Meghan Althoff, MD, PhD, on Implementing the New Asthma Guidelines

In response to new evidence on the management of asthma, the Global Initiative for Asthma (GINA) and the European Respiratory Society/American Thoracic Society (ERS/ATS) have updated their guidelines. Severe asthma continues to be difficult to treat, as these guidelines only provide a recommendation to be used on a case-by-case basis.

Meghan Althoff, MD, PhD, who is a second-year fellow in the Division of Pulmonary Sciences and Critical Care Medicine at the University of Colorado, discussed how these new updates can be implemented into physicians’ everyday clinical practice at CHEST2020.1 Dr Althoff answered Pulmonology Consultant’s questions about her session.

Pulmonology Consultant: Your session at CHEST2020 was about implementing the new recommendations for treating severe asthma. Could you give our readers a brief overview of the new severe asthma guidelines?

Meghan Althoff: Our session discussed the most recent asthma guidelines from GINA and ERS/ATS. The newest GINA guidelines included several important changes to asthma management. For patients on GINA step 1, it is now recommended that an inhaled corticosteroid (ICS)-formoterol inhaler be used as a reliever therapy instead of a short-acting bronchodilator (SABA) alone. Similarly, in patients on GINA step 3 and above, it is recommended to use ICS-formoterol as the reliever inhaler if the patient is taking a formoterol-containing ICS-long-acting β agonist (LABA) for maintenance therapy.  

The GINA and ERS/ATS guidelines also provide new guidance on managing severe asthma. After the addition of a high-dose ICS-LABA, there are a number of additional therapeutic options. The GINA guidelines provide a useful flowchart for managing severe asthma. Both guidelines recognize asthma as a heterogenous disease with different mechanisms that drive inflammation. The GINA guidelines recommend phenotyping patients by Th2 high or low inflammation. ETS/ATS recommends a trial of a long-acting anti-muscarinic (LAMA) inhaler or chronic macrolide therapy in patients with severe asthma, whereas GINA recommends this in patients with low-Th2-driven inflammation. Both guidelines recommend the addition of a biologic agent in patients with severe asthma. However, the minimum peripheral absolute eosinophil count to start each therapy differs by guideline. 

PULM CON: How can these recommendations be implemented?

MA: While these guidelines are helpful, there are practical considerations for implementation. If a patient is taking an ICS-formoterol inhaler for maintenance and reliever therapy, they may need to refill their inhaler prescription earlier than insurance companies are expecting, since this has previously only been a maintenance inhaler. If patients use their reliever inhaler more than daily, their refill request may be denied by their insurance. Alternative regimens include ICS for maintenance therapy with ICS-formoterol as a reliever inhaler, ICS for maintenance therapy with SABA and ICS taken together as reliever therapy, or ICS-LABA for maintenance and continuing SABA as a reliever.   

The guidelines recognize that there is not a one-size-fits-all approach for severe asthma. Our toolbox for treating asthma that remains poorly controlled after high-dose ICS-LABA includes addition of a LAMA, chronic macrolide therapy, and/or 1 of 5 biologic medications. Which medication to choose for each patient remains a challenge. Practically speaking, adding a LAMA to the treatment regimen is cost effective, low risk, and often effective in many patients. As we are still learning which patients will benefit most from LAMA therapy, we feel that it is worth a trial in patients whose asthma remains uncontrolled on high-dose ICS-LABA. Chronic macrolide therapy has been shown to decrease asthma exacerbation risk; however, it is an off-label use in asthma. The biologic therapies have more robust data supporting a reduction in exacerbations among patients with Th2 asthma. Therefore, we recommend a trial of a macrolide among patients who do not qualify for biologic therapy. 

There are 5 FDA approved biologic therapies for severe asthma: the IgE antagonist omalizumab, IL-5/5R antagonists (mepolizumab, reslizumab, and benralizumab), and the IL-4 receptor-α subunit antagonist dupilumab. The GINA and ERS/ATS guidelines differ somewhat on the eosinophil threshold for starting one of these medications. For omalizumab, both guidelines agree that a patient may benefit from the medication if they have a peripheral eosinophil count greater than or equal to 260 and a fraction of exhaled nitric oxide (FeNO) of greater than or equal to 19.5 (ERS/ATS) or 20 (GINA). For the IL-5/5R antagonists, GINA recommends considering one of these medications if the patient’s peripheral eosinophil count is greater than or equal to 300, whereas ERS/ATS recommends a peripheral eosinophil count greater than or equal to 150. GINA recommends considering dupilumab if a patient has a peripheral eosinophil count greater than or equal to 150 or a FeNO greater than or equal to 25, whereas ERS/ATS recommends considering dupilumab in any patient who is dependent on oral corticosteroids regardless of eosinophil count. There are been no head-to-head trials comparing these therapies, and all have been shown to decrease the exacerbation rate by approximately 50% in placebo-controlled trials. 

