The purpose of this activity is to ensure that all APRNs within primary care and emergency medicine fields are aware of and able to implement the most up-to-date information regarding the pathophysiology, signs, symptoms, risk factors, and diagnosis of asthma into their practice.
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At the conclusion of this exercise, the learner will be prepared to:
- Outline the epidemiology and utilize 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.
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 [WHO], 2019). According to the Centers for Disease Control and Prevention (CDC), asthma affects 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 workdays in the United States alone. Amongst patients diagnosed with asthma, roughly half of adults and 40% of pediatric patients are not well controlled (Hsu et al., 2018). When discussing asthma, the term control refers to the presence of symptoms, any limitations in daily activities, and general quality of life (QOL) (Bostantzoglou et al., 2015).
Pathophysiology
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), 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 overly sanitized, reducing the number of environmental exposures and infections, and thus altering our immune systems (National Heart, Lung, and Blood Institute [NHLBI], n.d.). The bronchiolar inflammation and airway constriction lead to resistance and the hallmark symptoms of cough, wheezing, and SOB. Inflammation may exist without obvious symptoms and can affect the trachea, bronchi, or the smaller bronchioles. The source for the inflammation is still being studied, but the current understanding is that airway capillaries become dilated, causing microvascular leakage. In addition, the 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 damages the epithelium and eventually causes epithelial peeling, which leads to airway hyperresponsiveness. If left untreated, this chronic damage to the epithelial layer of the respiratory tract eventually causes permanent fibrotic damage and airway remodeling, which decreases lung function as well as responsiveness to treatment. In addition to this underlying inflammation, bronchospasms are caused by sharp contractions of the smooth muscles that line the bronchi (Lynne & Kushto-Reese, 2015).
Different subtypes of asthma have emerged in the last couple of decades, called phenotypes. The Global INitiative for Asthma (GINA, 2018), a collaborative report between the WHO and the 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). Early-onset atopic asthma typically diagnosed during childhood is characterized by reports of wheezing and associated allergies or triggers from external environmental factors such as dust mites, animal fur/dander, and 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 affects 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 (a chemokine that attracts eosinophils) (deGroot et al., 2015). Subsequent exposures to certain allergens or triggers cause an excessive release of IgE by then-activated B-lymphocytes, leading to the 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, few to no allergies, more severe disease, and a poorer prognosis. This phenotype was first described in 1999 by Wenzel and colleagues. Symptoms typically include reports of dyspnea on exertion (DOE) and chronic rhinosinusitis. Further examination and testing typically reveal fixed airflow obstruction and a decreased forced vital capacity (FVC) 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 on a bronchial biopsy or induced sputum sample, but due to the invasiveness, cost, and difficulty of obtaining those tests, this phenotype may be estimated using clinical presentation, LFT results, and a peripheral blood sample showing positive eosinophilia. In patients that fit the clinical picture of eosinophilic asthma of late-onset, sputum analysis may be beneficial. However, difficulty and limited access to capable labs are obvious barriers to this being used on a widespread basis. This phenotype is largely believed to be driven by innate lymphoid cells (ILCs), which produce IL-5 and IL-13 when activated. Similar to T and B lymphocytes, ILCs are derived from lymphoid progenitor cells but do not express antigen receptors and instead function as an important component of the innate immune system (deGroot et al., 2015). The 2014 European Respiratory Society/American Thoracic Society (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). 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).
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 [LTRAs]), the presence of chronic obstructive pulmonary
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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, it may also assist with selecting the most appropriate treatment (Hirose & Horiguchi, 2017).
Risk Factors and Prevention
According to the NHLBI (n.d.), 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; in adulthood, it 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 et al., 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 assesses 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. All participants received a prenatal multivitamin daily with 400 IU of vitamin D. They 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 the age of three. 98 of the 405 (24%) children in the high-dose group had been diagnosed with asthma/wheeze by the completion of the study, while 120 of the 401 (30%) in the low-dose group had been diagnosed. While this primary endpoint was not statistically significant, a significantly higher number of women in the high-dose group (289 of 386, 75%) were found to have a normal vitamin D level (greater than 30 ng/mL) during the third trimester versus the low-dose group (133 of 391, 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).
Diagnosis
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 correspond positively with the level of symptoms. 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 with exertion or at night, often causing nighttime awakenings. 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 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 the days of high stimulation (hydraulic fracturing) or production activity (Rasmussen et al., 2016). NHLBI (2007) provides more information to asthma patients regarding possible triggers and how best to avoid them in Figure 2 below:
The most recent GINA report (2018) states that diagnosis of asthma should be based on history, as well as evidence of variable airflow limitation via spirometry testing (FVC and forced expiratory volume [FEV1]) or peak expiratory flow (PEF or peak flow) measurements with reversibility test. For further details regarding GINA's diagnostic criteria, see Table 1 below (GINA, 2018).
