MEDICINE II

3B ASTHMA
M-22.1 Dr. Oliver D. Lac ambra | April 2020
 Asthma is a syndrome characterized by airflow obstruction that Infections
varies markedly, both spontaneous and with treatment o Viral infections (Rhinovirus)
 Narrowing of the airways is usually reversible, but in some o RSV in infancy
patients with chronic asthma there may be an element of o Mycoplasma, Chlamydia “hygiene hypothesis” - less exposure to
irreversible airflow obstruction infections during childhood preserves the T-helper cells instead
PREVALENCE of the protective T- helper 1
 Most common chronic disease among children worldwide o Intestinal parasitism - associated with reduced risk of asthma
 300 million people are living with asthma Diet
 250,000 deaths annually — Controversial
 10-12% of adults; 15% of children — Diets low in antioxidants, high in sodium & omega-6 polyunsaturates
 Over 80% of asthma-related deaths occur in low-and lower-middle — Vitamin D deficiency
income countries — Obesity
 Treatment and effective management of asthma saves lives Air Pollution
 Peak age of 3 years o Sulfur dioxide, ozone & diesel particulates
 Children: twice as many male as female o Exposure to road traffic pollutions
 Adult: male & female equal o Indoor air pollution
 Adolescence - mostly asymptomatic o Maternal smoking
 Deaths – uncommon Allergens
o Inhaled allergens
RISK FACTORS & TRIGGERS o House dust mites
Atopy o Domestic pets
— Major risk factor Occupational Exposure
— Allergic rhinitis – found in > 80% of asthmatic patients — Occupational asthma - affect up to 10% of young adults
— Most common allergens: house dust mites, cat & dog fur, — > 300 sensitizing agents
cockroaches, grass & tree pollens, rodents — Chemicals
— Allergens in the workplace
— Aerosol & cleaning liquids
— Improves during weekends & holidays
Obesity
— Asthma occurs more frequently in obese people
 BMI > 30kg/sq mtr
— More difficult to control
Other Factors
o Lower maternal age
o Duration of breastfeeding
o Prematurity & low birth weight, inactivity

INTRINSIC ASTHMA
 (-) Skin tests to common inhalant allergens
 Normal serum concentration of IgE
 Later onset
 Nasal polyps, aspirin-sensitive
 More severe, persistent asthma
Genetic Predisposition  Staphylococcal enterotosoxins
— Familial association
— Severity is genetically determined ASTHMA TRIGGERS
— Polygenic  airway narrowing
— Polymorphisms of genes on chromosome 5q, including the T  wheezing
helper 2 cells, IL-4, IL-5, IL-9 & IL-13  dysphasia
Epigenetic Mechanism 1. ALLERGENS
— in the early development of asthma — Activates mast cells with bound IgE - release of
— DNA methylation & histone modification bronchocontrictor mediators
— may occur in the fetus

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— Dermatophagoides = most common allergens to trigger  Vasodilator and angiogenesis
asthma - Bronchoscopy: airways are narrowed, erythematous and
— Grass/tree pollen, fungal spores - cats & other domestic edematous
pets, cockroaches  These pathologic changes are found in all airways,
2. VIRUS INFECTIONS but do not extend to the lung parenchyma;
— Rhinovirus, RSV, coronavirus — Peripheral airway inflammation is found
— ↑ in airway inflammation particularly in patients with severe asthma.
— ↓ Production of type 1 interferons, resulting in ↑ — Involvement of airways may be patchy and
susceptibility to viral infections & greater inflammatory this is consistent with bronchographic
response findings of uneven narrowing of the airways
3. PHARMACOLOGIC AGENTS
o Beta blockers AIRWAY INFLAMMATION
o ACE inhibitors  Inflammation from trachea to bronchioles
o Aspirin  Associated with airway hyperresponsiveness
4. EXERCISE  Pattern of inflammation → allergic diseases
— Particularly in children  Acute inflammatory episodes on top of chronic inflammatory state
— Linked to hyperventilation → mast cell mediator release  Eosinophilic infiltration; severe → neutrophilic pattern of
→ bronchoconstriction inflammation
— After exercise has ended
5. PHYSICAL FACTORS
— Cold air & hyperventilation
— Laughter
— Weather changes
— Strong odors/perfumes
6. AIR POLLUTION
— ↑ Levels of sulfur dioxide, ozone, diesel particulates &
nitrogen oxide
7. FOOD & DIET
— Allergic reactions to food → little evidence
— Shellfish, nuts
— Food additives
8. OCCUPATIONAL FACTORS
— Associated with symptoms at work with relief on
weekends and holidays
9. HORMONES
— Premenstrual worsening of asthma
— Thyrotoxicosis, hypothyroidism
10. GERD
— Reflex bronchoconstriction
11. STRESS
— Worsening symptoms with stress
— Psychological factors might trigger reflex
bronchoconstriction
* Bereavement - may even improve asthma

