MEDICINE 2  PC20

BRONCHIAL ASTHMA o Methacholine challenge test

Dr. Ruel Revilla; October 2, 2014 o Drop of FEV1 by 20% after administering an allergen or irritant
o Before: used as tool for monitoring response for treatment
CASE  Fall in FEV1 >10% after exercise challenge test
Jake is a 35 year-old call center agent with a smoking history of 5 pack years. He frequently
***#s 1, 3, 4 are done by spirometry
visits the company clinic due to his shortness of breath (daytime) and wheezing at night which
***#2 do not require spirometry
makes it difficult for him to receive calls. He also has recurrent rhinitis. He is on Montelukast
10mg OD and Salbutamol Inhaler TID.
Side Notes:
 What is the case of Jake? ASTHMA
 Symptoms of asthma are often nocturnal in nature
o If the symptoms occurs during day time, it means that the asthma is
DEFINITION becoming severe
HARRISON’S PRINCIPLE OF INTERNAL MEDICINE  If the patient has asthma, the FEV1 is low
 A syndrome characterized by airflow obstruction that varies markedly, both
spontaneously and with treatment ETIOLOGY
 The narrowing of the airways is usually reversible  Atopy (Skin allergy/Skin asthma)
o Major risk factor for asthma
GLOBAL INITIATIVE FO R ASTHMA (GINA): o Only known established predisposing factor of developing asthma from
childhood to adulthood
 A heterogenous disease usually characterized by airway inflammation
 When the child has atopic dermatitis, the risk for developing
o Obstruction is secondary to inflammation (hallmark of asthma)
asthma in adulthood is very high but those without atopic
 It is defined by history of respiratory symptoms such as wheezes, shortness of
dermatitis in childhood has very low propensity to develop
breath, chest tightness, and cough that vary overtime and intensity (Variable
asthma except when they have intrinsic asthma
Respiratory Symptoms)
 Intrinsic asthma
o Variable, spontaneous and with treatment
o Negative skin test for allergens and normal IgE levels
 With variable expiratory airflow limitation
o Adult onset of asthma
o Stands for the reversibility of airflow obstruction
 No atopy during childhood but develops asthma in adulthood
o Should be documented objectively and the only test would be
o Concomitant nasal polyps or allergic rhinitis and may be aspirin-sensitive
SPIROMETRY
 Genetics
o Highly familial
VARIABLE RESPIRATORY SYMPTOMS
o With genes but no trigger = no asthma
 >1 respiratory symptom o Exposed to trigger but no genes = no asthma
o Cough, wheeze, shortness of breath, chest tightness
 Environment
 Variable frequency and intensity
 More common at night or on waking
o Due to circadian rhythm of cortisol levels ASTHMA PATHOGENESIS: GENOTYPE-PHENOTYPE
o Time where cortisol levels are very LOW
 With noted triggers
o Smoke, dust mite
 Symptoms often appear or worsen with viral infection
o Most common trigger for worsening exacerbation

VARIABLE EXPIRATORY AIRFLOW LIMITATION

 FEV1 response >12 % and > 200ml after SABA or after 4 weeks of trial therapy
o Try to improve exhalation of air
 Average daily diurnal PEF variable >10% 1

