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The Practical Application of Allergic Trigger Management to Improve Asthma Outcomes: Step 1: Identify Patients with Allergic Components of Asthma.

Kim thought back through her recent asthma visit. She had mentioned her concern about "hay fever" and wondered if anything else was triggering her asthma attacks. She completed the intake sheet and circled some things she thought made her asthma worse--but no one had commented on any of them. Did she have allergies? And were they making her asthma worse? Her asthma was certainly causing problems, including missing sleep and work, and interfering with her ability to care for her children and family. What should she do next?


Kim's experience is not unusual. Although widely disseminated asthma-treatment guidelines are available, along with a variety of effective pharmacotherapies, most patients with asthma continue to have symptoms. Across all types of practices, almost half of adults with asthma (47%) report very poorly controlled asthma and another 24% report not well-controlled asthma. (1) Similarly, the prevalence of uncontrolled asthma in children with asthma in all practices is 46%. (2) In primary care practices, 63% of adults, 52% of adolescents, and 56% of children with asthma have inadequate asthma control. (3) Most people with asthma receive their care in a primary care setting, and most continue to have suboptimal control of symptoms and exacerbations. (3-7)

National and international guidelines strongly support the importance of evaluating and addressing environmental triggers that can make asthma worse and cause exacerbations. (8,9) The 2007 National Asthma Education and Prevention Program (NAEPP) US guidelines recommend evaluating the potential role of allergens, particularly indoor inhalant allergens. (8) This recommendation is considered "Evidence Category A" (ie, strong evidence from randomized controlled trials with a rich body of supportive data). (8) Since publication of these guidelines, additional compelling evidence has been published on the importance of recognizing and treating the allergic components of asthma. (10,11)


Asthma is a condition of hypersensitivity to common exposures, associated with chronic airway inflammation, bronchial hyperreactivity with increased mucus, and airway edema, obstruction, and narrowing. Symptom frequency and severity are variable, but the underlying inflammation and hyperreactivity of the airways are chronic and present even when a person "feels well." Over time, these symptoms may be associated with persistent narrowing and remodeling of the airways (FIGURE 1 (12)).


More than 80% of children and adolescents and 60% of adults (13,14) with asthma are sensitized to inhaled environmental allergens. Among all ages, 70% of patients with severe asthma are allergic. (15-17) There is a direct and causal relationship between allergic sensitization and asthma control and exacerbations. (18) For most people with asthma, hypersensitivity includes reactions to environmental exposures. Liu and colleagues summarized multiple pathways linked to asthma severity, including allergen sensitization (FIGURE 2). (19)

Long-term implications of inhaled allergen sensitization and exposure

In children, allergy is also a risk factor for asthma persistence (FIGURE 3 (20)). Only 10% of children with nonallergic asthma at age 5 years continue to have asthma by age 12 years. In contrast, approximately 50% of children with allergic asthma continue to have symptoms at age 12 years. (20) Early sensitization to multiple inhalant allergens (21-23) and sensitization combined with perennial exposure in the home in early life (24) predict asthma persistence, exacerbation, and lung dysfunction.

In sensitized children, adolescents, and adults, exposure to allergic triggers is associated with an increase in asthma symptoms, decreased lung function, and recurring asthma exacerbations, in addition, those with multiple inhaled allergen sensitizations are at increased risk of worse control, often resulting in sick visits to the office and visits to urgent care and the emergency department (ED), (25) as well as hospitalizations (FIGURE 4). (26) The number of asthma triggers a patient has is associated with the risk of exacerbations, more severe exacerbations, and poorer quality of life. (18)

Although viral infection is a common trigger for asthma exacerbations, especially in younger children, recent data demonstrate that allergen sensitization results in a significant increased risk of asthma exacerbation when there is a combination of allergen sensitization, exposure, and viral infection (FIGURE 4 (26)). The allergic phenotype of asthma is associated with an impaired innate immune response to respiratory viral infection, mediated through immunoglobulin E (IgE). The link between viral infections and allergen sensitization is confirmed by the decreased risk of asthma exacerbation due to viral upper respiratory infection (URI) when IgE-directed therapy is prescribed for sensitized or "allergic" children and adolescents. (27,28)

The role of serum IgE

Total IgE levels have been used as an indicator of allergic asthma. Although higher levels of total serum IgE have been associated with poorer asthma outcomes (29,30) and higher health care costs, (31) these levels are variable, affected by genetics, race, cigarette smoking, and steroid use, and are, therefore, not a reliable indicator of allergen sensitization and not a substitute for specific IgE allergen testing. Significant allergy may exist with low or "normal" total IgE levels, and higher total IgE levels may exist without any significant specific allergic sensitization. Increasingly, overall allergen sensitization is being recognized as a major factor in asthma across all age groups and all levels of asthma severity. (32)

