CI and Pulmonary Disease

COPD
Asthma 
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
  • 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.
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
  • PO steroids
  • High-dose ICS + LABA 
Patient 2
  • PO steroids
  • High-dose ICS + LABA 
  • Singular
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: 
  • Onset: Unclear 
  • Symptom severity: 
  • BMI: Normal 
  • Gender: Male
  • Summary of Phenotype: 
Patient 2: 
  • Onset: Unclear 
  • Symptom severity: High
  • BMI: 
  • Gender
  • Summary of Phenotype: 

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: 
  • IgE:
  • Eosinophiles: not increased in blood
  • ASA: Not taking. 
  • Airway cytology: 
  • Airway Inflamamtion as assessed by FeNO:
Patient 2: 
  • IgE:
  • Eosinophiles: Not increased in blood
  • ASA: Unclear 
  • Airway cytology: 
  • Airway Inflamamtion as assessed by FeNO:

At this time, lets 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 airway.
  • 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 


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
  • 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 epinephrine pen.
  • 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. 
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 
  • Monitor treatment: FeNO, Periostin,  
  • Define treatment strategy: Inflammatory vs Non-inflammatory; Eiosinophilic vs Non-eosinophilic; IgE vs Non-IgE;

Sarcoidosis
  • Pathophysiology Lancet 2014
    • Exagerated immune response to far unidentified antigens most likely pathogen-associated molecular patterns of killed and partly degraded mycobacteria and priopionobacteria
    • Innate and Adaptive Immune mechanisms are involved in pathogenesis. 
      • Innate Immune System
        • Epithelial cells :
        • Phagocytic defects: 

          Mycobacteria and propionibacteria persist in macrophage phagosomes because their high lipid content in membranes makes them acid-fast, and many of their glycolipoproteins are not very soluble and resist degradation. 

        • Cell Signaling: Antigen associated molecular pattern trigger
          • 4 types: 
            • 2 Membrane bound 
              • TLR (7 types)  TLR2 and TLR9
                • Also, alveolar macrophage in response to antigen via TLR 4 signal pathway leads to TNF alpha production
              • CLR (5 types) C-Type Lectin
            • 2 Cytoplasmic 
              • NLR (6 Types) NOD Like Receptors
              • RIG - 1 Helicase receptors (2 Types)
        • Complement (Alternate and Lectin Pathways)
      • Adaptive Immune System 
        • T-Cell
          • T-Cell Development
          • T-Cell Maturation
          • T-Cell Activation and antigen presentation or Functioning: Macrophage activation and phagocyte defects leads to T cell activation. TNF alpha through e.  
            • Th1: There is also influx of Th1 cells in organs with sarcoid manifestation. In-situ activation of T-Lymphocytes causes production of interferon γ, TNF alpha, IL 2
              • These Th1 cytokines in turn activate more antigen presenting macrophages 
            • Th2 : IL4, TGF Beta
            • Th17: Even though there is increased IL17 in sarcoidiosis, role of Th17 pathway is still undefined. 
        • B-Cell
          • Impaired Development
            • Why some patients have spontaneous resolution of sarcoidiosis and others have persistent disease is not fully clear. In progressive disease antigen is postulated to persist, thereby inducing chronic immune response. However, in patient with spontaneous resolution, there is increased release of IMMUNOSPPRESSIVE cytokine TGF Beta 
          • Impaired Functioning 
            • T-cell mediated
            • T-cel independent 
      • Regulatory Immune System
        • Innate System Regulation
        • Adaptive System Regulation
          • Absence of negative immunological feedback signals delivered. ie. Tregs leads to further exaggerated Th1 response
      • Summary of pathogenesis: Increased inflammation by TNF alpha. Suppression by TGF Beta leads to spontaneous resolution. 
  • Clinical Features
  • Diagnosis
  • Treatment
  • Monitoring
  • References:
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