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  The Th0 gene can either develop into Th1 or Th2 o When an asthmatic pregnant patient develops viral infection like RSV then
o If TH0 gene develops to Th1, it is protective. There is no development of the child has high risk of developing asthma
asthma or the risk in developing asthma is LOW  Pharmacologic agents
o If TH0 gene develops to Th2, there will be more allergic antibody o Beta blockers
responses, more interleukin development → ASTHMA  Block β2 receptorsbronchoconstriction
 What triggers the development of Th0 gene to Th1 and Th2?  Airways have beta receptors. Blocking the receptors will cause
o Answer: Hygiene Hypothesis/Dirty Gene Hypothesis severe bronchospasm
 Th1 gene: seen in patients exposed to dirty environment  Topical β-blockers (most common: ophthalmic drugs used in
 Protective antibodies against asthma glaucoma) can cause fatal bronchospasm
 Th2 gene: developed by people isolated from the dirty world :p o ACE-I
 Prevents disintegration of bradykinin which causes cough that
ASTHMA PATHOGENESIS: GENOTYPE  PHENOTYPE CLINICAL ASTHMA can trigger bronchospasm
o Aspirin
 Inhibits phospholipase-a2
 Blocks arachidonic acid pathway → blocks COX more than LOX
pathway thus there is preferential generation of leukotrienes 
more inflammation
 Exercise
o Exercise Induce Asthma (EIA)
o Increase airway osmolality
 In normal/silent breathing (inhalation is through the nose), the
nasal hairs moistens the air thus warming the air that we inhale
but in exercise inhalation is through the mouth
 In exercise the cold air causes the shift of the fluid in the
bronchial mucosa increasing the airway osmolality causing
edema in the airway → bronchospasm
Genes do not automatically develop into asthma  Physical Factors
 Genetic make-up: genotype o Change in weather, perfume, laughter
 What switches on that gene: phenotype  Food
 Triggers: Allergens, sensitizers, air pollutants, viruses (most common for the switch o Metabisulfite
on)  Preservative in wines, liquor and beer
 Gene (genotype)  trigger (switch-on)  airway hyper responsiveness (phenotype)  Bronchoconstrictor and vasodilator
 any exposure to a trigger  asthma  Reason why others can only tolerate 1 bottle of beer and they
 When the switch-on is triggered by an exposure to these triggers, there is a chronic turn red
inflammation making the airways hyper responsive. Symptoms of cough, dyspnea o Tartrazine yellow
and wheezing appears. After the switch on mechanism, any form of trigger, can  Preservative in food, drugs, and cosmetics
trigger recurrent exacerbation.  FD and C #5
 Oranges, juices, make-up
ASTHMA TRIGGERS  Air Pollution
o Sulfur dioxide, ozone
 Allergens
 Occupational Factors
o Dermatophagoides (house dust mite)
o Ex: Banker  allergy is money
 Most common trigger for asthma exacerbations
o One way to assess: ask when the patient is having symptoms because
o Microscopic organism that harbors in pillows, blankets, thick curtains,
asthma attack can happen during work hours
mattress, carpets, beds, comforters
 Hormonal Factors
o Cannot be killed by Lysol, killed only by direct sunlight
o Pregnancy
 Virus infection
 1/3 – will have asthma will have worsening of asthma when they
o Most common trigger for severe exacerbation 2
become pregnant
o Rhinovirus, coronavirus, RSV, adenovirus
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  1/3 – no change in their asthma when they become pregnant ASTHMA PATHOLOGY: THE ASTHMATIC AIRWAY
 1/3 – improvement of asthma when they become pregnant
MICROSCOPIC FINDINGS:
o Hypo/hyperthyroidism
 Thickened basement membrane:
 No established reason for developing asthma
o NO established/clear-cut mechanism for the development of asthma most common
 Mucus plug: 2nd MC
 Gastro-esophageal Reflux
o Acid reflux is the most common overly looked trigger for asthma  Denuded mucosa
 Stress  Inflammatory cells
 All edema
 Hypertrophic airway smooth
THE ASTHMA PHENOTYPE : AIRWAY HYPERRESPON SIVENESS
muscle

DIAGNOSIS
BENEFITS OF PERFORMI NG OBJECTIVE TEST FO R ASTHMA
 Enhances diagnostic confidence even when the diagnosis of asthma is usually based
in the presence of characteristic symptoms
 Assesses:
o Severity of air flow limitation
 Level of FEV1
o Reversibility
 Bronchodilator use
o Variability
 Change depending on time of the day
o Degree of asthma control
 Controlled or partly uncontrolled
 Even if the patient does not have acute exacerbation the airways are chronically o Treatment response
inflamed and irritable
POOR CORRELATION BETWEEN ASTHMA SYMPTOMS AND ACTU AL DEGREE OF
 Airway: inflamed, swollen and irritable → trigger → bronchospasm and mucus
AIRWAY OBSTRUCTION E XPRESSED AS FEV1
plugging
 Bronchial asthma
o Before: inflammation + bronchospasm + mucus plugging
o Now: inflammation (only) which will then cause bronchospasm and mucus
plugging

***WHAT IS JAKE’S ASTHM A PHENOTYPE?

Answer: Allergic Asthma (because he has allergic rhinitis)