PULM CON: What was the previous standard of care for treating patients with severe asthma?

MA: In the previous iteration of the GINA guidelines, the only approved biologic therapy was omalizumab (anti-IgE). For severe asthma, consideration of omalizumab and/or tiotropium were the recommended options for asthma that remained uncontrolled on a high-dose ICS-LABA. 

PULM CON: How do these new guidelines add to the treatment landscape for severe asthma?

MA: With respect to severe asthma, the GINA and ERS/ATS guidelines address the 4 biologic agents that were approved since the 2015 GINA guidelines. These guidelines provide recommendations for minimum peripheral eosinophil counts for each of these agents. The ERS/ATS guidelines specifically address chronic macrolide therapy as an option for severe asthma. Aside from more treatment options, there is increasing recognition of the underlying heterogeneity of asthma, as the GINA severe asthma guidelines recommend determining asthma phenotype prior to deciding on additional treatment options.

PULM CON: What do you expect to be some common pitfalls when diagnosing and treating severe asthma after the implementation of these new recommendations? How can these pitfalls be avoided?

MA: As discussed above, there are challenges with prescribing ICS-formoterol as a maintenance and reliever inhaler because of concerns with insurance-rejected early refills, since this was previously considered a maintenance-only inhaler. While there are several alternatives to the regimen, 1 that should be avoided is combining multiple types of LABA medications. For example, prescribing fluticasone-salmeterol as a maintenance inhaler with budesonide-formoterol as a reliever inhaler. It is not recommended to combine different LABA inhalers.  

Other challenges include selecting an appropriate biologic agent and what to do in the case of treatment failure. As there are no head-to-head trials comparing the biologic therapies, there is no clear guidance for selection if a patient meets criteria for multiple agents. If a patient has a second qualifying diagnosis for 1 of the medications, like atopic dermatitis, then choosing the medication that treats both conditions is a straightforward choice. Practical considerations, including cost and frequency of injections, can help with selection.  

Trial data show that not all patients will respond to each medication. There have been retrospective studies that have shown treatment response after switching classes of biologic therapy in the case of inadequate treatment response to an initial agent. Another challenge with biologic therapy is determining the duration of therapy. In the case of treatment response, there have been a number of studies demonstrating effectiveness and safety over 3 to 4 years. These medications are appropriate to be used indefinitely. Among patients who choose to stop biologic therapy, there are increased exacerbations among those not receiving therapy. However, there also appears to be a proportion of patients who have sustained treatment response after stopping the medication. Patients who discontinue IL-5/5R antagonists have an increase in peripheral eosinophils 8 to 12 weeks after stopping the medication, and some develop recurrent symptoms and/or exacerbations after this time. We do not have a good understanding of which patients will do well after stopping biologic medications and which patients will need long-term therapy. It is reasonable to stop biologic therapy if a patient wishes given that there are patients who do well off therapy. Patients have been able to restart the same biologic medication with the same effectiveness as their first course of therapy.  

PULM CON: What are the key takeaways of your session? How do you suggest physicians implement the key takeaways of your session into their everyday practice?

MA: There were several takeaways from the session. The first being to use ICS-formoterol as maintenance and reliever inhalers for patients requiring GINA step 3 and above, if able, but you may need to substitute ICS maintenance with ICS-formoterol reliever or ICS-LABA maintenance with SABA reliever because of payor problems.

In patients with severe asthma that is uncontrolled with high-dose ICS-LABA, consider adding tiotropium for a low-cost and often effective option. In patients with Th2-high asthma, consider the addition of a biologic agent, though there is no current data supporting superiority of any 1 medication. The duration of biologic therapy is likely long term; however, patients may trail off biologic therapy and maintain the ability to restart the medication with the same effect. Finally, further research is needed on therapies for non-Th2 asthma, biologic selection and duration, and understanding the heterogeneity of treatment response and durability.  

Reference:

Althoff M. The new asthma guidelines: implementation of the recommendations. Talk presented at: CHEST2020; October 18-21, 2020; Virtual. https://chestmeeting.chestnet.org/event/treatment-of-severe-asthma-updates-from-the-guidelines-part-2/