Asthma: Diagnosis and Treatment

• Asthma is a heterogeneous disease characterized by chronic airway inflammation.
• Respiratory symptoms include wheezing, shortness of breath, chest tightness, and cough that vary over time.
• GINA (Global Initiative for Asthma) guidelines for asthma are updated yearly in the summer.
• Airflow obstruction is often reversible with treatment, but may not be complete in every patient
• The prevalence of people in the US affected by asthma is 8.4%

Epidemiology

• The prevalence of asthma was 7.3% in 2001, which means it is increasing
• Socioeconomic disparities exist in asthma cases
• Asthma can occur in children but may disappear or continue into adulthood
• Boys are more affected at a younger age, while women are more affected as adults
• Between 80% to 90% of asthma deaths are preventable, despite a low number of deaths at 0.19 per 1,000 persons with asthma

Etiology

• Asthma development is linked with genetic predisposition such as interleukin genes integrated with environmental factors such as atopy
• Environmental risk factors for asthma include:
  • Socioeconomic status
  • Family size
  • Secondhand tobacco smoke exposure
  • Allergen exposure
  • Ambient air pollution
  • Urbanization
  • Viral respiratory infections like respiratory syncytial virus RSV and rhinovirus
  • Decreased exposure to common childhood infectious agents
• In asthma, the altered immune response involves Th₂ > Th₁.

Pathophysiology

• Asthma involves acute and chronic inflammation.
• Early phase reaction is initiated by activation of cells bearing allergen-specific immunoglobulin E (IgE)
• Airway mast cells and macrophages release histamine, eicosanoids, and reactive O₂ species.
  • This induces airway smooth muscle contraction, mucus secretion, and edema.
• Inflammatory mediators induce microvascular leakage with exudation of plasma in the airways and leads to airway obstruction
• Characteristics of asthma include thickened airways and reduced mucus clearance.
• Formation of exudative plugs is promoted when mixed with mucus, inflammatory, and epithelial cells.
• Late-phase inflammatory events occur 6 to 9 hours post-allergen provocation.
  • They recruit activation of eosinophils, basophils, neutrophils, CD4+ thymically derived lymphocytes (T cells), and macrophages.
• T cells release Th₂-related cytokines after allergen challenge which modulates the late-phase response

Epithelial Cells

• Epithelial cells participate in mucociliary clearance and removal of noxious agents, and may also enhance inflammation.

• Extensive epithelial shedding occurs, especially in fatal asthma cases.

• Eosinophils release pro-inflammatory mediators, cytotoxic mediators, and cytokines

• Lymphocytes Th₂ cells secrete cytokines, such as IL-4, 5, and 13, and mediate allergic inflammation while decreasing the production of Th₁ cytokines

• Neonates cord blood T-cell population is skewed toward a Th₂ phenotype

• Exposure to pathogens correct imbalance and antibiotics/urban environments may perpetuate it

• Th₁ and Th₂ endotypes exist

• Th₂ high: Interleukin activation causes inflammatory cell activation with IgE secretion

• Th₂ low: Neutrophilic asthma/mixed/pauci-granulocytic asthma which is less understood and less responsive to corticosteroids.

  • These patients may only been diagnosed later in life as they have fewer allergic symptoms

Mast Cells

• Cell-bound IgE binds to allergen for release of mediators:
  • Histamine
  • Eosinophil and neutrophil chemotactic factors
  • Leukotrienes (LTs) C4, D4, E4 prostaglandins, etc.
  • Platelet-activating factor (PAF)
• Sensitized mast cells account for exercise-induced bronchospasm (EIB)

Other Cell Types

• Alveolar macrophages engulf/digest bacteria and release pro/anti-inflammatory mediators
• Neutrophils contribute to occupational exposures and release inflammatory mediators
• Fibroblasts are induced by interleukins.
• Myofibroblasts increase beneath reticular basement membrane.

