Summary of EPR-4 and GINA Asthma Guidelines for Professionals

The National Heart Lung and Blood Institute (NHLBI) convened the National Asthma Education and Prevention Program (NAEPP) Expert Panel 4 (EPR-4) Working Group in 2018 to update asthma treatment guidelines.  The NHLBI asthma guidelines were first developed in 2007. Since then, there has been considerable progress in asthma diagnosis, management and treatment. NHLBI released a focused update to their asthma guidelines in 2020. It included data through 2016.

The Global Initiative for Asthma (GINA) released their own asthma treatment report in 2020 using data through 2019.

NHLBI EPR-4 Asthma Guidelines 2020

The EPR-4 updates included 19 recommendations. While these asthma guidelines were recommended by the EPR-4, they do vary from some of the GINA asthma report. The topics explored were:

• Intermittent inhaled steroids
• Long-acting muscarinic antagonists
• Indoor allergy relief
• Immunotherapy in the treatment of allergic asthma
• Fractional exhaled nitrous oxide (FeNO) testing
• Bronchial thermoplasty

Intermittent Inhaled Steroids

• Intermittent use of inhaled corticosteroids (ICS) for children ages 0 to 4, with a current wheeze triggered by respiratory infections only and no wheezing in between. The expert panel conditionally recommends a short course of daily ICS at the first onset of respiratory tract infection with a long-acting beta agonist. This is a conditional recommendation with high certainty.
• ICS in individuals 12 years of age and older with mild persistent asthma. Either of the following two treatments are recommended as part of step two therapy:
  • A daily low dose inhaled corticosteroid with as needed SABA (short acting beta agonist) for quick relief. (GINA no longer recommends SABA by itself)
  • Intermittent use of as needed ICS and SABA – use one right after the other for worsening asthma

This is a conditional recommendation with moderate certainty.

• Individuals ages 4 or older with moderate to severe persistent asthma. The recommended treatment is a single inhaler with ICS and formoterol. This is referred to as single maintenance and labor therapy or smart therapy. This inhaler is used both on a daily and as-needed basis. This is a strong recommendation with high certainty for patients 12 years of age or older and moderate certainty for 4 to 11 years of age. (Note: GINA has different recommendations).
• Individuals ages 12 or older with moderate to severe persistent asthma. The recommended treatment is a single inhaler with ICS and formoterol. The inhaler is used both daily and as needed; or with a higher dose of ICS-long-acting beta agonist (LABA) combined with as-needed SABA. (Note: GINA has different recommendations)
• Should a short-term increase of inhaled corticosteroid be used in children greater than 4 years of age? Should it be used in adults with mild to moderate persistent asthma who are adherent to daily ICS? The expert panel conditionally recommends against a short-term increase in the ICS dose for increasing symptoms or decreased peak flow. This is a conditional recommendation with low certainty.

Long-Acting Muscarinic Antagonists

• Use of long-acting muscarinic antagonists (LAMAs) for patients aged 12 or older.
  • In patients with uncontrolled asthma with ICS therapy alone, or with ICS  therapy alone, adding a LABA rather than a LAMA and ICS is recommended. This is a conditional recommendation with moderate certainty.
  • If a LABA cannot be used, adding a LAMA to ICS is an acceptable alternative. This is a conditional recommendation with moderate certainty.
  • If asthma is not controlled with ICS-LABA, then adding a long acting muscarinic is recommended for many people because it offers a small potential benefit. This is a conditional recommendation with moderate certainty.

Indoor Allergy Relief

• • Individuals with asthma, with no history of exposure and no IgE sensitization or allergy, or symptoms after exposure to indoor allergens. Environmental control is not recommended. This is conditional with low certainty.
  • Individuals with asthma who are exposed and allergic to a specific indoor allergy and substance. Using multiple strategies to reduce the allergen is recommended. These strategies may include cleanup of allergens, repairing leaky pipes or installing HEPA air filters. Using only one strategy often does not improve asthma outcomes. This is a conditional recommendation with low certainty.

• Individuals with asthma who are sensitive to house dust mites. Dust mite-proof pillow and mattress covers are recommended, but only as part of a multi-component intervention strategy. This is a conditional recommendation with moderate certainty.

• Individuals with asthma who are allergic and exposed to cockroaches, mice or rats. Pest management in the home is recommended. This is a conditional recommendation with low certainty.

Immunotherapy as a Treatment of Allergic Asthma

• Individuals with mild to moderate asthma who have demonstrated a sensitization to the allergen and evidence of worsening asthma symptoms after exposure. Immunotherapy is recommended as an adjunct treatment to standard pharmacotherapy. This is a conditional recommendation with moderate certainty. (Note: The GINA report does not recommend this strategy.)

