Pt Care 3: Module 8, 9, 10- Asthma, COPD, HAP, VAP, Lung Cancer, Cough and Cold

Module 8: Asthma

Module 8: Asthma

Two components of asthma:

Heterogeneous disease characterized by chronic airway inflammation

1. History of respiratory symptoms (wheezing, SOB, chest tightness or cough) that vary over time and intensity

2. Variable expiratory airflow limitation (there is improvement or deterioration of symptoms or lung function)

What lymphocyte is dominant?

Th2

What cells to ICS target?

Eosinophils, they curb the inflammation in asthma patients

Pathophysiology of Asthma

• Chronic inflammatory airway disease that can progress to persistent airflow limitation

• Inflammatory processes → airway narrowing

- Smooth muscle contraction

- Mucus hypersecretion

- Airway thickening

• Consists of an acute and chronic inflammation phase

• Allergen → Dendritic Cells + Mast Cells → TH2 → IL-4 & IL-13 → B cells → IgE → Eosinophils

• Bronchial hyperresponsiveness enhances susceptibility to airway narrowing

What medication should you avoid in giving to asthmatics?

NSAIDs like aspirin

Asthma: Acute Inflammation

• Early phase reaction that occurs within minutes after exposure to an allergen

• Activation of immunoglobulin E (IgE) - the allergen binds to IgE

• Mast cells and macrophages activate

• Pro-inflammatory mediators are released

– Histamine, eicosanoids, reactive oxygen species

• Induce contraction of airway smooth muscle, mucous secretion, edema that contributes to airway obstruction

Asthma: Chronic Inflammation

• Recruitment of inflammatory cells

• Epithelial cells promote mucociliary clearance and remove harmful agents

– Asthma → Epithelial shedding → Decreased function

• Eosinophils release pro-inflammatory mediators

• Lymphocytes express surface markers of inflammation

– Th1: protective immunity

– Th2: allergic inflammation

• Mast cells degranulate and release pro-inflammatory mediators

• Macrophages digest bacteria → amplify inflammatory process

• Neutrophils have an unclear role

Airway Remodeling

• Inflammation ✓ - acutely it is beneficial

• Inflammation in asthmatics X - no bueno since it is chronic

• Abnormal airway healing

• Chronic inflammation leads to

- Extracellular matrix fibrosis

- Increased smooth muscle contraction

- Increased mucus gland mass (More mucus-secreting cells)

- Angiogenesis

- Increased in smooth muscle cells

What is responsible for the mucus plug?

Th2 cells are responsible

TH2

Activate eosinophils and B cells to produce IgE

Asthma Diagnosis

• Spirometry > Peak expiratory flow (PEF)

• FEV1/FVC is < 0.75 - 0.8 in adults; < 0.90 in children

• If FEV1 increased by more than 12% AND more than 200 mL in adults) after bronchodilator administration

• If PEF ≥ 20% following bronchodilator administration ARe

Are crackles and inspiratory wheezing features of asthma?

• False, they are not. During a physical exam, when making a diagnosis, the patient often seems normal and may wheeze upon exhalation on auscultation (using a stethoscope). During a severe exacerbation, a pt's chest might be silent.

What are some tests used to diagnose asthma?

• Bronchial provocation test - can rule not, not rule in

- Used to assess airway hyperresponsiveness

• Allergy testing

- Used to determine.if there is a causative agent for the asthma

• Imaging

- Not routinely used

- Can determine comorbid conditions, differential diagnosis, congenital abnormalities

• Fractional concentration of exhaled nitric oxide (FeNO) - can't rule in or out

- Used as an adjunct test

Allergic asthma

• Most easily recognized phenotype

• Begins in childhood

• Past/Family history of

- Eczema, allergic rhinitis, food/drug allergies

• Eosinophilic airway inflammation

• Respond well to inhaled corticosteroid treatment

Non-allergic Asthma

• Not associated with allergies

• Develops later in life or continued from childhood

• May be neutrophilic, eosinophilic, or contain few inflammatory cells (paucigranulocytic)

• Less short-term response to inhaled corticosteroids

Adult Onset (Late Onset) Asthma

• Adults presenting with asthma for thefirst time

– Women > men

• Non-allergic

• Require high doses of inhaled corticosteroids

• Occupational asthma should be ruled out

Asthma with Obesity

• Prominent respiratory symptoms

• Minimal eosinophilic airway inflammation

Cough Variant/Predominant

• Cough is the only symptom

• Absent variable airflow limitation

Asthma with Persistent Airflow Limitation

• Result of long-standing asthma

• Airflow limitation is persistent or incompletely reversible

• Possibly due to airway remodeling

Exercise Induced Bronchospasm

• Drop in FEV1 of ≥ 10% from baseline

• Many patients with persistent asthma experience this

• Provoked by cold, dry air and airborne allergens

• Refractory period can last up to 4 hours post-exercise and can be prevented by appropriate therapy