PATHOPHYSIOLOGY
 Asthma is associated with a specific chronic inflammation of the
mucosa of the lower airways. One of the main aims of treatment is
to reduce this inflammation.
 Airway mucosa infiltrated with activated eosinophils, T
lymphocytes, mast cells
 Thickening of the basement membrane due to subepithelial
collagen deposition
 Increased numbers of epithelial cells in the lumen
 Airway is thickened and edematous However, many inflammatory cells are involved in asthma with no key cell
 Occlusion of lumen by mucus plug that is predominant

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MAST CELLS CYTOKINES
- Initiate acute bronchoconstriction in response to allergens - Regulate chronic inflammation
- Found at the airway surface, airway smooth muscle layer - TH2 cytokines IL-4,IL-5, IL-9, IL-13 mediate allergic inflammation
- Activated by allergen thru IgE-dependent mechanism - Pro inflammatory cytokines TNF alpha & IL-1 beta amplify
- Release bronchoconstrictor mediators: histamine, inflammation, more severe disease
prostaglandind2, leukotrienes, cytokines, chemokines, growth - IL-10 & IL-12 which are anti- inflammatory maybe deficient in
factors, neurotrophins asthmatic patients
MACROPHAGES CHEMOKINES
- Derived from monocytes - Attract inflammatory cells
- Traffic into airways OXIDATIVE STRESS
- Release of certain pattern of cytokines - ↑ is related to disease severity
DENDRITIC CELLS - Amplify inflammation
- Take up allergens - ↓ response to steroid
- Production allergen-specific T cells NITRIC OXIDE
EOSINOPHILS - Related to the eosinophilic inflammation
- Eosinophil infiltration  The level of NO in the expired air of patients with asthma is higher
- Marked increase in activated eosinophils in the airways than normal. Increased NO may contribute to the bronchial
- Linked to the development of AHR through the release of basic vasodilation observed in asthma
proteins and oxygen-derived free radicals
NEUTROPHILS EFFECTS OF INFLAMMATION
- Increased numbers of activated neutrophils are found in sputum AIRWAY EPITHELIUM
and airways of some patients with severe asthma and during - Airway epithelial shedding → AHR
exacerbations - Loss of barrier function
LYMPHOCYTES - Loss of enzymes
- Release specific patterns of cytokines: recruitment & survival of - Loss of relaxant factor
eosinophils, maintenance of mast cell population - Exposure to sensory nerve
- Asthmatic immune system: th2 cells FIBROSIS
- Normal airways: TH1 cells predominate - All asthmatic patients have thickened basement membrane due
- TH2 cells thru IL-5 - associated with eosinophilic inflammation to subepithelial fibrosis with deposition of types III and V collagen
- TH2 cells thru IL-4 & IL-13 - associated with increased IgE below the true basement membrane and is associated with
formation eosinophil infiltration
 STRUCTURAL CELLS AIRWAY SMOOTH MUSCLE
- Epithelial cells, fibroblasts, and airway smooth-muscle cells - Hypertrophy & hyperplasia
- Important sources of inflammatory mediators such as cytokines and - ↓ Responsiveness to beta-agonist
lipid mediators, in asthma - Chronic inflammation
- Major sources of mediators driving chronic inflammation in asthmatic VASCULAR RESPONSES
airways. - ↑ Airway mucosal blood flow → airway narrowing
- Epithelial cells may have key roles in translating inhaled - Angiogenesis
environmental signals into an airway inflammatory response - Airway edema & plasma exudation
MUCUS HYPERSECRETION
INFLAMMATORY MEDIATORS - Viscid mucus plugs → occlude airways
 Mast cell mediators (histamine, prostaglandin, leukotrienes): - Hyperplasia of submucosal glands
o Contract airway smooth muscle - ↑ Number of epithelial goblet cells
o ↑ microvascular leakage
o ↑ airway mucus secretion AIRWAY REMODELLING
o Attract other inflammatory cells - ↑ Airway smooth muscle
- Fibrosis
- Angiogenesis
- Mucus hyperplasia