Asthma phenotypes

Recent evidence demonstrates that the common exacerbation-prone phenotype in US inner city children with asthma, representing 16% of these children, included sensitization to most common inhalant allergens for which they were tested (a mean of 14 sensitizations from a 22-allergen panel). (33) This indicates that exacerbation-prone asthmatic children are typically highly allergic to their environ ment. In the Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study, there was a direct relationship between the number of allergens to which adults, adolescents, and children were sensitized and their rates of exacerbations, the severity of those exacerbations, and the person's asthma-related quality of life. (32)

Zoratti and colleagues distinguished 5 potential asthma phenotypes (A, B, C, D, and E) in US inner city children, with asthma severity burdens ranging from minimal to high (FIGURE 5). (33) Children with phenotypes C, D, and E demonstrate progressively greater allergen sensitization and increasingly worse clinical conditions, likely representing classic T-helper type 2-driven allergic asthma. These allergic phenotypes also represent 70% of the study population and exhibit striking parallel relationships between allergic sensitization and indicators of asthma severity. Compatible with this picture of allergen-driven asthma, phenotype A represents the group with low sensitization levels and low asthma burden. Only phenotype B appears to highlight other non-allergic mechanisms of asthma that may result in significant asthma symptom burden.


Three-quarters of people with asthma receive care in a primary care practice. (34) These people and their families continue to experience a significant asthma-related disease burden, with over 10.5 million offices visits, most of which are unscheduled and in primary care offices, added to 1.8 million ED visits and more than 400,000 hospitalizations annually. (12,35,36) Three of every 5 children and more than half of adults with asthma have had their life disrupted by the need to seek urgent or emergency care for their asthma each year. (37) About 10% of people with asthma have severe asthma, resulting in several urgent and emergency visits and a high risk of asthma-related hospitalization, in addition to missed school, work, and activity days. (38,39) Several studies have demonstrated that this continuing asthma burden is not simply the basis for prescribing more asthma medications; further evaluation should be undertaken.

Allergen avoidance and abatement (eg, environmental control), as well as allergy treatments such as immunotherapy (subcutaneous or sublingual), require identification of allergen sensitization. Particularly in children, allergy avoidance and immunotherapy have improved asthma control with decreased symptoms, decreased exacerbations, and decreased oral and inhaled corticosteroid(s) use. (40) Yet allergy evaluation was only discussed in about 33% of primary care office visits for asthma, and allergy testing was only documented in 2% of cases of asthma over the course of a year. (3) Several questionnaires to assess asthma control are available (FIGURE 6). A newly published study is the first to find that introducing an asthma tool--the Asthma APGAR Plus--into primary care practices improves patient and practice outcomes. (7) The Asthma APGAR Plus is the only tool that includes a brief patient query regarding allergies and triggers, designed to facilitate discussion of allergens and need for further allergy evaluation with patients. Using a tool to assess potential "allergies" is the first step in allergy evaluation, which often requires investigation and care over a number of visits, an important hallmark of the continuity of primary care.


All patients who have been given a diagnosis of persistent asthma should be evaluated to identify their allergic triggers. But this recommendation is not typically implemented in the primary care setting, where there are concerns about limited time, cost, and patient burden. A more practical approach is to identify the specific patient groups most likely to benefit from evaluation of the potential allergic contribution to asthma burden (FIGURE 7).

1. Patients of any age who continue to have high asthma burden or high risk despite treatment,

a. A severe exacerbation requiring hospitalization

b. Two or more ED asthma visits a year resulting in treatment with systemic corticosteroids, such as prednisone and dexamethasone

c. Prescribed step-4 or step-5 asthma treatment, which includes high-dose ICS

d. Those whose primary care clinician may consider them a potential candidate for biologic therapy but who have not yet had an allergy evaluation.

In this high-burden/high-risk asthma group, diagnostic testing for inhalant allergen sensitization can help identify people with high-risk asthma who are highly allergic; identify specific allergen exposures that can underlie their high asthma burden; and identify those who may benefit from specific asthma therapies to reduce their asthma burden, lower the risk of future exacerbation, limit the risk of side effects from high-dose ICS, and limit the morbidity and mortality of future exacerbations and the side-effects of "bursts" of oral corticosteroids (OCS) used to treat them.
FIGURE 7 Patients in need of an allergy evaluation

Patients of any age experiencing a high asthma burden or high risk
despite treatment

* An asthma-related hospitalization or 2 or more emergency
department visits

* Step 4 or higher medication regimen

* Potential candidate for biologics

Young children with recurrent cough/wheeze symptoms to help predict
the likelihood of asthma persistence beyond 6 years.

