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Practical Considerations for Moderate to Severe Asthma, Part 1: Management, Biomarkers, and When to Refer

Key Points
  • Asthma affects approximately 8% of the general population in the United States.
    • Severe, poorly controlled asthma affects approximately 5% to 10% of all patients with asthma and is associated with increased morbidity and mortality and impaired quality of life.
  • In addition to recommended pharmacologic treatment, key components of patient care include repeated evaluation for inhaler technique and adjustment of maintenance medicines, when needed, as well as identification of environmental risks.
    • In their role as both educators and clinicians, nurse practitioners and physician assistants have an essential role in performing these services.
  • For patients with moderate to severe asthma that is poorly controlled with inhaled corticosteroid/long-acting β2-agonist treatment, the most appropriate course of action may be referral to an asthma specialist.
  • The goal of this newsletter is to provide practical guidance for identifying patients with poorly controlled asthma who should be referred to an asthma specialist for further evaluation and possible biologic therapy.


Introduction

Asthma is a heterogeneous disease where patients may present with varying symptoms, such as expiratory wheezing, dyspnea, or coughing, and clinical features, such as airflow limitation, with varying intensity over time.1 Approximately 8% of the general population in the United States has asthma.2 Among patients with asthma, it is estimated that 5% to 10% have asthma that is severe or difficult to treat and poorly controlled.3,4 This may be due in part to poor adherence to treatment regimens, the rates of which range from 30% to 70%.5 Uncontrolled asthma can lead to increased morbidity and mortality, impaired quality of life, and increased absenteeism from work and school.6-8 In contrast, controlled asthma is associated with decreased morbidity, improved quality of life, increased productivity, and improved health outcomes,6,9 as well as decreased health care costs.8

Nurse practitioners (NPs) and physician assistants (PAs) have essential roles in patient care, educating patients about the importance of asthma control as well as performing or ordering tests and prescribing appropriate medications. The NP and PA also coordinate medical care and encourage self-monitoring and treatment adherence. However, for the patient with poorly controlled, moderate to severe asthma, the most appropriate course of action may be referral to a pulmonologist or allergist for further evaluation.1,6 The goal of this newsletter is to provide guidance to NPs and PAs on the identification and treatment of patients with poorly controlled, moderate to severe asthma and when referral to an asthma specialist is appropriate.

The Burden of Uncontrolled Moderate to Severe Asthma

Based on data from the US 2006-2010 National Health Interview Survey, more than 50% of respondents with current asthma reported having had an exacerbation within the previous year.10 Overall, approximately 5% to 10% of all patients with asthma in the United States have severe asthma that is not well controlled.3,4 Asthma affects numerous aspects of daily life including sleep, work, and exercise; patients with severe asthma are at high risk for future severe exacerbations and death.11

Asthma control and severity may be viewed as separate but interrelated aspects of asthma management.8 The European Network for Understanding Mechanisms of Severe Asthma (ENFUMOSA) study evaluated outcomes in patients with severe asthma (defined as ≥1 exacerbation in the previous year despite high doses of corticosteroids [≥1200 μg/day budesonide or beclomethasone or equivalent]) relative to patients with controlled asthma (no asthma exacerbation in the previous year on a maximum of 1000 μg/day budesonide or beclomethasone or equivalent). Among patients with severe asthma, 40% had been hospitalized in the previous year despite intensive therapy (in addition to high-dose inhaled corticosteroids [ICS], 96% of these patients also received long-acting β2-agonists [LABAs] and 33% required regular oral corticosteroid therapy).12 The authors suggested that severe asthma may represent a different form of asthma, rather than a mere intensification of symptoms12; the severe asthma group had similar age and asthma duration, but less atopy (based on age- and sex-adjusted immunoglobulin E [IgE] levels and skin prick tests), greater presence of sputum neutrophils, and worse lung function compared with those with controlled asthma.12

There are quantitative differences observed in lung function between patients with mild to moderate asthma and patients with severe asthma.13 In the US-based TENOR (The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens) study, which evaluated patients with severe or difficult-to-treat asthma (as described by their physicians), the relationship between lung function (based on forced expiratory volume in 1 second [FEV1]) and asthma burden was assessed.14 Health care utilization was greatest and the number of missed days of work or school was highest in patients with lower FEV1 values (Figure 1).14,15 Other observations from the TENOR study included an inverse relationship between total serum IgE levels and FEV1/forced vital capacity ratio, and a greater likelihood for patients with positive skin tests for common allergens to report dust, pollen, and animals as asthma triggers; the strongest risk factor for future exacerbations was previous exacerbation history.14 In contrast, the ENFUMOSA study found that atopy was a relatively weak risk factor for the development of severe asthma and, by definition, future exacerbations.12,16

