Pathophysiology-Definition, Epidemiology, and Pathophysiology of Asthma

Video Transcription

I want to start with the definition of severe asthma, and this was really clarified in the  2014 ERS, ATS asthma guidelines, where asthma was defined as asthma, severe asthma was defined  as asthma that requires treatment at GINA steps 4 or 5, or requires systemic corticosteroids  for more than 50% of the prior year to prevent it from becoming uncontrolled or remains uncontrolled  despite this therapy, or asthma, uncontrolled asthma that worsens if any effort is made to taper this level of therapy.  Now I want to share with you again two updates that are relevant to severe asthma. GINA in 2019 separately published guidance on difficult-to-treat and severe asthma, and  the European Respiratory Society and American Thoracic Society issued a joint task force guidelines as well. What proportion of adults with asthma have severe asthma?  This question actually was answered by this elegantly done Dutch study where they took all patients who had high-intensity therapy, and it turns out the prevalence of true severe  refractory asthma is quite low, it's less than 5%, although it makes up for a large portion of healthcare utilization.  Difficult-to-treat asthma is much higher, but the difference between these two is really identification of modifiable risk factors, comorbidities, triggers, non-interference,  things like that. So there are many available biologics that have become available in asthma. It's really been great to see the growth in the advanced therapy field in asthma.  As you know, melizomab was the first biologic to become available in asthma, and this was in 2003 for treatment of moderate to severe allergic asthma.  But following this, we've had, there was a long hiatus until 2015, and then rapid introduction  of multiple biologics, and currently we have five biologics with a sixth one, hopefully, to become available soon.  The interleukin-5 pathway is targeted by three biologics, which is the mepolizumab, reslizumab, and venrelizumab, and then dopilumab, which targets interleukin-4 and interleukin-13  because it targets the interleukin-4 alpha receptor, and that is utilized by both IL-4 and IL-13, so as a result, it leads to blockage of both of these cytokines.  And I've listed here the table of the mechanism of available biologics, the route of administration, and where they're available.  Until very recently, melizomab was only available for administration in a medical facility due  to a low risk of anaphylaxis, but in some select patients who are low risk, a pre-filled syringe is now available, and it can be administered at home.  Mepolizumab can be administered either at home or in clinic, given every four weeks. Reslizumab is an intravenous infusion, targets interleukin-5, and also has a low risk of  anaphylaxis associated with it, so only given in an infusion center or clinic. Beneralizumab targets the receptor alpha, given subcutaneously, either home or clinic,  and then dupilumab, which is the full receptor alpha, is given subcutaneously every two weeks and only available for home administration.  So omelizumab binds to free-circulating IgE at the same site as high-affinity IgE receptor. It's indicated for treatment of moderate to severe allergic asthma as add-on therapy,  and it's dosed based on serum IgE level and the patient's weight. And to qualify, the serum IgE has to be between 30 to 700 international units per ml, and  there has to be sensitization to more than one perennial allergen. Like I mentioned, there's a low risk of anaphylactic reaction, but in some patients, it has become  available as a pre-filled syringe if they do not have history of prior anaphylaxis.  If they have had at least three doses of omelizumab in a monitored setting, they're able to recognize  and treat for symptoms of anaphylaxis and can inject themselves utilizing the proper technique.  Anti-interleukin-5 pathway, there are, for the interleukin-5 pathway, there are three antibodies available.  Two, mepolizumab and reslizumab are against the ligand, interleukin-5 and relizumab is against the receptor.  Again, they're approved for adult therapy for patients with severe asthma with an eosinophilic phenotype, and the dosing and route are listed here.  Dupilumab is a fully human monoclonal antibody binds to the alpha subunit of interleukin-4 receptor and inhibits activity of both L4 and L13.  It is approved for use in moderate to severe eosinophilic asthma and also corticosteroid-dependent asthma, regardless of eosinophil count.  And depending on the severity of asthma and comorbidities, it can be, it's available in two different loading dose and then administered as maintenance dose every two weeks.  And the higher dose of 600 milligram loading and 300 milligram every two weeks is mainly  utilized for patients who have corticosteroid-dependent asthma or have comorbid atopic dermatitis. So I've listed here the available dosing mechanism indication.  Just note that mepolizumab is approved for age six or older, as is omelizumab and reslizumab is only approved for adults greater than 18.  And this is just a comparative efficacy of the available biologics. There are no head-to-head comparisons, so these are really data from the randomized control trials.  They all decrease exacerbations. That's really been the primary endpoint for most of these biologics by about half.  There is modest benefit in lung function and asthma control, but it does not really meet the clinically important difference.  And I do want to mention that there are three drugs, mepolizumab, benrelizumab, and dupilumab,  that have been systematically studied in randomized control trials in patients who have corticosteroid-dependent asthma and have found to be effective.  So if there's a patient who has evidence of peripheral eosinophilia and is corticosteroid-dependent, either of these would be good options.  If there's no evidence of eosinophilia, then dupilumab can still be considered due to its indication. Moving on to type 2 low asthma, there's not that many targeted therapies.  Actually, there are no targeted therapies available yet, even though about 50% of patients with asthma do not have type 2 inflammation.  And really, these are patients who are not steroid-responsive and can have fairly severe asthma.  And potential treatments for type 2 low asthma that can be considered are macrolides. So azithromycin has been studied in randomized control trials.  And this particular trial showed that there was the use of 500 mg of azithromycin three times weekly versus a placebo was associated with a significant decrease in exacerbation.  And the hazard ratio was 0.65. This was a year-long study in adults with symptomatic asthma despite use of inhaled steroid and a long-acting beta agonist.  And they also were screened for any hearing impairment or acuity prolongation at the study enrollment.  I've listed bronchothermoplasty here, but this is being considered and used less and less. And I shared the recommendations from the NAEPP against using it unless patients placed  less importance on harm and more on the potential benefit. But I do want to mention it here. This was approved after this AIR2 study that was published in 2010.  That was a sham-controlled study. And use of bronchothermoplasty was associated with improvement in asthma quality of life  and decrease in health utilization, and particularly in decrease in ER visits, hospitalization, and severe exacerbations.  And I think you probably know this, the thermoplasty is really a bronchoscopic procedure where there's applied three weeks apart over three different sessions where there's ablation  of the epithelium and it's thought to affect the airway smooth muscle and perhaps also inflammation related to neural modulation.  And I think the big caveat here is that we still don't quite understand the patients that are most likely to respond to this therapy.  So predictors of response still have not become clear, which makes patient selection difficult. The recent asthma study did not find association with airway smooth muscle mass.  So I think there's still more to be learned. I want to finish with this slide on the tezapilumab, which is anti-TSLP antibodies.  You remember TSLP is a epithelial-derived cytokine, it's one of the alarmants, and it is central to the regulation of type 2 immunity through its activity on dendritic cells, TNB  cells, and innate immune cells. And tezapilumab binds specifically to TSLP and has significant downstream effect.  And it has really shown promise in treatment of uncontrolled asthma, severe asthma as add-on therapy.  And it is thought to have an effect on allergic inflammation and eosinophilic asthma, as well as may impact type 2 lower neutrophilic asthma, as you can see here.  So I want to share the results from a Navigator study that was just recently published in  New England Journal of Medicine and showed that tezapilumab was very effective in decreasing  exacerbations, regardless of the eosinophil count.  As you can see, the overall rate ratio was 0.44, and it was definitely lower, so more effect in high eosinophil count group, but also significant in patients who had low eosinophil,  even less than 150 ml, and also in patients who had low exhaled nitric oxide, including  less than 25 parts per billion.  So this really may be a therapeutic option for patients who have both type 2 high and non-type 2 asthma.