• The evidence does not support using sublingual immunotherapy to specifically treat allergic asthma. This is a conditional recommendation with moderate certainty. (Note: The GINA report  recommends sublingual immunotherapy for house dust mite allergy for adults only.)

Fractional Exhaled Nitrous Oxide Testing

• For patients ages 5 or older. Fractional exhaled nitric oxide (FeNO) may support a diagnosis of asthma. This is after a complete examination and spirometry with bronchodilator responsiveness. This is a conditional recommendation with moderate certainty.

• • FeNO testing may be used as part of ongoing asthma monitoring and management when there is uncertainty and adjusting therapy using clinical and laboratory assessment. This is a conditional recommendation with low certainty.

• For patients ages 5 or older, FeNO testing should not be used in isolation to assess asthma control or to predict future exacerbations or assess the severity of an exacerbation. This is a strong recommendation with low certainty.

• In children ages 4 years and younger who have recurrent episodes of wheezing, FeNO measurement does not predict the development of future asthma. This is a strong recommendation with low certainty.

Bronchial Thermoplasty

• Most individuals 18 years and older with uncontrolled asthma should not undergo bronchial thermoplasty because the benefits are small, the risks are moderate, and long-term outcomes are uncertain. This is an unconditional recommendation with low certainty.
  • Some individuals with persistent asthma may be willing to accept the risk of bronchial thermoplasty and therefore might choose this medical procedure afterShared Decision- Making with a healthcare provider. This is a strong recommendation with low certainty.

The Global Initiative for Asthma (GINA) Asthma Treatment Report 2022

GINA convenes yearly to update its asthma management report. They review scientific information and then meet in a committee to update recommendations.

Diagnosis of Asthma

The 2022 GINA report outlines diagnosing asthma and emphasizes the importance of testing before initiating treatment. This is because it is more difficult to confirm the diagnosis once controller treatment has been initiated. They developed a flow chart to address different diagnostic approaches for an initial diagnosis of asthma as compared to a confirmation in patients already on treatment.  

Asthma Treatment in Adults and Adolescents

In 2020, GINA no longer recommended treating adults and adolescents with asthma with SABA alone. In 2022, the report updated the recommendation to note that asthma treatment has two options – track 1 and track 2. Track 1 is preferred and recommends using ICS-formoterol as the reliever. This is because evidence suggests that it reduces the risk of exacerbations compared to using SABA alone. In Track 2, SABA is the reliever medication. This is not the preferred track and should only be considered for patients with good medication compliance and no exacerbations in the previous year. 

As-needed ICS-formoterol reduces the risk of severe exacerbations by 60-64% as compared to as-needed SABA. The risk of exacerbations is similar for those using ICS-formoterol as needed vs. as-maintenance therapy.

Additionally, LAMA should not be used as standalone therapy without due to risk of exacerbations. Patient who are on ICS-LABA should be on medium doses before the consideration of add-on LAMA.  And chromome pMDIs have been discontinued around the world. 

The greatest burden of asthma deaths falls upon low- and middle-income countries. Increasing access to ICS-formoterol would have the greatest impact. But in cases where access is limited, utilizing track 2 is acceptable. 

Mild Asthma

Recently there has been a greater understanding of “mild asthma.” The name can be misleading because patients with what appears to be mild asthma are still at risk for serious adverse events. Of adults with asthma, 30-37% of patients will have an acute asthma exacerbation. Of adults with near fatal asthma, 16% have been labeled as having mild asthma. Among adults who have died of asthma, 15-20% are labeled as mild asthmatics.

What causes an exacerbation or what is a trigger will vary. Viruses, pollen, pollution and poor adherence to therapy all increase the risk of an asthma flare. Inhaled SABA has been the first-line treatment for 50 years. This dates to the era when asthma was thought to be primarily a disease of bronchoconstriction.

Patient satisfaction with and reliance on SABA for treatment is reinforced by its rapid relief of symptoms as well as its prominence in the emergency department and hospital management. Given this, as well as its low cost (for generic), patients often do not see the need for additional therapy.

However, as shown, the evidence demonstrates that those even with “mild asthma” are at risk for serious, and even fatal outcomes. So for now, they recommend limiting the use of the term “mild asthma.” And, if used, reinforce the need for ICS-containing treatment and emphasize the risks of exacerbations.

Asthma Control

The frequency of SABA use is included in asthma symptom control assessment in the GINA report. Higher SABA use is associated with worse outcomes, even in patients taking ICS. When assessing asthma control in adults, adolescents and children ages 6 to 11, there are several questions that can be asked, such as:

• Has the patient had daytime symptoms more than twice a week?
• Has the patient had any nighttime awakening due to asthma?
• Has the patient experienced any activity limitations?

