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PBL PHC561 GROUP B2, image, Manifests extrapulmonary symptoms, such as…

- - - - Elevated expression of 5-lipoxygenase (5-LO) and leukotriene synthase C4 (LTC4S) was observed in NERD patients with CysL T overproduction, increased the CysL Ts binding to CysL T receptor.
        
        In bronchi, it leads to bronchoconstriction
        
        Leading to chest tightness, shortness of breath and wheeze. Hence, worsening the asthma.
        
        In nasal polyps, it leads to nasal congestion and profuse rhinorrhea
      - NERD induced reactions involve the release of mast cell and eosinophil-derived mediators (neutrophils, monocytes and basophils)and enhance the production of CysL Ts after exposure to NSAID.
      - The lower expression of the EP2 receptor is closely associated with abnormal regulation of the autocrine loop involved in the COX-2 pathway.
      - The level of PGE2 is decreased in patients with NERD. PGE2 has protective effects against bronchoconstriction, recruitment of eosinophils and degradation of mast cells after binding to the E prostanoid 2 (EP2) receptor.
        
        As a result, a decrease in PGE2 and its receptor levels may contribute to CysL Ts overproduction in NERD patient
      - NSAID triggers a biochemical cascade that are known to cause asthma via inhibiting COX-1 which is enzyme that responsible to convert arachidonic acid into prostaglandin, thromboxanes and prostacyclin, where it can cause reaction in patient that sensitive towards NSAID.
        
        This can be explained by the fact that COX-2 could not produce enough PGH2 (the first unstable precursors of PG products from AA metabolism) without the presence of COX-1.
    - - It can lead to both asthma and NERD
        
        How Type 2 Inflammation develop?
        
        Triggered by cytokines, IL--25 & IL-33
        
        Innate lymphoid cell differentiate
        
        Triggered by irritants
        
        activate Type 2 Helper T cell.
        
        Produce Type 2 cytokine, IL-4, IL-5, IL-13
        
        IL-4➡stimulates B cell to produce IgE➡activate mast cell
        
        IL-5➡recruits eosinophils
        
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        IL-13➡cause airway hyperesponsiveness➡leading to smooth muscle contraction, mucus production, and airway remodelling.
        
        How Type 2 Inflammation connected to NERD?
        
        In NERD person, Type 2 inflammation is linked with epithelial dysfunction
        
        Lower level of surfactant protein D ➡ activation of eosinophils cannot be inhibited
        
        High level in epithelial follicum and periostin.
        
        increased CysLT-induced signaling in airway epithelial cells ➡ induce the release of pro-inflammatory cytokines including IL-33, TSLP and IL-25
        
        Increase in leukotriene B4 (LTB4)
        
        CysLTR2 ➡ activate platelet ➡ release IL-33➡IL-33 interact with leukocyte ➡ leukocyte migrate into inflammatory tissue➡ increase the severity airway inflammation.
  - - - Avoidance of the drug induce asthma.
        
        Ibuprofen, Naproxen, Furbiprofen, Aspirin
      - Use alternative NSAIDs
        
        Selective COX-2 inhibitors (celecoxib and etoricoxib)
      - Tolerance tests with alternative NSAIDs
      - Dietary intervention
        
        Low Salicylate Diet.
    - - Anti-inflammatory agent
        
        Monoclonal Antibody
        (Omalizumab)
        
        Binding to circulating IgE, decreasing cell-bound IgE
        
        Decrease expression of high affinity receptors
        
        Decrease mediator release
        
        Reduce asthma symptoms & exacerbations
        
        Corticosteriods
        
        Enhanced beta-adrenergic response
        
        Decrease vascular permeability by vasoconstriction
        
        Inhibit the release of LTC4 and LTD4
        
        Inhibit the late phase reaction by inhibiting the inflammatory response and interfering with chemotaxis due to the inhibition of LTB4 release
        
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        Types of corticosteroid
        
        Inhaled corticosteroid
        
        Oral corticosteroid
        
        Nasal spray
      - Leukotriene pathway inhibitor
        
        Lipoxygenase inhibitor(Zileuton)
        
        Leukotriene antagonist(Montelukast, Zafirlukast)
        
        Membrane Phospholipids
        
        Arachidonic acid
        
        5-HPETE
        (5-hydroperoxyeisatertaenoic acid)
        
        LTA4
        
        LTB4
        
        LTD4, LTE4
        
        Prostanoids
      - Long-acting Beta Antagonist (LABA)
        
        Mimicking catecholamines, beta-2 agonists act as ligands to adrenergic receptors with increased selectivity towards beta-2 adrenergic receptors.
        