Figure 1: Healthcare use and missed days from work/school according to asthma severity in patients with severe or difficult-to-treat asthma15

In a cohort of 4756 patients from the TENOR study,15 use of asthma-related healthcare and school/work days missed were associated with degree of asthma severity, as assessed independently by physicians.
Mild, ≥80% predicted forced expiratory volume in 1 second (FEV1); moderate, >60 to <80% predicted FEV1; severe, ≤60% predicted FEV1. *P <0.05 for difference among severity groups.
Source: Dolan CM, Fraher KE, Bleecker ER, et al; for the TENOR Study Group. Design and baseline characteristics of The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study: a large cohort of patients with severe or difficult-to-treat asthma. Ann Allergy Asthma Immunol. 2004;92(1):32-39, with permission from Elsevier.

It should be noted that there is no general agreement among practitioners regarding what constitutes severe, uncontrolled asthma. Although the severity and control of asthma overlap, the terms should not be used interchangeably.17 Severity of asthma should be defined by the level of treatment needed to control symptoms. Control of asthma is best described as the decrease or resolution of symptoms.17 Evaluation of asthma control includes not only current symptoms, pulmonary function, and medication requirements, but also the reduction of future exacerbation risk, decline in lung function, and economic burden. The use of biomarkers in the treatment of asthma guides the practitioner’s decisions regarding treatment.17 Biomarkers identify the patient’s phenotype, which can indicate airway inflammation and reactivity and can predispose the patient to increased severity of asthma and a decrease in control.17

Regardless of asthma severity, uncontrolled asthma results in substantial economic burden. Costs associated with asthma increase directly with the number of parameters considered in controlling asthma (eg, daytime symptoms, nighttime awakenings, and loss of productivity at work or in school).8 Costs for uncontrolled asthma are approximately double those for controlled asthma.8 Even for mild to moderate asthma, the additional cost for uncontrolled asthma was found to be increased by over 60% compared with controlled asthma.18

Case Study – Part 1

Al is a married man in his mid-40s who has had asthma since early adulthood. Al never smoked, nor lived with anyone who smoked. He’s been on medium-dose ICS for several years, which had controlled his asthma adequately. For the past several months, his asthma has not responded well to treatment, and he has needed to use his rescue inhaler nearly daily since the start of spring. Al comes to your practice for evaluation of his asthma.

As part of the visit, Al’s full history was reviewed. There were no significant changes in Al’s life (ie, no divorce, job change). Al reported he noticed the onset of more intense symptoms with the arrival of spring and, consequently, an increase in use of his rescue inhaler. Al had expiratory wheezing, reported shortness of breath, and described feeling pressure in his chest; this has been ongoing for several months. On physical examination, a prolonged expiratory phase was noted.

Spirometry testing was performed, which showed an obstructive pattern and that Al’s FEV1 was 70% of predicted, which is decreased from his previous value of 90% at his last routine assessment. An asthma control test (ACT) was completed, showing a score of 16, indicating asthma is not well controlled. Proper inhaler technique and adherence to treatment regimen were confirmed with Al. Based on the spirometry data and clinical findings, Al’s treatment regimen was changed to medium-dose ICS/LABA plus a 7-day burst of oral prednisone, with recommended follow-up in 2 to 4 weeks.

Note: This is a hypothetical case description for teaching purposes.

Diagnosing Severe Asthma: Guideline Recommendations for Patients With Moderate
to Severe Asthma

The American Thoracic Society (ATS) defines severe asthma as a disease difficult to control despite high-dose ICS maintenance therapy or continuous oral corticosteroids.19 This differs from the definition used by the ATS/European Respiratory Society4 and the Global Initiative for Asthma,1 which make a clear distinction between severe asthma and asthma that is difficult to control. According to the ATS guidelines, patients must have required treatment with oral corticosteroids ≥50% of the previous year and/or required treatment with high-dose ICS, as well as satisfied 2 out of 7 of the following criteria for a diagnosis of severe/refractory asthma19:

  1. Requiring additional controller medication daily (eg, LABA);
  2. Requiring short-acting β2-agonist daily or nearly daily;
  3. FEV1 consistently <80% predicted;
  4. At least 1 urgent care visit for asthma per year;
  5. At least 3 oral steroid bursts per year;
  6. Prompt deterioration upon ≤25% reduction in oral corticosteroid or ICS dose;
  7. Near-fatal asthma event in the past.

