ASTHMA

Oliver D. Lacambra
Dept of Internal Medicine
CSU - College of Medicine

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 ASTHMA
PREVALENCE
• most common chronic disease among
children worldwide
• 300 million people are living with asthma
• 250,000 deaths annually
• 10-12% of adults; 15% of children
• Over 80% of asthma-related deaths occur in
low-and lower-middle income countries
• treatment and effective management of
asthma saves lives
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• peak age of 3 years
• children: twice as many ♂ as ♀
• adult: male & female equal
• adolescence - mostly asymptomatic
• deaths - uncommon

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 RISK FACTORS & TRIGGERS
ATOPY
- major risk factor
- allergic rhinitis - found in > 80% of
asthmatic patients
- most common allergens: house dust
mites, cat & dog fur, cockroaches,
grass & tree pollens, rodents

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 RISK FACTORS
ENDOGENOUS ENVIRONMENTAL
Genetic predisposition Indoor allergens
Atopy Outdoor allergens
Airway hyperresponsiveness Occupational sensitizers
Gender Passive smoking
Ethnicity Respiratory infections
Obesity Air pollution
Early viral infections Diet
Dampness & mold exposure
Acetaminophen

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 TRIGGERS
- allergens
- upper respiratory tract viral infections
- exercise & hyperventilation
- cold air
- sulfur dioxide & irritant gases
- drugs (beta blockers & aspirin)
- stress
- irritants (household sprays, paint, fumes)

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RISK FACTORS
GENETIC PREDISPOSITION
- familial association
- severity is genetically determined
- polygenic
- polymorphisms of genes on chromosome
5q, including the T helper 2 cells, IL-4,
IL-5, IL-9 & IL-13

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RISK FACTORS
EPIGENETIC MECHANISMS
- in the early development of asthma
- DNA methylation & histone modification
- may occur in the fetus

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RISK FACTORS
INFECTIONS
- viral infections (Rhinovirus)
- RSV in infancy
- Mycoplasma, Chlamydia
- “hygiene hypothesis” - less exposure to
infections during childhood preserves the
T-helper cells instead of the protective T-
helper 1
- Intestinal parasitism - associated with
reduced risk of asthma
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RISK FACTORS
DIET
- controversial
- diets low in antioxidants, high in sodium
& omega-6 polyunsaturates
- vitamin D deficiency
- obesity

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RISK FACTORS
AIR POLLUTION
- sulfur dioxide, ozone & diesel particulates
- exposure to road traffic pollutions
- indoor air pollution
- maternal smoking

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RISK FACTORS
ALLERGENS
- inhaled allergens
- house dust mites
- domestic pets

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RISK FACTORS
OCCUPATIONAL EXPOSURE
- occupational asthma - affect up to 10% of
young adults
- > 300 sensitising agents
- chemicals
- allergens in the workplace
- aerosol & cleaning liquids
- improves during weekends & holidays

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RISK FACTORS
OBESITY
- asthma occurs more frequently in obese
people (BMI > 30kg/sq mtr)
- more difficult to control

OTHER FACTORS
- lower maternal age
- duration of breastfeeding
- prematurity & low birth weight, inactivity
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 INTRINSIC ASTHMA
• (-) skin tests to common inhalant allergens
• normal serum concentration of IgE
• later onset
• nasal polyps, aspirin-sensitive
• more severe, persistent asthma
• staphylococcal enterotosoxins

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ASTHMA TRIGGERS
• airway narrowing
• wheezing
• dysphasia

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ASTHMA TRIGGERS
ALLERGENS
- activates mast cells with bound IgE -
release of bronchocontrictor mediators
- dermatophagoides = most common
allergens to trigger asthma
- grass/tree pollen, fungal spores
- cats & other domestic pets, cockroaches

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ASTHMA TRIGGERS
VIRUS INFECTIONS
- rhinovirus, RSV, coronavirus
- ↑in airway inflammation
- ↓ prod’n of type 1 interferons, resulting
in↑ susceptiblility to viral infections &
greater inflammatory response

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ASTHMA TRIGGERS
PHARMACOLOGIC AGENTS
- beta blockers
- ACE inhibitors
- aspirin

EXERCISE
- particularly in children
- linked to hyperventilation → mast cell
mediator release → bronchoconstriction
- after exercise has ended 19
ASTHMA TRIGGERS
PHYSICAL FACTORS
- cold air & hyperventilation
- laughter
- weather changes
- strong odors/perfumes

