Chronic Asthma / Acute Exacerbation


UNDERSTANDING ASTHMA AS A SYNDROME:

Is asthma a homogeneous disease or heterogeneous disease? 
What are the asthma phenotype? What do you mean by Clinical Phenotype and Endotype? What is TH2 and Non-TH2 endotype- give examples? 




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. 

Asthma Endotype include
Type 2 vs Non-Type 2 Inflammation
Aspirin exacerbated respiratory disease (AERD)
Eiosinophlic vs Non-eiosinophlic inflammation

UNDERSTANDING PATHOMECHANISM OF THE ASTHMA  

What are the pathomechamism going on in acute asthma and chronic asthma?
Key Features of Acute Asthma are 
  • Airway Hyperactivity
  • Mucus Hypersecretion 
  • Eosinophilic inflammation in the pun g
  • IgE production 
Key features of Chronic Asthma are 
  • Goblet cell metaplasia 
  • Smooth muscle hypertrophy
  • Epithelial cell changes 
  • Fibrosis and remodeling 

Understand the chronic changes associated with chronic airway hyperresponseiveness 
  • Epithelial changes
  • Goblet cell metaplasia and hypertrophy
  • Thickened basement membrane 
  • Mast cells, Eiosinophils, Th2, Basophils
  • Hypertrophic smooth muscle 



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 
  • Eiosinophils
  • Neutrophils
  • Paucicellular
  • Mixed Cellular 
BY WHAT MECHANISM DO THESE CYTOKINES AND INFLAMMATORY CELLS COME INTO PLAY IN A PATIENT WITH ASTHMA 


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 

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. 


DIAGNOSIS OF ASTHMA


Normal spirometry can you rule out asthma?

ASSESSMENT OF ASTHMA CONTROL 

Assessment of Asthma Control
  • Many patients do not accurately assess  if their asthma is well controlled. Even when it is not well controlled, they tend to say it is well controlled. 
  • Of note, many physicians also do not assess how well Asthma is well controlled. Regardless of adherence, approximately 1/3 of patients remain uncontrolled. 
  • Note: Of chronic disease, adherence to medication is least in Asthma patients. 
  • ACT - Q is the best test to do. For adult it is to be done by Adult only without any help. Best is to integrate this in EMR and have patient fill the form by themselves. 
  • Note: ACQ is also there, and is done in moderate to severe asthma. 
  • More objective assessment with Spirometry is better.


WHAT ARE THE STEPS IN CHRONIC ASTHMA MANAGEMENT 

Asthma management is done by evaluation of 
  • Current impairment 
  • Future risk 

ASTHMA 
  • ASTHMA: CHRONIC MNT
    • Asthma Control Test
    • Asthma Action Plan 

How many steps in NHLBI treatment algorithm for Asthma? What is the limitation of this strategy? 



What is the role of FeNO in the management of Chronic Asthma of asthma
  • marker of airway inflammation (airway disease not related to inflammation may be detected)
    • Note: Neutrophilic airway inflammation may not be detected. NO is not produced in these case. 
    • High results: Start steroid. 
    • Intermediate results: Start and see the response. 
  • Adequacy of steroid treatment (we can go up on the treatment), or compliance all steroid treatment can be assessed. 


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)
  • Indication: Chronic Asthma related to allergy (not for other groups, not for asthma exacerbation; not for status asthmatics)
  • By injection only. Anaphylaxis is real risk. Hence, should be used in a set up where set up is ready to treat anaphylaxis.  Hence, they all go out with 



  • Late onset asthma. 
  • Allergic asthma or atopic asthma or IgE mediated asthma. 60 % of asthma patient may be allergic asthma. Perineal allergens: Indoor Mold, Cat, Dogs, Cockroaches. Dust mites. Here, patients have allergen specific IgE production. 
    • Test by skin PRICK test to perineal allergen. Allergen specific IgE assay in blood can also be done.  
    • Th2 mechanism is in play in these patients. IgE is linked to mast cells and activates Mast Cells. 
    • Xolair is monoclonal antibody binds directly to free IgE in a portion of IgE that binds to  Mast cells. Hence, cannot bind to bound IgE. Thus, limiting the number of Mast Cell bound IgE. 
    • Number of IgE that are bound to IgE, down regulates the number of IgE receptor in Mast cells, as there are more IgE receptor that are free and unbound. 
    • Note: Xolair is not also approved in chronic allergic urticaria. 
    • Total IgE and Skin allergy to perineal allergen has to be done before giving Xolair. Level of IgE defines the dose of Xolair. If they are allergic, but not to perineal allergen, then it is not given. 
    • Note: IgE is not measured for diagnosis. Absolute level of IgE dose not correlate to IgE to perineal allergen. Hence, skin test for these allergen has to be done before treatment. Again, IgE test is done only for dosing. 
  • Paucicellular asthma. 



ASTHMA: ACUTE EXACERBATION: 
  • Severity of asthma exacerbation
  • 2/2 Viral Infection, Allergen exposure etc
  • Tests to consider in appropriate clinical scenario are 
    • CXR (note: not used for routine evaluation of asthma)
    • High resolution CT of chest (if Interstitial opacities are seen in CXR, or if DLCO is decreased to evaluate for ILD / Bronchiectasis)
    • CT of sinuses
    • Methacholine challenge to evaluate bronchial hyperresponsiveness with larynoscopy to evaluate upper airway dysfunction (vocal cord dysfunction)
    • ABPA testing
    • Ig E (for evaluation of ABPA and for patient selection for Anti-IgE therapy)
    • Alpha-1 antitrypsin deficiency testing (for lifelong non-smoker and persistent and irreversible airway obstruction) 
    • ANCA (for Eiosinophilic-GPA)
    • Inspiratory & expiratory flow loops (for vocal cord dysfunction)
    • Oxygen diffusion capacity (for ILD)
    • Consider baseline urine cortisol – can recheck after therapy to see if compliant
    • Baseline blood eosinophilia (for E-GPA)
    • Bone densitometry 
    • Test for specific allergen 
    • BNP (for CHF)
  • Management
http://www.nhlbi.nih.gov/files/docs/guidelines/11_sec5_exacerb.pdf
  • Rx 
Initial Management of Life-Threatening Asthma Exacerbations MKSAP 16 PCCM Table 49  



Other references
Efficacy and safety of fluticasone furoate/vilanterol compared with fluticasone propionate/salmeterol combination in adult and adolescent patients with persistent asthma (is SAME) Chest 2013





SEVERE ASTHMA

 
   

  • Identify the asthma Phenotype
    • Could be high symptom low inflammation phenotype. Assess degree of inflammation by FeNO. 
  • Assess the role of IgE. 
    • Patient may benefit from Anti-IgE therapy. 
  • Assess the role of Eiosiniphils, and Type 2 Cytokines. You can look for eiosinophils in blood, but also look for in sputum. 
    • Anti-IL 5, and Anti-IL 13 may be the target of the asthma therapy. 
  • Assess the utility of Anti-cholinergics. 




   


   

  


References: Bradley Chipps. During ACAAI 2015. Available in Internet. 


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