PHYSIOLOGY
- limitation of airflow:
1. bronchoconstriction
2. airway edema
3. vascular congestion
4. luminal occlusion

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- This results in:  No limitations on activities, including exercise
o ↓ in FEV1, FEV1/FVC ratio  Peak Expiratory Flow (PEF) circadian variation < 20%
o ↑ airway resistance, residual ventilation, lung  (Near) normal PEF
hyperinflation  Minimal (or no) adverse effects from medicine
o V/Q mismatch (increased pulmonary blood flow result in
mismatching of ventilation and perfusion and in bronchial BRONCHODILATOR THERAPIES
hyperemia) - Reverse bronchoconstriction
o ↓Arterial PCO2 - Rapid relief of symptoms
- Little or no effect on the underlying inflammatory process
AIRWAY HYPERRESPONSIVENESS - 3 classes:
- Characteristic physiologic abnormality a. beta-2- adrenergic agonists
- Linked to the frequency of symptoms b. anticholinergics
- Important aim of therapy is to reduce AHR c. theophylline
- Beta-2-agonist - most effective
CLINICAL FEATURES BETA 2 AGONISTS
 The characteristic symptoms of asthma are wheezing, dyspnea, and MODE OF - Relaxes smooth muscles
coughing, which are variable, both spontaneously and with therapy. ACTION - Inhibit mast cell mediator release
 Symptoms may be worse at night, and patients typically awake in the - Reduction in plasma exudation
early morning hours. Patients may report difficulty in filling their - Inhibition of sensory nerve activation
lungs with air. - No effects on inflammation
 Typical physical signs are inspiratory, and to a greater extent - No reduction in AHR
expiratory, rhonchi throughout the chest, and there may be CLINICAL - inhalations
hyperinflation. USE  SABA: (albuterol & terbutaline)
 Some patients, particularly children, may present with a - 3-6h (rapid onset)
predominant nonproductive cough (cough-variant asthma). - symptom relief (relievers)
- prevent EIA if taken prior to exercise
DIAGNOSIS  LABA: (salmeterol, formoterol)
 Symptoms of variable and intermittent airways obstruction - over 12h
 Measurements of lung functions - should not be given in the absence of ICS
LUNG FUNCTION TESTS therapy
- reduced FEV1, FEV1/FVC ratio & PEF - reversibility:  LABA + ICS (LABAs should not be given in the absence
 >12% and 200ml increase in FEV1 in 15 mins after an of ICS therapy because they do not control the
inhaled SABA underlying inflammation. They do, however, improve
- Twice daily measurement of PEF asthma control and reduce exacerbations when
- ↓ peak flow & maximum expiratory flow added to ICS, which allows asthma to be controlled
- Whole body plethysmography: ↑ airway resistance, TLC & RV at lower doses of corticosteroids.)
HEMATOLOGIC TEST: not usually helpful SIDE - tremors & palpitations
IMAGING: usually normal, maybe hyper inflated lungs in severe cases EFFECTS - hypokalemia
EXHALED NO (FeNO): a noninvasive test to measure eosinophilic airway TOLERANCE Potential problem when given chronically
inflammation SAFETY - There is an association between mortality the
amount of SABA used
DIFFERENTIAL DIAGNOSIS - LABA - no adverse effects in adults or children
 Upper airway obstruction ANTICHOLINERGICS
 Laryngeal edema - Ipatropium bromide
 Endobronchial obstruction with a fb - Prevent cholinergic nerve-induced bronchoconstriction & mucus
 LV failure secretion
 Vocal cord dysfunction - Less effective than beta-2-agonist
 Eosinophilic pneumonias & systemic vasculitis, polyarteritis nodosa - LAMA (tiotropium) maybe used as additional bronchodilator that
 COPD is not controlled by LABA-ICS combinations
- Slower onset of bronchodilator
TREATMENT - S/E: dry mouth, urinary retention
AIMS OF ASTHMA THERAPY THEOPHYLLINE
 Minimal (ideally no) chronic symptoms - Used to be widely used as oral bronchodilator
 Minimal (infrequent) exacerbations - Inexpensive
 No emergency visits - Side effects are common
 Minimal (ideally no) use of a required Beta-2- agonist - Inhibition of phosphodiesterase in airway smooth muscle cells