The treatment guidelines from The National Asthma Education and Prevention Program (NAEPP) for moderate to severe, poorly controlled asthma are summarized in Table 1.16 As part of the treatment plan, assessing asthma severity should include consideration of the risk of future exacerbations based on prior history.16 Spirometry is used most often to assess future risk of progressive loss of pulmonary function.16 The continual review and assessment of the patient’s asthma control is essential to prevent future exacerbations.1 The ATS recommends the use of high-dose ICS plus a second controller such as a LABA to prevent severe asthma from becoming uncontrolled,4 although they are not discussed as fixed combinations. Adherence to treatment schedule should be assessed, as estimates for nonadherence may be as high as 70% for “difficult-to-treat” asthma.5 After reviewing with the patient, it may be necessary to change or add new treatments to their plan. For guidance purposes, Table 2 describes the recommended thresholds for well-controlled, not well-controlled, and very poorly controlled asthma.16

Table 1. Pharmacologic management of moderate to severe asthma for patients ≥12 years of age16,a

Asthma Severity

Preferred Drugs

Alternative/Adjunct Treatment

Moderate
(Step 3)


  • Low-dose ICS/LABA
  • Medium-dose ICS

 

  • Low-dose ICS + LTRA or theophylline or 5-LO inhibitor zileuton
  • Consider subcutaneous allergen immunotherapy for patients with allergic asthma
  • Consider referral to an asthma specialist

Severe
(Step 4)

 

  • Medium-dose ICS/LABA

 

  • Medium-dose ICS + LTRA or theophylline or 5-LO inhibitor zileuton
  • Consider subcutaneous allergen immunotherapy for patients with allergic asthma
  • Referral to an asthma specialist is recommended

Severe
(Step 5)

  • High-dose ICS/LABA
  • Consider adding a biologic agent in appropriate patients
  • Referral to an asthma specialist is recommended

Severe, not well controlled
(Step 6)

  • High-dose ICS/LABA + oral corticosteroidsb
  • Consider adding a biologic agent in appropriate patients
  • Referral to an asthma specialist is recommended

aSeverity level is determined at diagnosis or when patient is not taking controller medication.
bLong-term systemic corticosteroids taken as maintenance therapy, not as a steroid burst.
For all patients: A SABA may be used as needed (up to 3 treatments at 20-minute intervals) for rapid relief of symptoms as needed; a short course of oral corticosteroids may be needed. If SABA use exceeds 2 days per week (not including relief of exercise-induced bronchospasm), lack of asthma control should be investigated, and patient advanced to next treatment step.
Abbreviations: 5-LO, 5-lipoxygenase; ICS, inhaled corticosteroids; LABA, long-acting β2-agonist; LTRA, leukotriene receptor antagonist; SABA, short-acting β2-agonist.

Table 2. Assessing asthma control in patients ≥12 years of age16,a

    

Components of Control

Classification of Asthma Control

Well
Controlled

Not Well
Controlled

Very Poorly Controlled

Impairment

Symptoms

≤2 days/week

>2 days/week

Throughout the day

Nighttime awakening

≤2 times/month

1-3 times/week

≥4 times/week

Interference with normal activities

None

Some limitation

Extremely limited

SABA use for symptom control (not prevention of EIB)

≤2 days/week

>2 days/week

Several times/day

FEV1 or peak flow

>80% predicted/
personal best

60%-80% predicted/
personal best

<60% predicted/
personal best

Validated questionnaires
    ATAQ
    ACQ
    ACT


0
≤0.75b
≥20


1-2
≥1.5
16-19


3-4
N/A
≤15

Risk

Exacerbations

0–1/year

≥2/yearc

Consider severity and interval since last exacerbation

Progressive loss of lung function

Evaluation requires long-term follow-up care

Treatment-related adverse events

Medication side effects can vary in intensity from none to very troublesome and worrisome. The level of intensity does not correlate to specific levels of control but should be considered in the overall assessment of risk

aControl assessment made when patient is taking daily maintenance medication.
bACQ values of 0.76 to 1.4 are indeterminate regarding well-controlled asthma.
cExacerbations do not have an exact correlation to level of asthma control.
Abbreviations: ACQ, asthma control questionnaire; ACT, asthma control test; ATAQ, asthma therapy assessment questionnaire;
EIB, exercise-induced bronchospasm; FEV1, forced expiratory volume in 1 second; N/A, not applicable; SABA, short-acting β2-agonist.