The use of SABA to treat symptoms more than twice per week and activity limitations are signs asthma symptoms are not well controlled. In the GINA report, the recommendation is that frequency of use of an ICS-formoterol containing inhaler should not be included in symptom control assessment, especially in patients not taking daily controller medication. This is because the ICS is providing controller therapy.

Adverse Effects with Montelukast (Singulair)

Montelukast has been available for decades. There is now a box warning about the potential for serious mental health side effects with the use of montelukast in patients with asthma and allergies. These side effects may include serious neuropsychiatric events, including suicide in adults and adolescents and nightmares and behavioral problems in children.

GINA advises restricting the use of montelukast for allergic rhinitis. Patients and parents should be counseled about these side effects prior to prescribing. Montelukast should be avoided in patients with a history of mental health issues.

Diagnosis and Management of Difficult to Treat or Severe Asthma in Adults and Adolescents

In 2019, GINA released a pocket guide for treating adults and adolescents with difficult to treat or severe asthma. In 2022 the “pocket” guide was eliminated. It is now full size, making it easier to read. They updated the decision tree for adults and adolescents with difficult-to-treat asthma.  

Some important changes to this guide include:

• Screening patients on maintenance OCS or high dose ICS-LABA for adrenal insufficiency
• For patients with eosinophils ≥300/µl, investigate non-asthma causes before starting biologics.
• If patients have hypereosinophilia, check for other conditions, such as EGPA
• Assess for the inflammatory phenotype
• Updated treatment options for those without evidence of Type 2 inflammation.
• OCS should only be used as a last resort option. For patients with hypereosinophilia, e.g. ≥1500/µl, investigate for conditions such as EGPA

Biologics

There are 5 biologics for asthma currently available in the United States. Per the GINA report, consider adding Type 2 targeted biologics in patients with exacerbations or poor symptom control with ICS-LABA who:

• Have eosinophilic or allergic biomarkers.

or

• Require oral corticosteroids for maintenance

Newly available biologics include dupilumab for severe eosinophilic/Type 2 asthma in adults and children over the age of 6. Tezepelumad is now approved for adults and children over the age of 12.

It is important to consider local payer eligibility criteria and predictors of response when choosing which therapy to begin. It’s important for doctors to consider the cost, dosing frequency, the route, and patient preferences.

Patients with Features of Asthma and COPD

There are patients who clearly have asthma and patients who clearly have COPD. And then there are those who have overlapping features of both. These are patients who have a history of asthma and have developed a more fixed obstructive lung disease. It could be due to either smoking or environmental or workplace exposure to irritants. These patients have a persistent expiratory airflow limitation with or without bronchodilator reversibility. Initial medication treatment should be prescribed.

It is important to also treat comorbidities. ICS treatment is essential to reduce the risk of severe flares. Add-on therapy with LABA and/or LAMA is needed. In patients with COPD, both LABA and/or LAMA are indicated. ICS should be used in addition to combined bronchodilator therapy.

Asthma Treatment in Adults and Adolescents

COVID-19 and Asthma

The key takeaways for patients with asthma during the COVID-19 pandemic:

• People with asthma are not at higher risk for acquiring COVID-19. There is not a higher risk of severe COVID-19 in people with well-controlled asthma. 
• Continue taking prescribed medications.
• Asthma medications are not a risk factor for making COVID-19 worse, particularly ICS and oral corticosteroids.
• Make sure all patients have a written Asthma Action Plan including:
  • instructions about increasing controller and reliever medication when asthma worsens
  • taking a short course of oral corticosteroids for severe exacerbations
  • when to seek medical help
• Follow infection control guidelines when using spirometry, peak flow measurement, or aerosol generating procedures (such as nebulizers)
• Practice strict infection control
• Use appropriate PPE (personal protective equipment) for healthcare providers.
• COVID-19 vaccines are safe and effective for people with asthma; they should be up to date on vaccines and boosters.
• COVID-19 vaccines and initiating biologic therapies should not be given on the same day as side-effects would be hard to differentiate.

Other Changes to GINA 2022

• Emphasis on written Asthma Action Plans – these should be handwritten, printed, digital or pictorial, not just verbal
• Acute asthma management in the healthcare setting is typically albuterol, but formoterol has similar efficacy and safety. And high dose budesonide-formoterol has similar efficacy to SABA.  ICS-containing therapy should continue or be initiated for all patients admitted for an asthma exacerbation.
• Air filters provide no consistent impact on asthma outcomes.
• E-cigarettes may cause an increase in respiratory symptoms and asthma exacerbations.