2.1: Wheezing and Breathlessness
Kristie Kim (480388069), William Lau (480345316), Joshua Lee (480344696), Jacqueline Lim (480345017), Florensia Natali (470275429)
Predisposing Factors
Pathophysiology
Maternal asthma (brother also has asthma)
Signs and Symptoms
Atopy (atopic dermatitis and HDM allergy)
Investigations
4 years old
Diagnosis
Pet dog
Management
Passive smoking (paternal smoking and maternal smoking during pregnancy)
Second hand exposure to particulates (father is a builder)
Potential allergens
Higher risk in children
Genetic tendency to develop allergic diseases
Allergen exposure to mucosal epithelium
Mechanism unknown - possibly induces mutation and damage
Epithelial cells release thymic stromal lymphopoietin
Cough at night, dyspnea, wheeze (respiratory Sx consistent with asthma)
Reversible airway constriction with salbutamol
CHRONIC ASTHMA
Reduces risk of asthma (hygiene hypothesis)
Dendritic cells activated
Exercise-induced bronchoconstriction
Dendritic cells detect + phagocytose allergen via PRRs
Allergen expressed on MHCII complex
Increased activation of allergic pathway
DC presents allergen to naive CD4+ T-cell (also OX-40/OX-40L costimulatory signal)
Pharmacotherapy
Lack of microbial burden leads to Th2 bias
Preventers
Spirometry
Relievers
Th0 cell differentiates into Th2, also clonal expansion
Reduced FEV1
Beta agonists
Reduced FVC
Th2 releases a range of cytokines
Reduced FEV1/FVC ratio (<80%)
LAβAs (Long Acting Beta Agonists)
ultraLAβA (ultra Long Acting Beta Agonists) mostly for COPD
IL4 + 13 - activates B-cell, causing differentiation to plasma cells and class-switching to stimulate IgE secretion
IgE bind to FcεR1 on mast cells; cross-linkage and binding with antigen
Increased RV (from gas trapping)
Inhaled corticosteroids
Dual therapy (LAβA + ICS)
SAβAs (Short Acting Beta Agonists)
Formeterol
Salmeterol
Increased FRC
Indacaterol
Vilanterol
Degranulation of mast cells (also basophils and eosinophils)
Firstly, release of preformed granules, including histamine, trypaste, and heparin (1-5 minutes)
Fenoterol
Asthma exacerbation
For Acute Exacerbations
Antimuscarinics (mainly for COPD, not asthma)
SAMAs
LAMAs
Oral corticosteroids
Ipratropium
Tiotropium
Leukotriene receptor antagonist (mainly for children)
TNFα, IL-8 and IL-6 recruit other immune cells
Montelukast
Phosphodiesterase inhibitors
Non-selective
IL5 and IL-3 recruit basophils and eosinophils
Leukotrienes are released
Leukotrienes bind to cysLT1R on smooth muscle cell
--> bronchoconstriction
Selective
Aminophylline
Caffeine
Monotherapy (preventers)
Histamine binds to H1R of airway smooth muscle cell
Fluticasone
Budesonide
Ciclesonide
Secondly, release of lipid-derived mediators (through activity of PLA2), including LT-4 and PGD2 (5-30 minutes)
Cromones
Cromoglycate
Thirdly, release of cytokines which maintain the allergic response (5-8 hours)
For Allergies
Rhinorrhoea - mucopurulent secretions
Sympathetic control (indirect)
ACh released by presynaptic neurons activates adrenal medulla
Short course, high dose OCS for acute exacerbations
Antihistamines particularly for allergies
Injected and red tympanic membrane and pharynx
Second generation (less sedating) antihistamines
Fexofenadine
α subunit of Gq protein dissociates from GPCR and activates PLC
Loratadine
Cetirizine
First generation (sedating) antihistamines
Corticoid release into blood stream - adrenaline and noradrenaline (4:1 ratio)
IP3 and DAG lead to increase in intracellular Ca2+
Smooth muscle contraction and bronchoconstriction
Adrenaline and noradrenaline bind to β2-adrenoceptors
Cysteinyl leukotrienes promote cytokine release, leukocyte recruitment and bronchoconstriction
G-s protein coupled receptor
Promethazine
GTP binds to G-s protein, α subunit unbinds, activates adenylyl cyclase
Symbicort: formeterol + budesonide
AC activates cyclic Adenosine Monophosphate (cAMP)
Acute asthma
cAMP activates PKA by phosphorylation
IL-4, IL-5, IL-13 induce goblet cell hyperplasia
Smooth muscle contraction inhibited, bronchodilation
Seretide: Salmeterol + Fluticasone propionate
Repeated inflammatory responses induce remodelling
Increased Type III collagen and angiogenesis
Smooth muscle hypertrophy and hyperplasia
Hyperplasia of submucosal mucus glands and Goblet cells
Thickening of basement membrane
Antihistamines blocks H1 receptor of airway smooth muscle cells
Increased airway hyperresponsiveness
Montelukast leukotriene receptor antagonist (mostly used in children)
Loss of ciliated columnar epithelial cells
Beta agonists relax airway smooth muscle by stimulating beta2 adrenoreceptor
Positive feedback loop where inflammatory responses and remodelling exarcebate each other
Parasympathetic control by vagus nerve
ACh released into neuromuscular junction, onto airway smooth muscle
Bilateral expiratory wheeze
ACh binds to M3ACh receptor
GTP binds to Gq, α subunit dissociates and activates PLC
Low SAO2 (<95%)
Alpha1 agonists (oral decongestants)
Activation of secondary messengers: IP3 & DAG
Pseudoephedrine
Phenylephrine
Antagonises bronchoconstriction
Theophyllines
Roflumilast mainly for COPD
Increase cytosolic Ca2+
Binds to calmodulin, interacts with myosin light chain kinase
Alpha1 agonists stimulates alpha1 adrenoceptors to cause vasoconstriction
Smooth muscle contraction & bronchoconstriction
Response is exacerbated by inflammatory mediators acting through the same pathway
Muscarinic Antagonists Block the action of ACh preventing smooth muscle constriction (mostly in COPD)
Histamine binds to H1R on endothelial cells
Vasodilation, increased vascular permeability
Binds to calmodulin, interacts with myosin light chain kinase
Non-pharmacological therapy
Avoid triggers
Salbutamol
Beclomethasone
Check puffer/spacer technique and drug adherence
Prednisone/Prednisolone
Adrenaline (for anaphylaxis)
Nedocromil
(Dex)chlorpheniramine