COPD Sarcoidiosis ILDs CAP / PCP Pneumonia and use of Steroids. COPD and Immunology Asthma How do you manage a severe asthma? Understand endotype, role of IgE, Role of Eiosinophils, Role of FeNO, Role of IL5, IL13. What is the pathophysiology / immunological basis of asthma. Why should you know this. Lets go through some patient example, and understand Asthma management. As, we do so, we will emphasize why is it important to understand the immunological basis of asthma. Patient 1: 40 yo of M is seen in the clinic for difficult to control asthma. Patient has visited ER on an average 2-3 times a month for last 4-5 months. Patient has received multiple doses of PO steroids. WBC is increased around 18K on each occasion. Eiosinophil count is not elevated. Ig E is 330 IU/ml. Initial use of steroids and advair improves his symptoms. PEFR on a daily measurement is consistently over 400 while on steroids. Another follow up after the completion of PO steroids, patient says his symptoms are controlled, but shows ACT of 17. Patient says his symptoms have gotten worse after moving to this house. He has carpeted floor,and has many birds in the locality. Inhaler technique is verified. Onset of asthma symptom is not clear. Airway inflammatory cells has not been looked into. Patient is not on ASA. BMI is normal. How do you manage this patient? Patient 2: 68 yo F is seen in the clinic for difficult to control asthma. Patient on Pulmonary visit acknowledges that her symptoms are at baseline and fairly controlled. ACTQ is 5 in our clinic evaluation. Patient has reported moth ball at home. Also, has history of atopic dermatitis / allergic contract dermatitis. Ig E is 179 IU/ml. Eosinophil count is normal. FeNO is 21. Inhaler technique is verified Onset of asthma symptoms is not clear based on the symptoms. Airway inflammatory cells has not been looked into. Also, it is unclear if patient is taking ASA or note. BMI is 35.72. Discussion: Goal of Asthma Management: Note: The terminology above does not include intermittent, vs persistent asthma. Rather, well controlled, not well controlled,and poorly controlled asthma. But, in essence it is the same. Based on where the patient are the above table also guides you the step of asthma treatment. Note, Many patient with asthma have very poorly controlled asthma or moderate-severe persistent asthma . Assessment of Asthma Control
These patients on subjective assessment of patient often say they have fairly well controlled asthma. However, using validated questionnaire like ACT Q or ACQ 6 or ACQ 4 will help better define how well control their symptoms are. This can also be assessed by ACT. Score: 19 or <: Not well controlled asthma. On using these formal validated questionnaire, we find that many patient with asthma have poorly controlled asthma. Note: The number in this chart is in Million of the patient population. These patients have very poorly controlled asthma or moderate-severe persistent asthma. Back to our patient. Our patient had; Poorly controlled asthma. Treatment patient were taking include: Patient 1
Patient 2
Despite this, symptoms are not fully controlled. Hence, are in step 5 or step 6 of the treatment in the following algorithm. Some thing else is desperately needed now. WHO ARE THESE PATIENTS WHO DO NOT RESPOND TO TYPICAL TREATMENT of ASTHMA. AND why do they behave in such way? To understand this one has to appreciate that Asthma is not a homogeneous disease. Rather it is a heterogeneous disease. Not everyone will respond to same treatment strategy. So, it is important to identify the patient phenotype. Patient 1:
Patient 2:
Given the high symptom severity, it is also important to identify Th2 phenotype. This is important because Non-Th2 mediated asthma are steroid resistant. Asthma is a syndrome not a disease. Majority have IgE disease. It is a heterogenous disease. Asthma is not same in all patients. Influenced by various genes. There are various subtypes or endotypes. Some of the examples of various types of asthma is as below. Patient 1:
Patient 2:
What are the pathomechamism going on in acute asthma and chronic asthma? Key Features of Acute Asthma are
Key features of Chronic Asthma are
Understand the chronic changes associated with chronic airway hyperresponseiveness
IL-4, IL5, IL13 are directly or indirectly involved in the pathogenies of Asthma WHAT ARE THE VARIOUS TYPES OF INFLAMMATORY CELLS SEEN IN ASTHMA
BY WHAT MECHANISM DO THESE CYTOKINES AND INFLAMMATORY CELLS COME INTO PLAY IN A PATIENT WITH ASTHMA Why is this important to understand. 1) If it is mediated by IgE, and patient has perineal allergen, symptoms are not fully controlled, we can use Anti-IG E treatment. Note: large number of asthma are allergic asthma. 2) If it is mediated by IL-5, we can use anti-IL 5 for asthma treatment. 3) If is is eiosinophilic inflammation as seen by increased FeNO: continue to use steroids. Adaptive Immune Response Type 2 Inflammation (IL4, IL5, IL13) cytokines is associated with inflammation - Ig E related IL 4, IL 13 increases IgE production IL 5 causes eiosinophlic recruitment Other function see in the chart Mast cells also release IL4, and IL 5 How, would the knowledge of asthma help define the Asthma treatment strategy. What are the emerging treatment strategy? For this knowledge of asthma phenotype, and more importantly, asthma endotype is essential. Innate Immunity due to microbes, glycolipids and pollutants 3 cytokines IL33, IL 25, TSLP TSLP - ILC2 is a pathway via innate immunity. But also works on APC (dendritic cells ) of Adaptive pathway IL 33 Causes neutrophil recruitment. (as does happen in IL 17 pathway) IL 25 These 3 cytokines lead to IL13, IL4, IL5 production not via TH2 but via innate lymphoid cells - IL C2 cells . Note: end product is the same cytokines as from Type 2 inflammation. The involvement of IL4, IL5, IL13 is called Type 2 inflammation. Not necessarily Eiosinophilic, or IgE or Mast Cells mediated due to presence of Innate pathway. Non Type 2 Inflammation IL - 17 -induces neutrophils . Note, in clinical study for severe asthma, Anti-IL 17 therapy has failed so far. What is the role of FeNO in the management of Chronic Asthma of asthma
What are the emerging asthma treatment? Anti-cholinergics, omalizumab, mepalizumab. How do you assess if Asthma is controlled or not? To what extent is patients and physician assessment of asthma control accurate? Omalizumab (antiIgE; Xolair)
SUMMARY: Very large number of patient with asthma are uncontrolled. That is of course due to medication non-adherence, but significant portion is due to different pathomechanism. Knowing the pathomechanism, helps you to
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