AIR POLLUTION
- ↑ levels of sulfur dioxide, ozone, diesel
particulates & nitrogen oxide

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ASTHMA TRIGGERS
FOOD & DIET
- allergic reactions to food → little evidence
- shellfish, nuts
- fod additives

OCCUPATIONAL FACTORS
- associated with symptoms at work with
relief on weekends and holidays

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ASTHMA TRIGGERS
HORMONES
- premenstrual worsening of asthma
- thyrotoxicosis, hypothyroidism

GERD - reflex bronchoconstriction

STRESS - worsening symptoms with stress

- psychological factors might trigger
reflex bronchoconstriction
* bereavement - may even improve asthma 22
PATHOPHYSIOLOGY

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PATHOLOGY
• airway mucosa infiltrated with activated
eosinophils,T lymphocytes, mast cells
• thickening of the basement membrane
• increased numbers of epithelial cells in the
lumen
• airway is thickened and edematous
• occlusion of lumen by mucus plug
• vasodilator and angiogenesis
• bronchoscopy: airways are narrowed,
erythematous and edematous
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AIRWAY INFLAMMATION

• inflammation from trachea to bronchioles

• associated with airway hyperresponsiveness
• pattern of inflammation →allergic diseases
• acute inflammatory episodes on top of
chronic inflammatory state
• eosinophilic infiltration; severe →
neutrophilic pattern of inflammation

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MAST CELLS
• initiate acute bronchoconstriction
• found at the airway surface, airway smooth-
muscle layer
• activated by allergen thru IgE-dependent
mechanism
• release bronchoconstrictor mediators:
histamine, prostaglandinD2, leukotrienes,
cytokines, chemokynes, growth factors,
neurotrophins

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MACROPHAGES & DENDRITIC CELLS
MACROPHAGES - derived from monocytes
- traffic into airways
- release of certain pattern of cytokines

DENDRITIC CELLS - take up allergens

- production allergen-specific T cells

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 EOSINOPHILS/NEUTROPHILS
EOSINOPHILS - eosinophil infiltration
- marked increase in activated eosinophils
in the airways
- linked to the dev’t of AHR

NEUTROPHILS - in severe asthma, during

exacerbations

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LYMPHOCYTES
• release specific patterns of cytokines:
recruitment & survival of eosinophils,
maintenance of mast cell population
• asthmatic immune system: TH2 cells
• normal airways: TH1 cells predominate
• TH2 cells thru IL-5 - associated with
eosinophilic inflammation
• TH2 cells thru IL-4 & IL-13 - associated
with increased IgE formation

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 INFLAMMATORYMEDIATORS
• mast cell mediators: histamine,
prostaglandin, leukotrienes:
- contract airway smooth muscle
- ↑ microvascular leakage
- ↑ airway mucus secretion
- attract other inflammatory cells

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 INFLAMMATORYMEDIATORS
CYTOKINES - regulate chronic inflammation
- TH2 cytokines IL-4,IL-5, IL-9, IL-13
mediate allergic inflammation
- pro inflammatory cytokines TNF alpha &
IL-1beta amplify inflammation, more
severe disease
- IL-10 & IL-12 which are anti-
inflammatory maybe deficient in
asthmatic patients

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 INFLAMMATORYMEDIATORS
CHEMOKINES
- attract inflammatory cells

OXIDATIVE STRESS
- ↑ is related to disease severity
- amplify inflammation
- ↓ response to steroid

NITRIC OXIDE
- related to eosinophilic inflammation
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 EFFECTS OF INFLAMMATION
AIRWAY EPITHELIUM
- airway epithelial shedding → AHR
- loss of barrier function
- loss of enzymes
- loss of relaxant factor
- exposure to sensory nerve
FIBROSIS - all asthmatic patients have
thickened basement membrane due to
subbepithelial fibrosis

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 EFFECTS OF INFLAMMATION
AIRWAY SMOOTH MUSCLE
- hypertrophy & hyperplasia
- ↓ responsiveness to beta-agonist
- chronic inflammation

VASCULAR RESPONSES
- ↑ airway mucosal blood flow → airway
narrowing
- angiogenesis
- airway edema & plasma exudation
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 EFFECTS OF INFLAMMATION
MUCUS HYPERSECRETION
- viscid mucus plugs → occlude airways
- hyperplasia of submucosal glands
- ↑ number of epithelial goblet cells