Case Study – Part 2

At the follow-up visit, Al reported improvement while on prednisone, but his asthma was still not well controlled on the new treatment regimen (ACT score at this visit was 17) and his FEV1 was still abnormal at 70%.

Two biomarkers for which testing was available—blood eosinophil and IgE levels—were evaluated. Blood eosinophil count was found to be elevated at 340 cells/µL. IgE level was 30 IU/mL. A referral was made to an asthma and allergy specialist for further evaluation, which would include specific allergen skin testing, pulmonary function testing with reversibility testing, exhaled nitric oxide, and additional assessments for possible comorbidities (eg, upper airway obstruction, pulmonary emboli), as well as possible adjunct treatment with a biologic agent. While awaiting referral, Al’s ICS/LABA was increased from medium- to high-dose in order to optimize therapy prior to specialist determination of the appropriateness of biologic therapy.

Note: This is a hypothetical case description for teaching purposes.

Beyond ICS and LABA, there are other approved drugs to be considered. The long-acting muscarinic antagonist tiotropium has been approved for the long-term, once-daily, maintenance treatment of asthma in patients ≥12 years of age.1,20 Novel biologics may be considered as adjunct to ICS/LABA therapy for poorly controlled, severe asthma21,22; these will be the focus of the next newsletter.

Assessment of Asthma Control

The NAEPP published guidelines for assessing asthma control.16 In brief, assessment consists of the following
key measures:

  • Signs and symptoms;
  • Pulmonary function;
  • Quality of life;
  • History of exacerbations;
  • Response to pharmacotherapy;
  • Communication between patient and provider.

Patients or their caregivers should be encouraged to use self-assessment tools, such as diaries or questionnaires.16 In addition, the guidelines recommend that the frequency of visits to a clinician be made according to the judgment of the clinician.16

Role of the NP and PA in Managing Patients With Moderate to Severe Asthma That Is Poorly Controlled

The major goal of asthma treatment should be the effective management of symptoms, in which NPs and PAs can have significant roles. In that regard, the role of the NP in asthma management has been described by a number of real-world and clinical studies that exemplify NPs as key primary providers and educators for asthma management, ultimately leading to favorable patient outcomes.6 In particular, NPs play a significant role in encouraging asthma self-management.6 A partnership between patients and caregivers is an important aspect of effective management.1 A study of 235 patients showed patients had high satisfaction with the education they received from NPs, and up to 50% of patients either preferred NPs or had no preference between NPs and physicians for education and routine aspects of visits.23 A qualitative study in the United Kingdom showed NPs (clinical nurse specialists in local terminology) were particularly effective where they had some autonomy and where asthma care was a priority.24 Overall, patients who responded to the study questionnaire found NPs to be approachable and informative.24 Although similar data are not available to describe the role of the PA in asthma management, PAs also play an essential role in patient education and optimizing care for patients with asthma.25

Table 3 shows what a working partnership between a primary care provider (eg, NP or PA) and a patient with asthma needing management might look like.1 For example, the NP and PA should work with the patient to ensure the inhaler device is being used properly. If appropriate, the NP or PA might recommend using a spacer or valve-holding device with the inhaler device.16 Spacers and valve-holding devices are sometimes used with metered-dose inhalers to prevent deposition of large particles in the oropharynx; they facilitate deposition of smaller particles in the lungs.16 Unlike spacers, valve-holding devices contain one-way valves, thereby preventing exhalation into the device. These devices obviate the need for hand-breath coordination and, thus, are preferred for children or anyone who has difficulty coordinating hand and breath.16 The NP/PA should invite the patient to share in deciding how to manage asthma treatment, as patient participation in asthma treatment decisions has been shown to result in greater adherence than treatment determined solely by the clinician.5 Furthermore, the NP/PA should teach the patient how to prevent common side effects associated with use of ICS (eg, oral candidiasis).16 For example, oral rinsing after ICS is commonly recommended to prevent the development of candidiasis.

