 113(2), 143–159. doi: 10.1016/j.anai.2014.05.017
Dunican, E. M., & Fahy, J. V. (2017). Asthma and corticosteroids: time for a more precise approach to treatment. European Respiratory Journal,49(6), 1701167. doi: 10.1183/13993003.01167-2017
Global Initiative for Asthma (GINA). (2018). Global Strategy for Asthma Management and Prevention. Retrieved from www.ginasthma.org
Hirose, M., & Horiguchi, T. (2017). Asthma phenotypes. Journal of General and Family Medicine, 18(5), 189–194. doi: 10.1002/jgf2.7
Hsu, J., Sircar, K., Herman, E., Garbe, P. (2018). EXHALE: A Technical Package to Control Asthma. Atlanta, GA: National Center for Environmental Health, Centers for Disease Control and Prevention.
Johnston, S. L., Szigeti, M., Cross, M., Brightling, C., Chaudhuri, R., Harrison, T., … Chauhan, A. (2016). Azithromycin for Acute Exacerbations of Asthma: The AZALEA Randomized Clinical Trial. JAMA Internal Medicine, 176(11), 1630–1637. doi: 10.1001/jamainternmed.2016.5664
Kercsmar, C. M., Beck, A. F., Sauers-Ford, H., Simmons, J., Wiener, B., Crosby, L., … Mansour, M. (2017). Association of an Asthma Improvement Collaborative With Health Care Utilization in Medicaid-Insured Pediatric Patients in an Urban Community. JAMA Pediatrics, 171(11), 1072–1080. doi: 10.1001/jamapediatrics.2017.2600
Leas, B. F., D’Anci, K. E., Apter, A. J., Bryant-Stephens, T., Schoelles, K., & Umscheid, C. A. (2018).Effectiveness of Indoor Allergen Reduction in Management of Asthma. Agency for Healthcare Research and Quality (AHRQ). doi: 10.23970/AHRQEPCCER201
Lemanske, R. F., Kakumanu, S., Shanovich, K., Antos, N., Cloutier, M. M., Mazyck, D., … Williams, P. (2016). Creation and implementation of SAMPROTM: A school-based asthma management program. Journal of Allergy and Clinical Immunology, 138(3), 711–723. doi: 10.1016/j.jaci.2016.06.015
Lin, S. Y., Azar, A., Suarez-Cuervo, C., Diette, G. B., Brigham, E., Rice, J., … Robinson, K. A. (2017). The Role of Immunotherapy in the Treatment of Asthma. Agency for Healthcare Research and Quality. doi: 10.23970/AHRQEPCCER196
Litonjua, A. A., Carey, V. J., Laranjo, N., Harshfield, B. J., McElrath, T. F., O’Connor, G. T., … Weiss, S. T. (2016). Effect of Prenatal Supplementation With Vitamin D on Asthma or Recurrent Wheezing in Offspring by Age 3 Years: The VDAART Randomized Clinical Trial. JAMA, 315(4), 362–370. doi: 10.1001/jama.2015.18589
Lynn, S. J., & Kushto-Reese, K. (2015). Understanding asthma pathophysiology, diagnosis, and management. American Nurse Today, 10(7), 49–51.
Molfino, N. A., Kuna, P., Leff, J. A., Oh, C. K., Singh, D., Chernow, M., … Yarranton, G. (2016). Phase 2, randomised placebo-controlled trial to evaluate the efficacy and safety of an anti-GM-CSF antibody (KB003) in patients with inadequately controlled asthma. BMJ Open, 6(1), e007709. doi: 10.1136/bmjopen-2015-007709
Nair, P., Wenzel, S., Rabe, K. F., Bourdin, A., Lugogo, N. L., Kuna, P., … Goldman, M. (2017). Oral Glucocorticoid–Sparing Effect of Benralizumab in Severe Asthma. New England Journal of Medicine, 376(25), 2448–2458. doi: 10.1056/NEJMoa1703501
O'Byrne PM, FitzGerald JM, Bateman ED, et al. (2018) Inhaled combined budesonide-formoterol as needed in mild asthma. New England Journal of Medicine, 378, 1865-76. doi: 10.1056/NEJMoa1715274
Ortega, H. G., Liu, M. C., Pavord, I. D., Brusselle, G. G., FitzGerald, J. M., Chetta, A., … Chanez, P. (2014). Mepolizumab Treatment in Patients with Severe Eosinophilic Asthma. New England Journal of Medicine, 371(13), 1198–1207. doi: 10.1056/NEJMoa1403290
Peters, S. P., Bleecker, E. R., Canonica, G. W., Park, Y. B., Ramirez, R., Hollis, S., … Martin, U. J. (2016). Serious Asthma Events with Budesonide plus Formoterol vs. Budesonide Alone. New England Journal of Medicine,375(9), 850–860. doi: 10.1056/NEJMoa1511190
Pruitt, B. (2018). Asthma, Spirometry, PFT, Plus? Engaging Newer Tools for Asthma Diagnosis and Management. RT: The Journal for Respiratory Care Practitioners, 31(7), 16–20.