Nocturnal Asthma

• Worsening of asthma during sleep

• Significant decline in pulmonary function between bedtime and awakening

– Lunch function nadir at 3-4 AM

• Numerous factors may precipitate nocturnal asthma

– Allergens, environment, GERD, OSA, sinusitis

• Sensitive indicator to both severity and inadequate control

Asthma triggers result in ________ phase responses (IgE triggers release of mediators responsible for bronchoconstriction). ________ phase responses related to the movement of inflammatory cells to the lung).

early; late

Pathophysiology of COPD (Guenther)

• Usually caused by cigarette smoking

• There is activation of epithelial cells and macrophages followed up by the attraction of monocytes, neutrophils and T-lymphocytes

• Fibrinogenic factors from epithelial cells leads to fibrosis of alveolar region

• Release of Proteases leads to alveolar wall destruction

• Mucus hypersecretion

• Airway closure on expiration, hyperinflation (air trapping), shortness of breath

• Systemic problems: muscle wasting, depression, osteoporosis

• Often resistant to Corticosteroids

What are the ideal characteristics of a inhaled pulmonary product?

• High pulmonary deposition

• Low oral bioavailability

• High systemic clearance

• Long pulmonary residence time

• High receptor selectivity

• Select the right Dose

→ Free drug concentrations in lung are higher than in systemic circulation (Lung targeting)

Corticosteroids

• Ex. Triamcinolone, budesonide, flunisolide, fluticasone, mometasone, beclomethasone (prodrug), circlesonide (prodrug), prednisone (prodrug), prednisolone

• Cortisol/cortisone are endogenous corticosteroids and are specific due to enzymatic inactivation in MR expressing tissues (11β-hydroxysteroid dehydrogenase) so that they can only bind to GR

• Causes lot of systemic effects (hyperglycemia, hepatic steatosis, hyper-insulinemia, insulin resistance, muscle wasting and fat distribution), so as a result, inhalation products are used for asthma/COPD

• MOA: Work to reduce protein synthesis of inflammatory mediators via trans-repression

• Drug-Drug Interactions: Most corticosteroids metabolized through CYP3A4 (hydroxylation, transformation in position 16, 17)

Cortisol is the (active/inactive) form.

Cortisone is the (active/inactive) form.

active; inactive

(They are readily interconverted by 11ß-hydroxysteroid dehydrogenase (11ß-HSD))

Trans-repression: Mechanism of anti-inflammatory action of corticosteroids in asthma:

• Inflammatory genes are activated by inflammatory stimuli (IL-1β, TNF-α, etc.), resulting in activation of IKKβ (inhibitor of I-κB kinase-β), which activates the transcription factor nuclear factor κB (NF-κB).

• A dimer of p50 and p65 NF-κB proteins translocates to the nucleus and binds to specific κB recognition sites and also to coactivators, such as CREB-binding protein (CBP), which have intrinsic histone acetyltransferase (HAT) activity.

• This results in acetylation of core histones and consequent increased expression of genes encoding multiple inflammatory proteins.

• Cytosolic glucocorticoid receptors (GR) bind corticosteroids; the receptor-ligand complexes translocate to the nucleus and bind to coactivators to inhibit HAT activity in two ways:

1. Directly

2. Recruiting histone deacetylase-2 (HDAC2), which reverses histone acetylation, leading to the suppression of activated inflammatory genes.

Systemic Corticosteroids: Side Effects

• Fluid and Electrolyte Disturbances

– Fluid retention, causing swelling in your legs

– Hypertension

• Musculoskeletal

– Steroid myopathy, Osteoporosis, growth retardation

• Gastrointestinal: Ulcer, Pancreatitis

• Dermatologic– Thin skin, bruising and slower wound healing

• Ophthalmic– Glaucoma, Cataracts

• Endocrine

– Cushing Syndrome, Suppressed HPA axis (Cortisol suppression)

– high blood sugar/worsening diabetes

What

• Neurological

– Problems with mood behavior, headache

What are corticosteroids the substrate of?

CYP3A4

Inhaled Corticosteroids: Side Effects

• Local adverse effects

– Pharyngitis

– Dysphonia

– Reflex cough

– Bronchospasm

– Oropharyngeal Candidiasis (need to counsel to rinse mouth!)