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 recommends 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 FVC, which is roughly the total lung capacity or volume of air exhaled in liters, and the FEV1, which is just 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 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 typically considered diagnostic for asthma 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 diagnoses 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).
A peak flow meter (see Figure 4 below) is a small handheld device that all asthma patients should be given for regular monitoring 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 PEF number. This can be repeated immediately two times, using the highest score out of the three attempts. This should be done at a consistent time, typically first thing in the morning before any medications. Immediately 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 from this period 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 later 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 PEF number will often start to decrease prior to an exacerbation before the patient even identifies any appreciable symptoms, serving as their initial warning sign. A record of highly variable PEF readings, as well as reversibility 10-15 minutes after taking a SABA inhaler, may be used as a diagnostic test for asthma if necessary in patients that are unable to perform spirometry successfully (AAFA, 2017; NHLBI, n.d.). GINA recommends that patients also check their PEF following an exacerbation to monitor recovery, following any medication changes, if they feel an increase in their symptoms, and to help identify and pinpoint domestic or occupational triggers. They recommend regular PEF monitoring in patients with a poor perception of airflow limitation, a history of sudden and severe exacerbation(s), or with severe and/or difficult to control asthma (GINA, 2018).
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 exercise-induced bronchospasms (EIB) to assess the effect that 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 a viral upper respiratory infection. FeNO results are often decreased in smokers, during bronchoconstriction, or in the 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, this decreases the 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 ERS/ATS both recommend against using FeNO to diagnose or guide asthma treatment in the general population at this time (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 five 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, yet the specificity increased to 0.94. There is insufficient evidence regarding FeNO’s utility to predict asthma in patients between the ages of 0-4 with chronic wheezing. Regarding the utility during asthma management, the NAEPP 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. The studies showed the use of management algorithms that incorporate FeNO results reduce the risk of exacerbations, but had no effect on the risk of hospitalization, QOL, asthma control, or FEV1. The NAEPP 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 an ICS, an LTRA, or omalizumab (Xolair), but not in patients taking a long-acting ß agonist (LABA) (Wang et al., 2017).
A 2018 meta-analysis of over 13,000 patients found FeNO to be "moderately" accurate in patients five and older, but again results were more reliable in nonsmokers, patients 18 and under, 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). An alternative to sputum eosinophil analysis 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).
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).
In a study published in 2017 by Aaron et al., 613 adult patients across 10 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 PEF monitoring at home and asked to maintain a symptom diary. Participants were also tested using spirometry before and after the 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 had been diagnosed without the appropriate pulmonary function testing. In those 203 patients, medications were gradually weaned, and after one year, only six of those patients had a recurrence of their symptoms and a positive bronchial challenge test and required a restart of their medications. 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 PFT such as spirometry, ideally prior to and following administration of a bronchodilator medication to assess reversibility, serial PEF measurements, and/or bronchial challenge tests (Aaron et al., 2017).
Assessing for differential diagnosis (see Table 2 below) is extremely important in asthma, as many respiratory and even cardiac conditions 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).
References
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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. https://doi.org/10.1001/jamainternmed.2016.2436
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Wang, Z., Pianosi, P., Keogh, K., Zaiem, F., Alsawas, M., Alahdab, F., Almasri, J. M., Mohammed, K., Larrea-Mantilla, L., Farah, W., Daraz, L., Barrionuevo, P., Gunjal, S., Prokop, L. J., & Murad, M. H. (2017). The clinical utility of fractional exhaled nitric oxide (FeNO) in asthma management. Agency for Healthcare Research and Quality. https://doi.org/10.23970/AHRQEPCCER197
Weiler, J. M., Brannan, J. D., Randolph, C. C., Hallstrand, T. S., Parsons, J., Silvers, W., Storms, W, Zeiger, J., Bernstein, D. I., Blessing-Moore, J., Greenhawt, M., Khan, D., Lang, D., Nicklas, R. A., Oppenheimer, J, Portnoy, J. M., Schuller, D. E., Tilles, S. A., & Wallace, D. (2016). Exercise-induced bronchoconstriction update—2016. Journal of Allergy and Clinical Immunology, 138(5), 1292-1295.e36. https://doi.org/10.1016/j.jaci.2016.05.029
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