Rabe, K. F., Nair, P., Brusselle, G., Maspero, J. F., Castro, M., Sher, L., … Teper, A. (2018). Efficacy and Safety of Dupilumab in Glucocorticoid-Dependent Severe Asthma. New England Journal of Medicine, 378(26), 2475–2485. doi: 10.1056/NEJMoa1804093
Rasmussen, S. G., Ogburn, E. L., McCormack, M., Casey, J. A., Bandeen-Roche, K., Mercer, D. G., & Schwartz, B. S. (2016). Association Between Unconventional Natural Gas Development in the Marcellus Shale and Asthma Exacerbations. JAMA Internal Medicine, 176(9), 1334–1343. doi: 10.1001/jamainternmed.2016.2436
Rower, J. E., Liu, X., Yu, T., Mundorff, M., Sherwin, C. M. T., & Johnson, M. D. (2017). Clinical pharmacokinetics of magnesium sulfate in the treatment of children with severe acute asthma. European Journal of Clinical Pharmacology, 73(3), 325–331. doi: 10.1007/s00228-016-2165-3
Sheehan, W. J., Permaul, P., Petty, C. R., Coull, B. A., Baxi, S. N., Gaffin, J. M., … Phipatanakul, W. (2017). Association Between Allergen Exposure in Inner-City Schools and Asthma Morbidity Among Students. JAMA Pediatrics,171(1), 31–38. doi: 10.1001/jamapediatrics.2016.2543
Sobieraj, D. M., Baker, W. L., Weeda, E. R., Nguyen, E., Coleman, C. I., White, C. M., … Lang, J. E. (2017). Intermittent Inhaled Corticosteroids and Long-Acting Muscarinic Antagonists for Asthma. Agency for Healthcare Research and Quality. doi: 10.23970/AHRQEPCCER194
Sobieraj, D. M., Baker, W. L., Nguyen, E., Weeda, E. R., Coleman, C. I., White, C. M., … Lang, J. E. (2018a). Association of Inhaled Corticosteroids and Long-Acting Muscarinic Antagonists With Asthma Control in Patients With Uncontrolled, Persistent Asthma: A Systematic Review and Meta-analysis. JAMA, 319(14), 1473–1484. doi: 10.1001/jama.2018.2757
Sobieraj, D. M., Weeda, E. R., Nguyen, E., Coleman, C. I., White, C. M., Lazarus, S. C., … Baker, W. L. (2018b). Association of Inhaled Corticosteroids and Long-Acting β-Agonists as Controller and Quick Relief Therapy With Exacerbations and Symptom Control in Persistent Asthma: A Systematic Review and Meta-analysis. JAMA, 319(14), 1485-96. doi: 10.1001/jama.2018.2769
Spirometry: An Integral Tool for Diagnosing and Managing Pediatric Asthma. (2018). RT: The Journal for Respiratory Care Practitioners, 31(2), 12–16. Retrieved from http://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=128861470&site=ehost-live
Stempel, D. A., Raphio, I. H., Kral, K. M., Yeakey, A. M., Emmett, A. H., Prazma, C. M, Buaron, K. S., Pascoe, S. J. (2016). Serious asthma events with fluticasone plus salmeterol versus fluticasone alone. New England Journal of Medicine 374, 1822-1830. doi: 10.1056/NEJMoa1511049
Tang, W., Sun, L., & FizGerald, J. M. (2018). A paradigm shift in the treatment of mild asthma? Journal of Thoracic Disease, 10(10), 5655–5658. doi: 10.21037/jtd.2018.09.127
Tschudy, M. M., Sharfstein, J., Matsui, E., Barnes, C. S., Chacker, S., Codina, R., … Wedner, H. J. (2017). Something new in the air: Paying for community-based environmental approaches to asthma prevention and control. Journal of Allergy and Clinical Immunology, 140(5), 1244–1249. doi: 10.1016/j.jaci.2016.12.975
Virchow, J. C., Backer, V., Kuna, P., Prieto, L., Nolte, H., Villesen, H. H., … Blay, F. de. (2016). Efficacy of a House Dust Mite Sublingual Allergen Immunotherapy Tablet in Adults With Allergic Asthma: A Randomized Clinical Trial. JAMA, 315(16), 1715–1725. doi: 10.1001/jama.2016.3964
Wang, Z., Pianosi, P., Keogh, K., Zaiem, F., Alsawas, M., Alahdab, F., … Murad, M. H. (2017). The Clinical Utility of Fractional Exhaled Nitric Oxide (FeNO) in Asthma Management. Agency for Healthcare Research and Quality. doi: 10.23970/AHRQEPCCER197
Weiler, J. M., Brannan, J. D., Randolph, C. C., Hallstrand, T. S., Parsons, J., Silvers, W., … Wallace, D. (2016). Exercise-induced bronchoconstriction update—2016. Journal of Allergy and Clinical Immunology, 138(5), 1292-1295.e36. doi: 10.1016/j.jaci.2016.05.029
U.S. Department of Health and Human Services, National Institutes of Health, National Heart, Lung, and Blood Institute (NHLBI). (2007). Asthma action plan. (NIH Publication No. 07-5251). Retrieved from https://www.nhlbi.nih.gov/health-topics/all-publications-and-resources/asthma-action-plan
U.S. Department of Health and Human Services, National Institutes of Health, National Heart, Lung, and Blood Institute (NHLBI). (2012). Asthma care quick reference: Diagnosing and managing asthma (NIH Publication No. 12-5075). Retrieved from https://www.nhlbi.nih.gov/health-topics/guidelines-for-diagnosis-management-of-asthma
U.S. Department of Health and Human Services, National Institutes of Health, National Heart, Lung, and Blood Institute (NHLBI). (n.d.). Asthma.Retrieved January 21, 2019, fromhttps://www.nhlbi.nih.gov/health-topics/asthma