Video Summary

Severe asthma is defined as asthma that requires high-intensity treatment. Prevalence is less than 5% but accounts for a large portion of healthcare utilization. There are several available biologics to treat severe asthma, targeting the interleukin-5 pathway and the interleukin-4 and interleukin-13 pathway. Efficacy data shows a decrease in exacerbations and modest improvements in lung function and asthma control. For patients with corticosteroid-dependent asthma and evidence of eosinophilia, mepolizumab, benralizumab, and dupilumab are effective options. For type 2 low asthma, azithromycin and bronchial thermoplasty may be considered. Tetralizumab, an anti-TSLP antibody, shows promise in treating uncontrolled asthma, regardless of eosinophil counts.

Asset Subtitle

This CHEST Board Review video defines asthma and discusses the burden of the disease and its prevalence in the United States. Early life determinants of asthma and genetic predisposition lead into a conversation about asthma pathophysiology and immunology. Participants will learn about airway inflammation and type-2 immune responses in asthma. The video concludes with a list of the cytokines in type 2 asthma.

Last Reviewed: September 2022

Asset Caption

This CHEST Board Review video defines asthma and discusses the burden of the disease and its prevalence in the United States. Early life determinants of asthma and genetic predisposition lead into a conversation about asthma pathophysiology and immunology. Participants will learn about airway inflammation and type-2 immune responses in asthma. The video concludes with a list of the cytokines in type 2 asthma.

Last Reviewed: September 2022

Keywords

severe asthma

biologics

eosinophilia

lung function

asthma control