Finally, the patient should be referred to an asthma and allergy specialist to treat poorly controlled, moderate to severe asthma for titrating doses, especially of oral corticosteroids, and/or for biomarker testing to help decide next steps, such as the addition of a biologic agent.16 Criteria for referral to a specialist are summarized in Table 4.6

Table 3. Role of the NP and PA in identifying and evaluating patients with poor asthma symptom control despite treatment1

1. Confirm the diagnosis
of asthma

  • If there is no evidence of variable airflow limitation on spirometry or other testing, consider reducing the ICS dose by half and repeating lung function testing after 2-3 weeks; check that the patient has an asthma action plan. Consider referring the patient for a methacholine challenge test

2. Watch patient use the inhaler device and instruct regarding inhaler technique as needed

Discuss adherence and barriers to use

  • Watch patient use the inhaler device(s), verify against inhaler checklist. Demonstrate the correct method if necessary, and recheck as needed. Recheck each visit
  • Discuss with the patient ways to improve adherence to prescribed medicines; discuss inhaler technique and
    medication schedule
  • Ask about the patient’s beliefs with regard to medication, whether cost of medications is a burden, and whether the patient is refilling on time
  • Check with pharmacy to determine if there have been appropriate refills of controller medication

3. If possible, remove potential risk factors

Assess and manage comorbidities if feasible

  • Check for risk factors or inducers such as smoking, β-blocker use, or allergen exposure. Address these where possible
  • Check for and manage comorbidities (eg, rhinitis, obesity, GERD, obstructive sleep apnea, depression/anxiety) that may contribute to symptoms
  • Check for upper airway abnormalities as detected via the inspiratory component of the flow volume loop from spirometry

4. Consider treatment
step-upa

  • Consider stepping up treatment to the next level or using an alternative option at the current level
  • Use shared decision-making, balancing potential
    benefits and risks

5. Refer to a specialist

  • Refer if asthma remains uncontrolled after 3-6 months on high-dose ICS + LABA, or in the presence of risk factors
  • Refer earlier than 6 months if the asthma is very severe or difficult to manage, or if there are doubts about the diagnosis
  • Refer if upper airway abnormalities are detected via the inspiratory component of the flow volume loop from spirometry
  • Refer to Table 4 (below) for additional information

aIt is possible to refer patient to a specialist for further evaluation and treatment recommendations prior to stepping up treatment.
Abbreviations: GERD, gastroesophageal reflux disease; ICS, inhaled corticosteroid; LABA, long-acting β2-agonist; NP, nurse practitioner; PA, physician assistant.

Table 4. Criteria for referral of patients with difficult-to-treat or poorly controlled asthma to a specialist6

Patients should be referred if they meet any of the following criteria:

  • Asthma is difficult to treat or poorly controlled
  • >2 oral corticosteroid bursts per year needed
  • Exacerbations have required hospitalization
  • Therapy at step 4 (see Table 1) or higher required to achieve adequate asthma control
  • Therapy with a biologic under consideration
  • Additional testing needed

Republished with permission of Dove Medical Press, from Helping patients attain and maintain asthma control: reviewing the role of the nurse practitioner, Rance KS, 4, 2011; permission conveyed through Copyright Clearance Center, Inc.

Conclusions

NPs and PAs have key roles in educating and managing patients with poorly controlled, moderate to severe asthma. They perform some of the essential asthma control testing to guide treatment, instruct patients in proper inhaler technique, and assess/discuss adherence to a prescribed asthma treatment regimen. For appropriate management of poorly controlled, moderate to severe asthma despite treatment, the NP/PA should refer patients to an asthma specialist. The specialist may perform IgE testing and evaluation of biomarkers (eg, eosinophil counts) to help determine the optimal evidence-based treatment, which could include biologic therapy for appropriate patients. Such patients include those on medium to high doses of ICS/LABA, who may have also had other agents added to their regimens, such as theophylline, tiotropium, or a leukotriene receptor antagonist.1 The next newsletter will focus on specific biologics for the treatment of moderate to severe asthma that is poorly controlled once the patient has been evaluated by an asthma specialist.

References

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  16. National Heart, Lung, and Blood Institute. National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for the diagnosis and management of asthma. 2007. http://www.nhlbi.nih.gov/health-pro/guidelines/current/asthma-guidelines/full-report. Accessed May 2, 2017.
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