Patients of any age meeting the asthma "Rules of 2" criteria while
on therapy

* >2 days/week of symptoms or quick relief inhaler use

* >2 nights/month of nighttime asthma symptoms

* [greater than or equal to] 2 asthma exacerbations/year (episodes
resulting in a burst of oral steroids) or >2 rescue albuterol inhaler
fills/refills per year

Rules of Two[R] is a registered trademark of Baylor Health Care
System. Adapted from: Millard et al. Proc (Bay! Univ Med Cent).

2. Young children with recurrent cough/wheeze symptoms to help predict their likelihood of persistence of "asthma" beyond age 6 years.

Inhalant allergen sensitization, atopic dermatitis, allergic rhinitis, and parental asthma are key risk factors to predict which preschoolers with recurrent respiratory symptoms, such as cough and wheeze, are most likely to develop persistent asthma. Allergen sensitization cannot be adequately assessed by history and physical exam alone. Diagnosing specific inhalant allergen sensitizations in at-risk children identifies those who are most likely to develop persistent asthma and allows opportunities for designing allergen-avoidance strategies that may improve outcomes.

3. Patients of any age meeting any of the asthma Rules of Two[R]* criteria while on daily controller or maintenance therapy.

a. Having >2 days/week of asthma symptoms or quick relief inhaler use

b. Having >2 nights/month of nighttime asthma symptoms

c. Having [greater than or equal to] 2 asthma exacerbations/year resulting in a burst ofOCS

d. Requiring >2 rescue albuterol inhaler fills/refills a year not when used just to cover different sites such as home/school/daycare/office.

* Registered trademark of Baylor Health Care System. Adapted from: Millard et al. Proc (Bayl Univ Med Cent). 2014;27(2):79-82.

The presence of daytime and/or nighttime symptoms and/ or the need for additional medication prompts the need for additional management. Diagnostic testing for inhalant allergen sensitization can identify specific allergen exposures that, when treated, may allow a step-down in high-dosage ICS therapy and may identify patients with asthma who may benefit from specific asthma therapies to reduce their asthma burden and risk of future exacerbations.


When exacerbations or out-of-control symptoms are recognized, a common approach is to simply add more medications, which is often expensive and ineffective. (4) Before considering any additional therapy, it is important that patients are receiving the prescribed therapy at the target site. High asthma burden is not necessarily a deficiency of prescribed pharmacotherapy. Two issues should always be addressed before adding more inhalers:

* Is the patient taking the medications?

* Are the medications getting into the lungs?

Nonadherence is a common problem that we discuss in the next article. Inadequate inhaler technique is also common and must be addressed by selecting inhaler or drug delivery devices tailored to the patient's age and capabilities. (3,41) After selecting the appropriate device, teaching, observing, and reassessing proper inhaler technique regularly can enhance drug delivery and improve unintentional nonadherence, decreasing symptom and exacerbation burden.

For many people with asthma, addressing adherence and inhaler technique fails to mitigate the underlying cause of bronchial hyperreactivity: the inflammatory response to allergic triggers. Identification of allergens to which the patient is sensitized and attempts to decrease allergen impact are also needed. (3) NAEPP guidelines (8) and the NAEPP Guideline Implementation Panel (42) recommend determining the patient's exposure to allergens, assessing sensitization from the medical history and skin or in vitro testing, and interpreting positive results in the context of the patient's medical history. (8) Accordingly, incorporating allergen identification into routine asthma management is the main goal of this supplement.


Assessing and dealing with asthma-related allergies can help prevent airway remodeling, reduce children's and adolescents' days of wheezing and asthma-related hospitalizations, and, in adults, reduce the necessity for quickrelief medications and nighttime awakenings. Although all people with asthma may be an appropriate candidate for aeroallergen sensitization assessment, the groups with the highest likelihood of benefit are those with high asthma burden, an uncertain asthma future, and uncontrolled symptoms.

Kim came into the office after another visit to the ED last month, where she was again given a diagnosis of "bronchitis," given oral corticosteroids plus antibiotics, and told to take her asthma medications regularly. The pharmacy filled the prescriptions from the ED, but told her that the usual asthma prescriptions were too old to refill and her children's prescriptions could not be refilled either, so she had no source of medication and is wheezing and short of breath again.

Today, Kim's Asthma APGAR score is 4--confirming her out-of-control asthma. She circled several triggers, including tobacco smoke, pets, and seasonal issues. She noted her incomplete adherence, due primarily to cost and lack of a current prescription for the asthma medications, and further reported that her asthma medications were only "somewhat helpful" even when used. Your diagnosis is difficult-to-control asthma, due to issues of adherence and unidentified triggers that have not been addressed. She asks you about allergies.