Inflammatory Mediators

• Histamine induces smooth muscle constriction/bronchospasm
• Platelet activating factor (PAF) cause bronchospasms, edema, chemotaxis of eosinophils
• Arachidonic acid and its metabolites are inhibited by steroids
• Prostaglandins promote bronchoconstriction, edema, vasodilation and inflammation
• Thromboxane A2 causes bronchoconstriction, inflammation and is a product of prostaglandin metabolism by thromboxane synthase.
• Leukotrienes are inhibited by montelukast and monoclonal antibodies
• LTD4 and E4 produces bronchospasm, mucus secretion, micro-vascular permeability, airway edema
• LTB4 granulocyte chemotaxis

Corticosteroids

• Glucocorticoids affect the immune system.
• Mineralocorticoids affect blood pressure/electrolytes
• Elevated mucus production by bronchial epithelial & goblet cells with a high viscosity
• Airway smooth muscle hypertrophy and hyperplasia occur, secondary to chronic inflammation

Inflammation

• Neurogenic inflammation involves stimulation of irritant receptors by mechanical, chemical, and pharmacologic agents, leading to reflex release and bronchoconstriction.
• Vasoactive intestinal peptide VIP inhibitory neurotransmitter is inhibited by peptidase release
• Nitric oxide (NO) is a neurotransmitter that produces smooth muscle relaxation and amplifies inflammation
• Airway remodeling in asthma involves chronic inflammation followed by healing and altered structure in the airways.
  • Repair involves the parenchymal replacement cells and maturation to scar tissue replacement.
  • Remodeling presents with extracellular matrix fibrosis, an increase in smooth muscle/mucous, and angiogenesis.
• Drugs and asthma
  • Estrogen replacement during menopause may exacerbate asthma, unless estrogen is given in combination with progesterone
  • Aspirin inhibits cyclooxygenase-1 (COX-1) and inhaled corticosteroids are the primary preventive treatment
  • Nonselective β-blocking agents (e.g., propranolol) do not precipitate bronchospasm, but prevent its reversal

Clinical Presentation

• Chronic asthma
• Acute severe asthma
• Exercise-induced bronchospasm
• Nocturnal asthma

Diagnostics for Chronic Asthma

• Asthma is characterized by exacerbation and remission.
• Symptoms include shortness of breath, chest tightness, coughing, wheezing
• These occur with exercise, spontaneously, or with known allergens, particularly at night
• Signs of asthma include wheezing, prolonged expiratory phase, dry cough and atopy
• Spirometry demonstrates obstruction, with FEV₁ increasing by 12% and 200 mL after inhaled ẞ₂-agonist administration. FEV1/FVC ratio normally >0.75 to 0.80 (adults), and >0.85 (children).
• Variability in PEF over 2 weeks >10% (adults) and >13% (children).
• Fall in FEV₁ ≥10% after near-maximal exercise for 6 minutes.
• Elevated eosinophil count and IgE concentration in blood.
• Elevated FeNO

Acute Severe Asthma

• An episode can progress over several days/hours, or rapidly over 1 to 2 hours.
• This anxiety-inducing condition includes severe dyspnea, chest tightness, or burning with symptoms unresponsive to treatment.
• Signs include expiratory and inspiratory wheezing, dry hacking cough, tachypnea, tachycardia, pale/cyanotic skin, and retractions.
• Laboratory: -Peak expiratory flow/or FEV₁ <40% of normal predicted values.
  • Decreased arterial O₂ (PaO2), and O₂ saturations by pulse oximetry with severe obstruction with decreased arterial/capillary CO2.
• Blood gases assess metabolic acidosis (lactic acidosis)
• Complete blood count if there are signs of infection
• serum electrolytes as therapy with B₂-agonist and corticosteroids to lower potassium, magnesium, and phosphate, and increase glucose
• Chest radiograph if signs of consolidation