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- At lower dose has anti-inflammatory effect - Little benefit in long term control
- CLINICAL USE: - Short duration of action
o OD or BID Anti-IgE
o Additional bronchodilator in severe asthma - Omalizumab
o Aminophylline - in very severe exacerbations - Given SQ q 2-4 weeks
- S/E: N/V, headache, palpitations, arrhythmia, seizure ;rare if - A blocking Ab → neutralizes IgE
plasma concentration is < 10mg/L - May reduce exacerbations & may improve asthma control
- Expensive
CONTROLLER THERAPIES - To highly selected patients who are not controlled on maximal
INHALED CORTICOSTEROIDS (ICS) doses of inhaler
- most effective controllers Anti-IL-5
- ↓ Inflammatory cell numbers - Mepolizumab, Reslizumab, Benralizumab
- ↓ Eosinophils in airways & sputum - ↓ Blood & tissue eosinophils
- ↓ AHR in chronic ICS therapy - ↓ Exacerbations in patients with have increased sputum
- Usually given bid eosinophils
- Rapidly improves symptoms IMMUNOTHERAPY
- Effective in preventing severe exacerbations ALTERNATIVE THERAPIES
- 1st line treatment in persistent asthma
BRONCHIAL THERMOPLASTY
FUTURE THERAPIES
- Beta- agonist + Steroid - effective
- Antileukotrines has weak effects
- Anti-TNF alpa Ab- not effective in severe asthma
- Anti-IL-13 blocking Ab has little clinical effects
- Dupilumab (antibody against both IL-4, Il-13) is more promising
in ↓ exacerbations

