For Medical Students and Residents: Some Study and Interaction on your own time!

It’s about time we as clinicians and “learners” can meet together to discuss asthma and new developments in the treatment of this very expensive and disruptive disease. Enter Dr. Mark Millard from Baylor in Dallas, TX who gave an excellent presentation on TSLP and the role this molecule plays in “causing asthma”. Allergists and pulmonologists have changed our approach to asthma many times in my practice lifetime. Here’s a few examples for you to ponder:

  • Prior to the development of albuterol (bronchodilator), medical doctors would administer strychnine for asthma. Obviously, that method didn’t work well and I wonder how many patients just died from the treatment.
  • In the early 1960’s epinephrine was the newest fad for asthma and you could actually go outside x 4 hours and not be home bound (the asthma curse). Why only 4 hours? That’s how long epinephrine lasts.
  • Next on the list of miracles for asthma was the development of bronchodilators such as albuterol. The MDI (metered dose inhaler) was born and to this day, we struggle with overuse of this quick acting treatment for asthma.
  • In the 1980’s, we began to understand that asthma is much more than bronchoconstriction and something had to be done about the INFLAMMATION that gives you asthma in the first place.
  • When inhaled corticosteroids were invented, I really thought this was the last frontier for asthma therapy. I was dead wrong, because some patients don’t respond well to the inhaled steroids as a class-specific treatment. ie, the severe asthma patient will often take every medication you prescribe and still have frequent visits to the ER and even hospitalization when recovering from a simple cold.
  • Our conference Monday night was focused on a novel Biologic therapy that may indeed be another target for asthma treatment: TSLP

We now have many biologicals that target novel molecules for asthma, so what’s the big deal about TSLP? Never thinking I would have to choose between biologics for asthma, when omalizumab (the first one) was released, I smugly said to myself, “this is too expensive, I’ll never use it!” Here’s the advantage of using a biological for asthma. Molecules such as IL-5, IL-4, IL-13 are very important in causing asthma, but if you block them, side effects are minimal. Steroids can block these molecules as well, but steroids affect many pathways of inflammation, and thus cause many side effects that nobody really wants. Most descriptions of asthma dissect pathways of signals from the airway epithelium down to the macrophage in the airway itself as the source of these inflammatory messengers. It’s way beyond the scope of this writing to explain every pathway as PubMed reveals 202,130 articles on asthma and 10,000 just in 2020!

With this writing, I’ll focus on TSLP which was last night’s topic presented by Dr. Millard. A great reference is American Academy of Allergy, Asthma & Immunology (J Allergy Clin Immunol Pract 2017;5:909-16) I’ll be happy to get you a copy–drop me a line.

TSLP originates from the airway epithelium which is unusual at best. But what a brilliant design as lung epithelial cells provide not only a physical barrier, but they produce mediators and cytokines that propagate innate and adaptive immune responses (keep you from infection). For our purposes today, the “alarmin” cytokines include TSLP, IL-25, and IL-33 which promote activation of TH2 cells and ILC2s. Who thinks of these abbreviations anyway? TSLP also promotes activation of mast cells, basophils, and dendritic cells all of which create inflammation; not good news if you have asthma. Studies now show that AMG 157 (once the product is released, the name will change to a sexy title, appropriate to catch the masses on TV!) can reduce early and late-phase allergen-induced bronchoconstriction and parameters of allergic airway inflammation.

And now some questions and discussion on asthma. Don’t be alarmed, this will give us a basis for understanding how asthma is triggered and the plethora of treatment options now available for asthma. Just use the “comments” section of this post for your answers and questions.

  • Asthma is a heterogenous disease that presents with multiple phenotypes and responds differently depending on which “type” of asthma you have. Can you list at least 3 triggers that cause asthma exacerbations in real life?

  • Fill in the blank with the appropriate molecule blocked by the following biologicals?
  • Omalizumab _____________
  • Mepolizumab _____________
  • Dupilumab ______________
  • Benralizumab ____________
  • AMG 157 _______________
  • Biologicals, regardless of their specificity carry the potential of reducing exacerbations of asthma and in some cases may reduce the use of oral corticosteroids? T or F

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