• Systemic Side Effects

– Suppressed HPA axis (cortisol suppression)

– Growth inhibition

– Decreased lower leg length

– Reduced bone mineral

density (bone fractures)

– Skin thinning

• glaucoma

Inhaled Corticosteroids: Monitoring

• Growth velocity (in kids being treated chronically)

• PFTs: FEV1, peak flow

Steroid Nomenclature

• ß face is coming toward you (top) and α face is going away (bottom)

• Numbered 1 to 21

Corticosteroids: Medicinal Chemistry

• Numbered from 1 to 21

• Modifications that enhance MR and GR activity

- 17α- and 21 hydroxyls

- 9α-F or Cl

• Modifications that ONLY increase GR activity

- 11ß-OH

- C1-C2 double bond

- 6α-F and and methyl

• Modifications that decreases MR activity

- C1-C2 double bond

- 6α-methyl

- 16α- and 16ß-methyl and 16a-OH

- 16α,17α-acetonide (end in -ide) and derivatives

• Modification the slows oxidation (1ß-OH) by 11ß-HSD

- 9α-F or Cl

• Esters on C-21 or C-17α can be used to alter physiochemical properties like having a

1. Ionizable group (hydrophilic)

2. Lipophilic group (lipophilic)

• C21 esters are prodrugs

What is the effect of activity by 17α- and 21 hydroxyls in a corticosteroid?

Increase in GR and MR

What is the effect of activity by 9α-F or Cl in a corticosteroid?

Increase in GR and MR + slows oxidation (1ß-OH) by 11ß-HSD

What is the effect of activity by 11ß-OH in a corticosteroid?

Increase GR

What is the effect of activity by C1-C2 double bond in a corticosteroid?

Increase GR + Decrease MR

(seen in all corticosteroids used in asthma and COPD)

What is the effect of activity by 6α-F in a corticosteroid?

Increase GR

What is the effect of activity by 6α-methyl in a corticosteroid?

Increase GR + Decrease MR

(Seen in Medrol)

What is the effect of activity by 16α- and 16ß-methyl and 16a-OH in a corticosteroid?

Decrease MR

What is the effect of activity by 16α,17α-acetonide and derivatives in a corticosteroid?

Decrease MR

What kind of esters are prodrug?

C21 esters

What corticosteroids are prodrugs?

Prednisone, Beclomethasone, Ciclesonide

Ketal or Acetal

• Looks like an X

• It decreases MR activity in corticosteroids when in the C16/C17 position

• Seen in flunisolide and budesonide and ciclesonide

Cis vs. Trans regulators

• Cis: Are in the same vicinity as the gene they control

Ex: promoters, enhancers, response elements

• Trans: Travel through the cell to their point of action

Ex: transcription factors

Beta-2- Agonists MOA

• Ligand binding → stimulatory G protein (Gs) → adenylyl cyclase (AC) → ↑ cyclic AMP → activation of Protein kinase A (PKA):

1. PKA phosphorylates a variety of target substrates

2. Decreased intracellular calcium

3. Increased membrane potassium conductance

4. Decreased myosin light chain kinase activity leads to smooth muscle relaxation and bronchodilation.

SA

• cAMP also leads to inhibition of release of mediators from mast cells in the airway 2

SABAs

• Low Selectivity: Epinephrine, Isoproterenol

• High Selectivity: Terbutaline. Salbutamol, Albuterol, Levalbuterol

LABAs

• Salmeterol, Formoterol, Olodaterol, Indacaterol, Vilanterol

Beta-2 Agonists: Side Effects

• Low because of topical delivery

– Tremor (lost through tolerance)

– Tachycardia (mainly due to beta-1-receptor)

– Cardiovascular complications

– Hypokalemia (significant for patients taking digoxin and diuretics), Restlessness

– Hyperglycemia

– Paradoxial bronchspasm

– Headache, tachycardia, pain, dizziness, pharnyngitis

Beta-2 Agonists: Monitoring

• Heart rate, blood pressure, ECG

• Inhaler technique +/- spacing device

• Airway symptoms and frequency of use

Beta-2 Agonists: Drug-Drug Interactions

• CYP3A4 inhibitors

• Monoamine oxidase inhibitors and tricyclic antidepressants: Use with extreme caution. May potentiate effect of salmeterol on vascular system.

• Beta-blockers: Use with caution. May block bronchodilatory effects of beta-agonists and produce severe bronchospasm (don't combine an agonist and antagonist of the same target!!)

• Digoxin: Beta Agonists may decrease digoxin levels

• Diuretics: may potentiate hypokalemia

What two enzymes break down NE?