ASTHMA PHENOTYPE
 Allergic Asthma
 Non-allergic asthma  Over estimators
 Late onset asthma/intrinsic asthma o People who have very high/good FEV1 but they think their symptoms are
 Asthma with fixed airflow limitation worse
 Asthma in obesity  Under estimators
o The patient is okay but the wheezing is severe
 Asthma in pregnancy
o More dangerous
o Low FEV1 but they think they are ok 3
*Those are the reasons why objective diagnostic tests should be performed
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OBJECTIVE MEASURES FOR ASTHMA DIAGNOSIS ***SPIROMETRY RESULT OF JAKE
 Measurement of lung function
o SPIROMETRY pre/post bronchodilator: reversibility of airflow limitation
 Peak flow rate (PEFR) measurement: variability of airflow limitation
 Measurement of airway responsiveness: methacholine and exercise
 Non-invasive markers of inflammation
 Measurement of allergic status  1st step: FEV1/FVC ratio: 60%
o Diagnosis: Obstructive airway Disease (OAD)
ASTHMA DIAGNOSIS BY SPIROMETRY  2nd step: Give bronchodilator then reassess the patient
o Presence of improvement in % change of >12 %
 Airflow limitation characteristic of Obstructive Airway Disease (OAD)
 In Jake’s case: 29% change
o FEV1/FVC ratio <0.70
o Presence of FEV1 improvement of ≥200ml
 Can be COPD or asthma
 Actual FEV1 post-bronchodilator – actual FEV1 pre-
 Reversibility indicates diagnosis of asthma
bronchodilator
o FEV1 improvement of >12% and ≥200mL from the pre-bronchodilator
 2.03 - 1.57= 0.46L or 460ml
value  REVERSIBLE
 There is FEV1 improvement of >12% and ≥200ml from the pre-bronchodilator value
o In asthma, there is airflow obstruction that makes it harder to exhale the
thus the diagnosis is ASTHMA
air out of the lungs, <70% will only be exhaled. Thus we give short acting
β2-agonist. It will bronchodilate the lungs, there will be more air exhaled.
*FEF 25-75% (L/sec) is used when all the rest is normal. It is for small airways
When the difference between pre-treatment and the post-treatment is
>12% or >200 ml, then the patient has bronchial asthma.
 If no reversibility seen? ROLE OF PEFR MEASUREMENT IN ASTHM A DIAGNOSIS
o Dose not exclude asthma Used if there is no access to lung function test
o Suggest: Repeat testing or monitor response to empiric therapy  Can be helpful in subset of asthmatics to suggest diagnosis of asthma:
o >20% diurnal (morning and evening) variation in (PEF) peak expiratory
Side Notes: flow (or >10% variation if with twice daily readings)
 FEV1  Most important
o Forced expiratory volume in the first second of forced vital capacity (FVC)  PEF value in the morning is lower than evening because of the
o In the first second of the vital capacity, you should have exhaled 70%-80% circadian variation in the cortisol level in our body which is
of air because it is the easiest time to exhale when the lungs are fully lowest in the morning because the attack is usually in the
inflated due to elastic recoil. The remaining 20%-30% will just be exhaled morning due to circadian rhythm and low cortisol level
for the last few second when the lungs are already deflated. o 60 L/min (or >= 20 % or pre-BD PEF) improvement post BD
 Tidal Volume o Drop >15% with 6 minute running or exercise
o Normal breathing
 Forced Vital Capacity (FVC) MEASUREMENT OF AIRWAY RESPONSIVENESS
o Amount of air that is maximally exhaled at the end of maximal exhalation
 Indicated for patients with symptoms consistent with asthma but normal lung
 Residual Volume
function to help establish a diagnosis of asthma.
o Amount of air remaining in the lungs after maximal exhalation
o Indicated for patients with a normal spirometry but clinically with
 Total Lung Capacity (TLC)
wheezing, nocturnal attacks, shortness of breath and with index suspicion
o The volume of air that remains in the lungs after forced inhalation
that the patient has asthma
o Vital Capacity + Residual Volume
 Reflects “sensitivity” of airways to factors (triggers) expressed as provocative
 When the PEF is normal, ask the patient to do exercise and test the FEV1. If the FEV1
concentration (or dose) of the agonist causing a fall in FEV1 (20%)
drops >10%, then it could be bronchial asthma.
o Give an irritant to trigger bronchoconstriction/airway hyper
responsiveness
 Bronchodilator → Spirometry:
 Sensitive but with limited specificity
o COPD: irreversible
o Asthma: reversible 4
 Bronchodilator is used to assess REVERSIBILITY
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BRONCHOPROVOCATION TESTING (INHALATION CHALLENGE USING TREATMENT
METHACHOLINE OR HISTAMINE)
The goal of asthma treatment is to achieve and maintain clinical control
 An allergen, which is the methacholine, is given to the patient to induce
bronchospasm
 If (+) bronchospasm: (+) 20% drop of FEV1 even in low dose of methacholine OVERALL ASTHMA CONTROL
 PC20: provocative concentration resulting to a drop of FEV1 to 20%