Exercise-Induced Bronchospasm

• Drop in FEV₁ of 10% or greater from baseline
• Returns back to baseline function within ≈ 30 minutes Nocturnal Asthma
• Usually has symptoms of inadequately treated persistent asthma, which may be worsened by GERD, sleep apnea or sinusitis

Asthma Treatment Goals

• Asthma management goals involve good symptom control and maintaining normal activity while reducing exacerbations, fixed airflow limitation, and side effects.
• All patients 6 years and older have quick-relief medication via inhaled B₂-agonists with or without ICS or MART for acute symptoms.
• For persistent asthma, ICS the the preferred long-term control therapy.
• In inadequately controlled low-dose ICS patients: they need both an increased dose of the ICS and combination of both ICS and LABA
• Other therapies: montelukast, theophylline, tiotropium, bronchial thermoplasty or given as subcutaneous injection.
• Patients must be assessed every three months, and ICS doses lowered by 25-50% every 3 months

Children

• The primary differences in management are Step 1 does not need controller treatment and Step 3 involves doubling the ICS rather than adding LABA. -In delivery, the use of an MDI with a valved spacer and facemask is preferred and should be given over 5 to 10 breaths
• ICS can cause reductions in growth

Elderly

Due to increased risk of osteoporosis/cataracts, those requiring high doses of ICSs must have the following: - Routine height measurements -Bone mineral density determinations - Ophthalmic examinations

• It is worth noting ICS use may contribute to skin bruising.

Those Pregnant and Lactating

• They should be given low-dose ICSs as the preferred treatment for mild persistent asthma
• It is important to add with a LABA if not well controlled and avoid stepping down therapy during gestation.
• Budesonide and albuterol are the preferred drugs for this population.
• Fentanyl, rather than morphine, should be used during delivery since Morphine release histamine.
• Factors for death from asthma are the following: near-fatal history, current use of oral corticosteroids, no current use of ICSs, and overuse of short acting beta agonists.

Management of Acute Exacerbations

• B2-agonists and, Systemic corticosteroids and Inhaled ipratropium, and Intravenous magnesium all given immediately
• Must monitor Pulse ox, Peak Flow and physical exam
• Must consider other causes: PNA

Management of acute exacerbations for Adults

• In intermittent dosing administration with 20 minutes for 3 hours results in equivalent improvement.
• However, higher improvement occurs with continuous therapy especially if less than 50 percent expected or personal best
• Elevated HR is not a reason to avoid beta agonists

Corticosteroids

• They affect beta receptors and reduce cytokines and cells
• Generic names include beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, and mometasone
• Systemic corticosteroids can be given to address severe situations
• Can cause leukocytosis and elevated glucose and lactic acid
• Beta agonist can cause hypokalemia and higher glucose/lactic acid
• Should use caution in those with heart and diuretics
• Ipratropium is a competitive M2 inhibitor to allow further acetylcholine release -Long term can dry stuff up
• Theophylline causes bronchospasm but don’t mix with b-agonist

Biologics

• Omalizumab xolair and recombinant anti IgE
• Used In moderate to severe

Dupixent

• il 4 antagonist reduces mediators

Cromolyn

• Mast cell stabilizer

Montelukast

• It is FDA approved as of the last year of this recording for EIB asthma

Theophylline

• Is a methylxanthine, Non-specifically inhibits phosphodiesterase and complicated dosing and has a narrow therapeutic Index.
• Can cause seizures and arrhythmias
• No drinking and beta agonist unless really critical
• Red green personal measure

Patient monitoring

• Monitor Peak Flow measures and keep a diary as well

Peak flow rate

• Monitor and measure 2-4 times daily and note any changes in peak flow rate or changes in asthma symptoms

This quiz covers diagnosis, treatment, and management of asthma, including the roles of Th1 and Th2 cells, medications like β2-agonists and corticosteroids, and nonpharmacologic therapies. It also addresses the interpretation of inhaler usage and goals in managing acute exacerbations.