COMT and MAO; so they determine the duration of action of beta agonists

Mechanism of Monoamine Oxidase (MAO)

• Flavin dependent enzymes that catalyze oxidative deamination of monoamines

– Reactions yield aldehyde + amine

– Utilize FAD (flavin adenine dinucleotide) in reaction

Beta-2 Agonists: Medicinal Chemistry

• Bulkier substituents favor ß receptors rather than a receptors

• Different aromatic ring substitution patterns incorporated which make them resistant to COMT and slowly metabolized by MAO but still make them capable of interaction with the receptor

1. Salicyl alcohol

2. Formamide

3. Resorcinol

4. Cyclic amides in the case of ultra long acting B2 agonists

• R isomer favored (at least for albuterol which made way for the development of levalbuterol which is only R)

- S isomer is inactive and can be associated with bronchial hyperesponsiveness

• LABAs have a higher DOA due long lipophilic chain

• Ultra long acting B2 agonists have cyclic amides for their aromatic groups

Advair

Fluticasone + Salmeterol (ICS + LABA)

Symbicort

Budesonide + Formoterol (SMART)

Dulera

Mometasone + Formoterol (SMART)

Breo Ellipta

Fluticasone + Vilanterol (ICS + LABA)

Theophylline

• Methylxanthines

• Has lots of side effects and has a narrow therapeutic window so it needs TDM but cheap

• MOA:

- Not fully known, but causes bronchodilation and has anti-inflammatory effects

- Phosphodiesterase inhibitor

- Adenosine receptor antagonism (cardiac arrhythmias)

- Interleukin 10 release increased; Effect on NF-kappa B

• Histone deacetylase activation (enhancement of anti-inflammatory effects of corticosteroids by restoring HDAC 2 to normal levels)

Theophylline: Medicinal Chemistry

• Structurally related to caffeine and theobromine

• Very poor aqueous solubility

• Contains an acidic nitrogen which can make salts with organic bases to increase the water solubility

What makes formoterol special?

Since it has a fast onset and lasts a long period of time

Roflumilast

• MOA: PDE4 inhibitor (similar to theophylline)

• Treatment of patients with severe COPD and a history of exacerbations

• Not indicated for the treatment of acute bronchospasm

• Side effects (5-10% of patients:

- Diarrhea

- Weight loss

- Nausea

- Headache

• Extensively metabolized by CYP1A2 and CYP3A4

- Interaction with rifampin (inducer), ketocanozole, erythromycin (inhibitors)

• Contraindicated in patients with moderate or severe hepatic impairment (Child–Pugh class B or C)

Leukotriene Mediators

• 5-LO Inhibitors: Zileuton

• LT Antagnists: -lukasts

• MOA: Reduces the synthesis of leukotrienes by mast cells and eosinophils which normally would lead to plasma exudation, mucus secretion, bronchoconstriction and eosinophil recruitment

• P450 3A4 and 2C9 metabolism, but drug interactions not reported

• Used as an add on therapy for corticosteroids (not listed by GINA)

• Side Effects

- URTI

- Fever

- Headache

- Pharyngitis

- Cough

- Abdominal pain

- Liver enzymes

- Black box warning (2020): evidence of serious neuro-psychiatric side effects (agitation, aggression, anxiousness, depression, sleep disturbances and suicidal thoughts), not for Zafirlukast

• Monitoring

- Hepatic dysfunction, LFTs

Zileuton: Medicinal Chemistry

• Inhibits 5-lipoxygenase oxidation of arachidonic acid to 5-peroxide

• Racemic mixture, both isomers pharmacologically active

• N-Hydroxyl group essential for activity - *glucuronide metabolite is inactive

Leukotriene Receptor Antagonists: Medicinal Chemistry

• Selective for cysLT1

• Structural Features:

1. Acidic functionality mimics C1 acid of leukotrienes in agonists

2. Three hydrophobic groups

• Metabolized by CYP3A4 and CYP2C9

• Zafirlukast inhibits both CYP3A4 and CYP2C9

Muscarinic Cholinergic Antagonists

• SAMA: Ipratropium

• LAMA: Tiotropium, Umeclidinium, Glycopyrrolate, Aclidinium

• MOA: Anticholinergic drugs inhibit vagally mediated airway tone, thereby producing bronchodilation. Really good for COPD

• Side Effects:

- Generally, well tolerated

- Systemic side effects are uncommon

- Bad taste (ipratropium)

- Glaucoma with nebulized delivery (direct ocular effect)•

- Bronchoconstriction when used in formulations with benzalkonium (bronchoconstriction)

- Dryness of mouth (tiotropium, 15% of patients)