PARAMETERS OF CONTRO L (MEMORIZE BY <3)

 Daytime symptoms
NON INVASIVE MARKERS OF AIRWAY INFLAMMATION (NOT IMPORTANT)  Nighttime symptoms
 Test to evaluate the airway inflammation associated with asthma:  Limitation of activities
o Sputum (induced) Eosinophilia  Need for reliever/rescue treatment
o Levels of Exhaled Nitric Oxide (FENO) o Salbutamol, Terbutaline, SABA
 No prospective valuation as aid in asthma diagnosis but potential use in determining  Others
optimal treatment o Exacerbation
o Abnormal lung function
MEASUREMENTS OF ALLE RGIC STATUS
 Test to determine allergic status: LEVELS OF ASTHMA CONTROL
o Skin test with allergens – the primary diagnostic tool in determining The level of asthma control is dependent on these parameters
allergic status
 Simple and rapid to perform
 Low cost and high sensitivity
 May lead to falsely positive or negative results when improperly
done
 Allergen: Cockroach, grass pollen (in concoctions)
 After knowing the type of allergen, desensitization is
done
o Specific serum IgE levels
 Less reliable and more expensive
 Main limitation of these methods:
o Even if the test is positive you cannot always say that it is due to the asthma
or it is the cause of the asthma

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  Global Initiative for Asthma 2014 guidelines already removed the last 2 components *Just memorize the PREFERRED CONTROLLER CHOICE STEPS 1-5
which are lung function and exacerbation because these are not clinically helpful *Step 1: Low dose ICS (inhaled corticosteroids)
and these are not routinely done to the patient in every visit
 Level of control: (parameters)  Any first-time patient seen in the clinic, always presume that the patient has partly
o 3-4: uncontrolled asthma controlled or uncontrolled asthma
o 1-2: partly controlled o The first action is STEP 3: low dose ICS + LABA
o None: controlled asthma  When the patient comes after several days for follow-up:
o 1st: Ask for the four parameters of control
SUMMARY: Spirometry  Reversibility testing  asthma is established  level of control  If the patient is still uncontrolled or partly controlled: STEP 4
 If the patient has controlled asthma: STEP 2
***CASE: JAKE  Step 5: given to patients with refractory asthma (patient is not improving)
o Before reaching step 5
Jake is a 35 year old call center with a smoking history of 5 pack years. He frequently visits the
 (1) check compliance to medication
company clinic due to his shortness of breath (daytime) and wheezing at night which makes it
 (2) make sure that the technique in using the drugs/inhaler is
difficult for him to receive calls. He also has recurrent rhinitis. He is on Montelukast 10 mg OD
correct
and Salbutamol inhaler TID.
 Controlled: Decrease
 Partly controlled / uncontrolled: Increase
WHAT IS JAKE’S LEVEL OF CONTROL
 Stop decreasing the dose when it’s in STEP 2
 Shortness of breath (Daytime symptom)
o Anti-inflammatory should be there for life due to the pathophysiology of
 Wheezing at night (Nighttime symptom) asthma which is chronic inflammation
 Salbutamol inhaler TID (Rescue/reliever treatment)  LABA
o Synergistic property with ICS
DIAGNOSIS o Steroid-sparing agent
Bronchial asthma, Uncontrolled (presence of 3 or more symptoms) o When LABA is used less ICS is needed

TREATMENT OF CHOICE
Steroids (anti-inflammatory)