AIRWAY REMODELLING
- ↑ airway smooth muscle
- fibrosis
- angiogenesis
- mucus hyperplasia
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 EFFECTS OF INFLAMMATION
PHYSIOLOGY
- limitation of airflow:
1. bronchoconstriction
2. airway edema
3. vascular congestion
4. luminal occlusion
- ↓ in FEV1, FEV1/FVC ratio
- ↑ airway resistance, RV, lung hyperinflation
- V/Q mismatch, ↓ arterial PCO2

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 EFFECTS OF INFLAMMATION

AIRWAY HYPERRESPONSIVENESS
- characteristic physiologic abnormality
- linked to to the frequency of symptoms
- important aim of therapy is to reduce AHR

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» CLINICAL FEATURES &
DIAGNOSIS

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DIAGNOSIS

- symptoms of variable and intermittent

airways obstruction
- measurements of lung functions

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DIAGNOSIS
LUNG FUNCTION TESTS
- reduced FEV1, FEV1/FVC ratio & PEF
- reversibility:
>12% and 200ml increase in FEV1 in
15 mins after an inhaled SABA
- twice daily measurement of PEF
- ↓ peak flow & maximum expiratory flow
- whole body plethysmography: ↑ airway
resistance, TLC & RV

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DIAGNOSIS
HEMATOLOGIC TEST - not usually helpful

IMAGING - usually normal, maybe hyper

inflated lungs in severe cases

EXHALED NO (FeNO) - a noninvasive test to

measure eosinophilic airway inflammation

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DIAGNOSIS
DIFFERENTIAL DIAGNOSIS
- upper airway obstruction
- laryngeal edema
- endobronchial obstruction with a FB
- LV failure
- vocal cord dysfunction
- eosinophilic pneumonias & systemic
vasculitis, polyarteritis nodosa
- COPD

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TREATMENT

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 AIMS OF ASTHMA THERAPY
• minimal (ideally no) chronic symptoms
• minimal (infrequent) exacerbations
• no emergency visits
• minimal (ideally no) use of a required
Beta-2- agonist
• no limitations on activities, including
exercise
• PEF circadian variation < 20%
• (near) normal PEF
• minimal (or no) adverse effects from
medicine 44
BRONCHODILATOR THERAPIES
- reverse bronchoconstriction
- rapid relief of symptoms
- little or no effect on the underlying
inflammatory process
- 3 classes:
a) beta-2- adrenergic agonists
b) anticholinergics
c) theophylline
- beta-2-agonist - most effective

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BETA 2 AGONISTS
MODE OF ACTION
- relaxes smooth muscles
- inhibit mast cell mediator release
- reduction in plasma exudation
- inhibition of sensory nerve activation
- no effects on inflammation
- no reduction in AHR

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BETA 2 AGONISTS
CLINICAL USE
- inhalations
- SABA: (albuterol & terbutaline) - 3-6h
- rapid onset
- symptom relief (relievers)
- prevent EIA if taken prior to exercise
- LABA: (salmeterol, formoterol) - over 12h
- should not be given in the absence of
ICS therapy
- LABA + ICS
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BETA 2 AGONISTS
SIDE EFFECTS
- tremors & palpitations
- hypokalemia

TOLERANCE
- potential problem when given chronically

SAFETY
- there is an association between mortality
the amount of SABA used
- LABA - no adverse effects in adults or children
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ANTICHOLINERGICS
• ipatropium bromide
• prevent cholinergic nerve-induced
bronchoconstriction & mucus secretion
• less effective than beta-2-agonist
• LAMA (tiotropium) maybe used as additional
bronchodilator that is not controlled by
LABA-ICS combinations
• slower onset of bronchodilator
• s/e: dry mouth, urinary retention

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THEOPHYLLINE
• used to be widely used as oral
bronchodilator
• inexpensive
• side effects are common
• inhibition of phosphodiesterase in airway
smooth muscle cells
• at lower dose has anti-inflammatory effect

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THEOPHYLLINE
CLINICAL USE
- od or bid
- addt’l bronchodilator in severe asthma
- aminophylline - in very severe
exacerbations

SIDE EFFECTS
- N/V, headache, palpitations, arrhythmia,
seizure
- rare if plasma conc < 10mg/L
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CONTROLLER THERAPIES
INHALED CORTICOSTEROIDS (ICS)
- most effective controllers
- ↓ inflammatory cell numbers
- ↓ eosinophils in airways & sputum
- ↓ AHR in chronic ICS therapy
- usually given bid
- rapidly improves symptoms
- effective in preventing severe
exacerbations
- 1st line tx in persistent asthma
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CONTROLLER THERAPIES
SYSTEMIC CORTICOSTEROIDS
- for acute severe asthma
- hydrocortisone/methyprednisolone
- oral form (prednisone/prednisolone)
- given 5-10 days; no tapering needed