MANAGEMENT OF CHRONIC ASTHMA

 Triggers should be avoided
 Assess asthma control by: symptoms, night awakening, need for
reliever inhalers, limitation of activity and lung function
SYSTEMIC CORTICOSTEROIDS  Avoidance of side effects & expense of medications
- For acute severe asthma
STEPWISE THERAPY
- Hydrocortisone/methyprednisolone
- Oral form (prednisone/prednisolone) SYMPTOMS TREATMENT
- Given 5-10 days; no tapering needed Mild Intermittent SABA for symptom relief
- S/E: truncal obesity, bruising, osteoporosis, diabetes, HPN, gastic Mild Persistent SABA + ICS low dose
ulcer, cataracts Moderate Persistent SABA + ICS (ld) + LABA
ANTILEUKOTRIENES Severe Persistent SABA + ICS (hd) + LABA
A. CYSTEINYL-LEUKOTRIENES Very Severe Persistent SABA + ICS (hd) + LABA + OCS
- Activation of cys-LT1 receptors  Regular controller is needed when use of reliever is required more
- Potent bronchoconstrictors than twice a week
- Cause microvascular leakage  Treatment of choice for all patients: ICS bid
- ↑ Eosinophilic inflammation  If not controlled by ICS → ICS + LABA
- Produced predominantly by mast cells  Controller dose should be adjusted
B. MONTELUKAST, ZAFIRLUKAST  Consider add-on therapy
- Blocks csy-LT1 receptors  Once controlled, slowly decrease therapy
- Modest clinical benefit
- Less effective than ICS ACUTE SEVERE ASTHMA
- Less effect on airway inflammation  ↑ Chest tightness, wheezing, dyspnea that are poorly relieved by
- Useful as an add-on therapy usual meds
- OD or BID  Breathless, cyanotic
CROMONES  ↑ RR, hyperinflation & tachycardia
- Cromolyn Na, Nedocromil Na  Pulses paradoxus
- Inhibit mast cell & sensory nerve activation  Marked ↓ in spirometric values & PEF
- Effective in blocking trigger-induced asthma (EIA, allergen-  ABG’s: low PCO2, hypoxemia
induced asthma)  CXR: normal or pneumonia or pneumothorax

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TREATMENT APIRIN-SENSITIVE ASTHMA
 O2 sat > 90% - high dose of SABA  1-5% worse with aspirin & COX inhibitors
 Seriously ill (impending respiratory failure), may give IV beta-2-  Preceded by rhinitis, nasal polyps
agonist  Rhinorrhea, conjunctival injection, facial flushing & wheezing -
 Add on: anticholinergic nebulization genetic predisposition to increased production of cysteinyl-
 Slow infusion of aminophylline leukotrienes
 Intubation  Responds to usual therapy with ICS
 Avoid sedatives
 Antibiotics if with pneumonia ASTHMA IN THE ELDERLY
 Principle of management is same
REFRACTORY ASTHMA  Side-effects of therapy more frequent
 5% have refractory asthma  Comorbids more common
 Adherence to therapy & inhaler technique  COPD more likely coexist
 Maintenance with OCS
 2 patterns of difficult asthma:
1. Persistent symptoms with poor lung function
2. Normal lung functions but intermittent, severe
exacerbations
Mechanisms
o Poor adherence with medications (ICS)
o Exposure to high ambient allergens or unidentified occupational
agents
o Severe rhinosinusitis
o Beta blockers, aspirin
o Hyper/hypothyroidism

CORTICOSTEROID- RESISTANT ASTHMA

 Poor response to steroid
 Affects <1 in 1000 patients
 Defined by: failure to respond to high dose of oral prednisone
(40mg OD x 2 weeks)
 Molecular abnormalities that impair anti-inflammatory action of
steroids.

BRITTLE ASTHMA
TYPE 1
- Chaotic variations in lung functions
- May require OCS or continuous infusion of beta-2-agonist
TYPE 2
- Normal or near-normal lung functions, but precipitous &
unpredictable fall in LF
- Most effective Tx: SQ epinephrine

REFRACTORY ASTHMA
 Difficult to control
 Adherence & correct use inhalers
 Identify & eliminate triggers
 Low dose of theophylline maybe helpful
 Many will require maintenance with OCS
 Steroid-sparing therapy are rarely effective
 Allergic asthma: Omalizumab
 (+) Sputum eosinophils: Anti IL-5
 Anti-TNF not effective
REFERENCES:
ASTHMA LECTURE BY DR. LACAMBRA
HARRISON’S PRINCIPLE OF INTERNAL MEDICINE 20TH Ed.

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