        Initiates a transmembrane signal cascade
        
        Adenylyl cyclase then increases intracellular cAMP via the hydrolysis of ATP
        
        The elevated cAMP concentration serves to activate cAMP-dependent PKA
        
        PKA acts to phosphorylate Gq-coupled receptors leading to a cascade of intracellular signals which have been proposed to reduce intracellular Ca2+ or decrease the sensitivity of Ca2+
        
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        In combination with an inhaled corticosteroid
        
        Salmeterol (most commonly used)
      - ASA desensitization
        
        When standard medical treatments are not effective or daily ASA/NSAIDs therapy is required for other medical conditions
        
        Improves deregulation of arachidonic acid metabolism by reducing activation of tyrosine kinase and generating inhibition of STAT6 phosphorylation, which leads to a decrease in IL4 production with downregulation of CysLT production and reduced expression of the CysLT1 receptor, ultimately leading to attenuation of airway inflammation and clinical improvement
        
        Reducing nasal polyps size and the need for sinus surgery as well as in improving nasal and bronchial symptoms with decrease in the doses of topical and oral corticosteroids
  - - - Development
        
        Begin with nasal congestion
        
        Followed by wheezing, coughing and shortness of breathe
        
        Progress into severe bronchospasms or death
        (in patients with unstable asthma)
      - Symptoms
        
        In upper/lower airways symptoms (30-180mins)
        
        Flushing
        
        Urticaria
        
        Gastrointestinal
    - - Development
        
        During the course of chronic airway disease
        
        Asthma
        
        Chronic rhinosinisitus with nasal polyps
        
        Prior to the onset of obvious respiratory disease
        
        Asthma
        
        Chronic rhinosinisitus with nasal polyps
      - Symptoms
        
        Upper airway symptoms
        
        1-5 years prior to asthma
        
        Chronic airway symptoms
        
        Loss of smell
        
        Asthma
        
        Increased prevalance of respiratory symptoms
        (after alcohol consumption)
        
        Nasal respiratory
        symptoms
        
        Bronchial respiratory
        symptoms
    - - Moderate to severe asthma
      - Increased in uncontrolled asthma
    - - Partial loss of smell (clinical marker to identify N-ERD patients)
      - Symptoms
        
        Nasal blockage
        
        Nasal congestion or stuffiness
        
        Facial pain or pressure
        
        Nasal discharge or postnasal drip
      - Presence of edema/mucosal obstruction, and/or nasal polyps, and/or mucopurulent discharge
      - Severe sinus opacification and extension than chronic rhinosinusitis with nasal polyps.
  - - - Acute asthma exacerbation at the lower airway.
      - Severe asthma morbidity
        (chest tightness, shortness of breath and wheezing).
      - Nasal congestions.
      - Bronchospasms.
    - - Aspirin
      - Ibuprofen
      - Naproxen
      - Diclofenac
  - - - Ask the patient if they have respiratory symptoms after taking aspirin or any NSAIDs. The respiratory symptoms may be accompanied by skin and gastrointestinal symptoms. Next, ask about underlying chronic respiratory disorders. The following clinical characteristics increase the probability of NERD diagnosis: loss of smell, moderate to severe asthma, intolerance of alcohol, blood eosinophilia. If the patient has all the symptoms, there is a higher probability of NERD.
    - - The EAACI recommended the oral challenge protocol with starting 20-40 mg of aspirin and gradually increasing the dose at 2-hour intervals. When no reactions occur within 3 hours after 325 mg of aspirin, the challenge is considered to be negative
        
        Bronchial
        
        Oral
        
        Nasal
    - - The basophil activation test
        
        Report the sensitivity and specificity values
      - LTE4 (in urine)
        
        Higher baseline concentration of urinary LTE4 after exposure to aspirin or NSAID
  - - - People with severe asthma and people who first experience asthma as adults and do not have known allergies as the cause is at high risk.
    - - Type 2 airway inflammation, patients with CRSwNP often have comorbid asthma and/or N-ERD
- - - - Chest tightness
      - Wheezing
      - Dry cough commonly at night
      - SOB
        
        Causes En Osman unable to complete his morning run
      - Hard to breathe
  - - - GERD
        
        Heartburn is one of symptoms of GERD
        
        As Mr. Osman experienced heartburn, he is likely to experience asthma-related GERD
        
        GERD can trigger several asthma symptoms.
        