SIDE EFFECTS
- truncal obesity, bruising, osteoporosis,
diabetes, HPN, gastic ulcer, cataracts

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ANTILEUKOTRIENES

CYSTEINYL-LEUKOTRIENES
- activation of cys-LT1 receptors
- potent bronchoconstrictors
- cause microvascular leakage
- ↑ eosinophilic inflammation
- produced predominantly by mast cells

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ANTILEUKOTRIENES
- montelukast, zafirlukast
- blocks csy-LT1 receptors
- modest clinical benefit
- less effective than ICS
- less effect on airway inflammation
- useful as an add-on therapy
- od or bid

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CROMONES
- cromolyn Na, nedocromil Na
- inhibit mast cell & sensory nerve activation
- effective in blocking trigger-induced
asthma (EIA, allergen-induced asthma)
- little benefit in long term control
- short duration of action

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Anti-IgE
- omalizumab
- given SQ q 2-4 weeks
- a blocking Ab → neutralizes IgE
- may reduce exacerbations & may
improve asthma control
- expensive
- to highly selected patients who are not
controlled on maximal doses of inhaler

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Anti-IL-5
- mepolizumab, reslizumab, benralizumab
- ↓ blood & tissue eosinophils
- ↓ exacerbations in patients with have
increased sputum eosinophils

Immunotherapy
Alternative Therapies
Bronchial Thermoplasty

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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

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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
• avoidance of side effects & expense of
medications

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MANAGEMENT OF CHRONIC ASTHMA
STEPWISE THERAPY
SYMPTOMS TREATMENT

mild intermittent SABA for symptom relief

mild persistent SABA + ICS low dose

moderate persistent SABA + ICS(ld) + LABA

severe persistent SABA + ICS(hd) + LABA

very severe persistent SABA + ICS(hd) + LABA +

OCS 61
MANAGEMENT OF CHRONIC ASTHMA
STEPWISE THERAPY
• regular controller is needed when use of
reliever is required more than twice a week
• treatment of choice for all patients: ICS bid
• if not controlled by ICS → ICS + LABA
• controller dose should be adjusted
• consider add-on therapy
• once controlled, slowly decrease
therapy

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ACUTE SEVERE ASTHMA
•↑ chest tightness, wheezing, dyspnea that
are poorly relieved by usual meds
• breathless, cyanotic
• ↑ RR, hyperinflation & tachycardia
• pluses paradoxus
• marked ↓ in spirometric values & PEF
• ABG’s: low PCO2, hypoxemia
• CXR: normal or pneumonia or
pneumothorax

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ACUTE SEVERE ASTHMA
TREATMENT
- O2 sat > 90%
- high dose of SABA
- seriously ill (impending respiratory failure),
may give IV beta-2-agonist
- add on: anticholinergic nebulization
- slow infusion of aminophylline
- intubation
- avoid sedatives
- antibiotics if with pneumonia
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REFRACTORY ASTHMA
- 5% have refractory asthma
- adherence to therapy & inhaler technique
- maintenance with OCS
- 2 patterns of difficult asthma:
1. persistent symptoms with poor lung function
2. normal lung functions but intermittent, severe
exacerbations

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REFRACTORY ASTHMA
MECHANISMS
- poor adherence with medications (ICS)
- exposure to high ambient allergens or
unidentified occupational agents
- severe rhinosinusitis
- beta blockers, aspirin
- hyper/hypothyroidism

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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

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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

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REFRACTORY ASTHMA
• difficult to control
• adherence & correct use inhalers
• identify & eliminate triggers
• low dose of theoryylline maybe helpful
• many will require maintenance with OCS
• steroid-sparing therapy are rarely effective
• allergyc asthma: omalizumab
• (+) sputum eosinophils: Anti IL-5
• anti-TNF not effective

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ASPIRIN-SENSITIVE ASTHMA
- 1-5% worse with aspirin & COX inhibitors
- preceded by rhinitis, nasal polyps
- rhinorrhea, conjunctival injection, facial
flushing & wheezing
- genetic predisposition to increased
production of cysteinyl-leukotrienes
- responds to usual therapy with ICS

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ASTHMA IN THE ELDERLY

• principle of management is same

• side effects of therapy more frequent
• comorbids more common
• COPD more likely coexist

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