Kim and you agree to her continued use of daily moderate-strength ICS, combined with a long-acting beta-agonist bronchodilator. Upon review of inhaler technique, the medical assistant noted some errors that were corrected; final observation demonstrated adequate inhaler technique. Following discussion of Kim's suspected allergies and your expressed concerns about the potential impact of allergies on her asthma symptoms and exacerbations, she agrees to have the blood test for possible allergen sensitization but declines to visit an allergist at this time, due to concerns about getting time off work and visiting yet another physician. As Kim makes an appointment to return to review the allergy test results, she comments to your receptionist, "She is the first doctor who has bothered to listen to me about my asthma and allergies. I will give her another try."

Given the importance of allergens to asthma morbidity and asthma management, patients with persistent asthma should be evaluated for the role of allergens as possible contributing factors. -NAEPP. GUIDELINES FOR THE DIAGNOSIS AND MANAGEMENT OF ASTHMA (EPR-3) (8)

Please Note: Illustration(s) are not available due to copyright restrictions.

Andrew Liu, MD; Allan Luskin, MD; Randall Brown, MD, MPH, AE-C; Michael D. Cabana, MD, MPH; Ivor Emanuel, MD; Len Fromer, MD, FAAFP; Christine W. Wagner, APRN, MSN, AE-C; Barbara P. Yawn, MD, MSc, FAAFP


Dr. Liu discloses that he is a consultant for Thermo Fisher Scientific.

Dr. Luskin has no conflicts to disclose.

Dr. Brown reports that he is on the Board of Directors for Allergy and Asthma Network; an advisor and speaker for AstraZeneca; a speaker for Circassia Pharmaceuticals plc; a speaker for Integrity Continuing Education Inc.; an advisor for Novartis AG; a speaker for Teva Pharmaceutical Industries Ltd.; and an advisor for Thermo Fisher Scientific.

Dr. Cabana is on the Merck Speakers Bureau and consults with Novartis AG, Genentech, Inc. and Thermo Fisher Scientific.

Dr. Emanuel has an ongoing relationship with Thermo Fisher Scientific.

Dr. Fromer has been a consultant and speaker for Thermo Fisher Scientific in the recent past.

Christine W. Wagner has an ongoing relationship with Thermo Fisher Scientific.

Dr. Yawn is a paid consultant and has an ongoing relationship with Thermo Fisher Scientific.


The Task Force appreciates the editorial support provided by Sarah Staples, whose work was financially supported by Thermo Fisher Scientific. The Task Force also acknowledges and appreciates the important logistical support provided by Kevin H. TenBrink and Gabriel Ortiz of Thermo Fisher Scientific.


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Please Note: Illustration(s) are not available due to copyright restrictions.

Caption: FIGURE 1 Airway remodeling caused by asthma-associated inflammation (12)

Caption: FIGURE 2 Pathways by which asthma risk factors contribute to asthma severity (19)

Caption: FIGURE 3 Children with persistent wheeze and inhalant allergies in preschool life are more likely to develop persistent asthma (20)

Caption: FIGURE 6 Assessment tools for asthma symptom control
FIGURE 4 Allergen sensitization, exposure, and viral infection greatly
increase the risk for asthma hospital admissions (26)

                                   Risk Factors

Sensitization, Exposure,
and Viral Infection                 19.4

Sensitization and Viral Infection    8.9

Viral Infection                      3.2

Sensitization and Exposure           2.6

Sensitization                        1.8

Odds Ratios

The risk (odds ratio) of severe asthma exacerbations resulting in
hospitalization increases across groups of patients experiencing
allergen sensitization, sensitization with exposure to allergen,
viral infection (upper respiratory infection), and combinations of
these factors.

Note: Table made from bar graph.

FIGURE 5 Children with high asthma burden are
highly allergic to their environment (33)

Asthma Phenotypes (N=616)

                         A (15%)   B (15%)        C (24%)

Asthma symptoms          Minimal   High           Minimal

Lung function/           Normal    Mild           Minimal

Allergen sensitization   1         2              9
(no. of positive tests
in 22-allergen panel)

Step in asthma           1.39      4.2            1.93
medication plan *

Rhinitis symptom         Minimal   Intermediate   Minimal

Asthma Phenotypes (N=616)

                         D (30%)        E (16%)

Asthma symptoms          Minimal        Highest

Lung function/           Intermediate   Most

Allergen sensitization   13             14
(no. of positive tests
in 22-allergen panel)

Step in asthma           3.4            4.7
medication plan *

Rhinitis symptom         High           High

* For a full description of asthma medication steps,
refer to pages 46-52 of the EPR-3 Summary Report 2007. (8)
The higher the step number (from 1 to 6), the more
intense the medication regimen.

Reprinted from Zoratti, et al. Asthma phenotypes in
inner-city children. J Allergy Clin Immunol.
[R] 2016 with permission from Elsevier.
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Author:Liu, Andrew; Luskin, Allan; Brown, Randall; Cabana, Michael D.; Emanuel, Ivor; Fromer, Len; Wagner,
Publication:Pediatric News
Date:Sep 1, 2018
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