STEPWISE APPROACH TO CONTROL SYMPTOM S AND MINIMIZE FUTURE RISK

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ANTI- ASTHMA DRUGS EVOLUTION OF ASTHMA PHARMACOTHERAPY
 β2 agonists
o Pathway: Adenylyl cyclase
o Preferential generation of cAMP → protein kinase A → bronchodilation
o Salbutamol, Terbutaline, etc.
 Anticholinergics
o Blocks acetylcholine prevent bronchoconstriction
o Ipratropium
 Theophylline
o Inhibition of phosphodiesterase (PDE) mechanism
o In the adenylyl cyclase mechanism, the cAMP is metabolized into AMP by
PDE. Inhibition of PDE, will shift the flow to the generation of protein
kinase A.
 Inhaled corticosteroids (ICS)
o Anti-inflammatory
o Acts directly on the airways
o Can cause very little adrenal insufficiency
o Used as maintenance
o Systemic absorption: 5-10% (almost negligible: will not cause any effects
of chronic steroid use)
 Systemic corticosteroids
o Chronic use of steroid will have severe adrenal insufficiency leading to
death
o Only be used during acute exacerbation
 Antileukotrienes (LTRA)
o Includes “-leukast” drugs
o Acts on LOX pathway
 Cromones
o Stabilize mast cells
o Prevents degranulation of mast cells that causes severe inflammation
o Used more in pediatrics  The more you use SABA (does not address inflammation), the higher the mortality
 Anti-IgE
 The more you use ICS (address inflammation), the lesser the mortality
o Step 5 component
 More SABA and no ICS use is attributed to increase in mortality and exacerbation
o Omalizumab
 ICS is the only drug that can decrease the mortality
o Blocks antibody that neutralizes circulating IgE without binding to cell-
bound IgE; thus inhibits IgE-mediated reactions
o Used in patients who did not improve FUTURE RISKS
 Future therapies  Uncontrolled asthma symptoms
 Too much SABA use
(READING ASSIGNMENT from Harrison’s): LAST 2 PAGES! Huhu  Haha   No ICS/Poor adherence
 Low FEV1
 Psychological/socioeconomic problems
 Smoking
 Pregnancy
 Obesity/rhinosinusitis
 History of intubation or ICU admission
7

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GINA 2014: THE CONTROL BASED ASTHMA MANAGEMENT CYCLE ASTHMA VS. COPD

ASTHMA COPD
Symptoms occur at a younger age Symptoms occur at 40 y/o
OTHER CONSIDERATIONS (Exposure of 10-20 pack-years to cigarette
smoke before symptoms develop)
 Acute severe asthma Allergens Cigarette smoking
o Exacerbation
Epithelial cells, mast cell, eosinophil, Alveolar macrophages, epithelial cells,
o Give drug as reliever CD4 T cell neutrophil
 Refractory asthma CD8 T cell
o You have given the drug but the patient is not improving TH2 TH1
o 50% of patients given medications do not comply with the drug—
Bronchoconstriction Airway narrowing
therefore, check for compliance
Alveolar destruction
 Brittle Asthma
Reversible Irreversible
o Do not have frequent asthma but when they do, attack can be fatal
Steroid responsive Less steroid responsive
o From normal to very severe asthma
o Dangerous because patients are usually intubated
 ACOS (Asthma-COPD Overlap Syndrome)
 Aspirin- sensitive asthma
o New diagnosis
 Asthma in the elderly
o Consider other maintenance medications and
other co- morbidities CASE OF NANAY ROSA
 Asthma in pregnancy 75 y/o, mother of 6, dependent on his 2 sons who work as construction worker. Can pay
o Manage as if the patient is not pregnant consultation fee (sometimes) but is having a hard time buying her maintenance meds.
o In poorly controlled asthma, there can Admitted 3x in one year, once in the ICU (this left my patient in deep debt) = REALITY OF
be a fatal outcome for the fetus CLINICAL PRACTICE
o Can give ICS, SABA and theophylline  Only 50-80% of Filipinos has access to essential drugs
 Cigarette smoking  50% cannot buy the medicine
o Needs to be stopped!  80% cannot use the drug properly due to poor education so physicians should
o Non-negotiable in asthma demonstrate how to use the drug
 ABPA (allergic bronchopulmonary aspergillosis)
o Infection with A. fumigatus (fungus) APPEAL: Knowledge is very important, you have to embrace it, you have to know how to use
o Causes severe wheezing because it it, and you have to know that ICS is the drug of choice for asthma so that you will not be
8
elaborates eosinophils prescribing other drugs. Demonstrate. – Dr. Revilla

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 9

#KAFC #LML #DAB #LGTM #DACM “MEDICINE 2016” “We acquire the strength we have overcome” – Ralph Waldo Emerson
 10

#KAFC #LML #DAB #LGTM #DACM “MEDICINE 2016” “We acquire the strength we have overcome” – Ralph Waldo Emerson