        Aspiration
        
        Bronchoconstriction of small airways
        
        Indirectly via neurogenically induced inflammation
        
        The development of GERD can also triggered by asthma
        
        Difficulties in breathing due to asthma and consumption of asthma medication may lead to gastroesophageal reflux as the esophageal sphincter muscle relaxes
        
        Other asthma mechanisms due to consumption of asthma medication that can lead GERD
        
        increased intrathoracic pressure
        
        decreased lower esophageal sphincter pressure
        
        altered diaphragmatic crural function
        
        vagus nerve dysfunction
        
        This comorbid condition is known as asthma-related GERD
      - Chronic Rhinosinusitis
        
        It is associated with asthma as nasal polyps usually occur and reoccur in patients with asthma. Asthmatic patients have a higher severity score and more presence of nasal polyps than non-asthmatic people
        
        The airflow limitation of an asthma patient leads to inflammation that may trigger the formation of nasal polyps as the fluid builds up in the nasal passage
        
        The presence of nasal polyps can block nasal passage hence interfering the breathing.
        
        The blockage of airflow or airflow limitation increase the risk of an asthma attack and may worsen the asthmatic condition and symptoms
      - Other co-morbid that commonly associated with AOA
        
        Diabetes Mellitus Type 2
        
        Metabolic syndrome
        
        Cardiovascular diseases
        
        Obesity
        
        Psychological dusfunction
      - Previously recognized comorbidities
        
        Respiratory conditions
        
        Atopy/ Allergy
        
        COPD
        
        Rhinitis
        
        Vocal cord dysfunction
    - - Many of the triggers for both childhood and adult-onset asthma are the same.
        
        Smoke
        
        Mold and mildew
        
        Air pollution
        
        Feather bedding
        
        Dust mites
        
        Cockroaches
        
        Animal dander or saliva
        
        Respiratory infections or colds
        
        Cold temperatures
        
        Dry air
        
        Emotional stress or excitement
        
        Exercise
      - Exposure to one of the following triggers may provoke an asthma attack in all people with asthma, while different persons have various triggers
        
        However, the symptoms of asthma in adults are typically persistent and in order to keep asthma symptoms and flare-ups under control, daily therapy is frequently required
      - If allergens are the causes of the asthma symptoms, one need to take measures to eliminate known or possible allergens in the surrounding environment.
        
        Examine the workplace for potential allergies and take the appropriate precautions to limit the exposure to them
      - Breathing changes during strong emotions (excitement or stress) causes muscles to tighten up or breathing rate to increase
        
        To reduce the risk of having a stress-induced asthma attack or episode, stress must be properly managed.
        
        Symptoms
        
        Wheezing
        
        Coughing
        
        Shortness of breath
        
        Rapid breathing
        
        Chest tightness
      - Exercise can cause trigger the symptoms of asthma due to narrowing of the airways in the lungs triggered by strenuous exercise.
        
        If the symptoms are not treated, it can result in serious or life-threatening breathing difficulties.
        
        Symptoms
        
        Wheezing
        
        Shortness of breath
        
        Chest tightness or pain
        
        Fatigue during exercise
        
        Coughing
  - - - Female is more prone to get AOA due to associated with the shift or the changes in the hormonal levels especially during menopause and menstrual cycle
    - - GERD cause asthma symptoms by:
        
        Aspiration (stomach acids enter the lungs directly)
        
        Refluxed gastric acid irritates the nerve endings in the esophagus generating signals to the brain, thus stimulate the muscle and mucus production in the airways and cause airway constriction
    - - NSAID can trigger bronchoconstriction of airways
    - - Stress triggers 'flight and fight' response and cause faster heart rate, shallow and fast breathing and tense muscles.