- Urinary retention

Muscarinic Receptors

• G-protein coupled receptors

• 5 subtypes

- M1, M3 and M5 utilizes Gq/G11 which involves the hydrolysis of phosphatidylinositol 4,5-diphosphate into diacyl glycerol + inositol triphosphate

• Activation of M3 receptors causes bronchoconstriction CH3 – inhaled muscarinic antagonists used in the treatment of asthma and COPD

Muscarinic Cholinergic Antagonists: Medicinal Chemistry

• Aminoalcohol esters

• Structurally related to atropine and scopolamine

• Contains a quaternary amine that has a permanent positive charge to prevent CNS penetration

• Glycopyrrolate is the only antimuscarinic that preferentially binds to M3 over M2 due to kinetic selectivity

• Revenefacin is very unique and is a carbamate and not an ester and also show kinetic selectivity for M3 over M2

Muscarinic Cholinergic Antagonists: Monitoring

• Moderate to severe renal impairment increases anticholinergic effect

What structural feature limits systemic absorption and CNS penetration of antimuscarinics?

Contains a quaternary amine that has a permanent positive charge to prevent CNS penetration

What antimuscarinics bind preferentially to M3 over M2?

Glycopyrrolate and Revenefacin (Like other antimuscarinics but dissociates much more slowly from M3 than M2 receptors(kinetic selectivity))

Revenefacin

• Very different structurally from other long-acting antimuscarinics

- Carbamate, not ester

- Also shows kinetic selectivity for M3 over M2 receptors

Mast Cell Stabilizers

• Cromolyn

• Interacts with sensitized mast cell and prevents release of inflammatory compounds (histamine, leukotrienes, etc.)

• Linker - chain length and Cromolyn attachment point important

Structure of Antibodies

1. Fab (fragment antigen binding) region;

2. Fc (fragment crystallizable) region;

3. Heavy chain (blue) with one variable (VH) domain followed by a constant (CH1) domain, a hinge region, and two more constant (CH2 and CH3 regions);

4. Light chain (green) with one variable (VL) and oneconstant (CL) domain;

5. Antigen binding; site; and

6. Hinge regions

Polyclonal vs. Monoclonal Antibodies

• Injection of an antigen into an animal results in production of multiple antibodies (polyclonal antibodies)

• Want single antibody for therapeutics

– But can’t culture isolated cells to produce monoclonal antibodies without modification

Production of Monoclonal Antibodies

• An animal (ex: mouse) is injected with antigen to produce specific plasma cells

• Plasma cells are removed and fused with tumor cells capable of endless divisions

• The resulting hybridoma will synthesize large quantities of the specific antibody (monoclonal)

Monoclonal antibody nomencalture

• Chimeric (-xi-)

• Chimeric/humanized (-xizu-)

• Humanized (-zu-)

• Fully human (-u-)

Monoclonal Antibodies for Asthma: Monitoring

• Parasitic infection risk/infection

• Xolair - weight + pre-dose IgE concentration

Omalizumab

• Monoclonal anti-IgE antibody that bind to only free IgE

• Dosing is dependent on IgE levels and weight

Mepolizumub

• Monoclonal anti-IL5 antibody

• Dosing is dependent on IgE levels and weight

Reslizumab

• Monoclonal anti-IL5 antibody

• Dosing is dependent on IgE levels and weight

Benralizumab

• Monoclonal antibody that binds to IL5 receptor

• Dosing is dependent on IgE levels and weight

Dupilumab

• Monoclonal antibody that binds to IL4 Rα, Anti IL4 and IL13

• Dosing is dependent on IgE levels and weight

Tezepelumab

• Newest MAB( approved 2021)

• Targeting thymic stromal lymphoprotein (TSLP), an inflammatory cytokine

Allergy Immunotherapy

• A therapy in which the patient is exposed to allergenic extracts or insect venoms to decrease sensitivity to the allergen.

• Place in Therapy

– Allergic component to asthma

• Adverse Effects

– SCIT (subq immunotherapy) → itching, pain, erythema

– SLIT (sublingual immunotherapy)→ oral irritation/itching

• Monitoring

– 30 minutes post administration

Maintenance

• Every day use with or without symptoms

• Describes frequency, NOT class

Controller

• Contain ICS to reduce airway inflammation, symptom control, lung function decline, and future risk

• Optimized to reduce risk of medication side effects -- used the lowest dose possible

Reliever

• For symptom relief, or before exercise (EIB) or allergen exposure

• Overuse of this is a sign of poorly controlled asthma

Anti-inflammatory Reliever (AIR)

ICS + rapid acting bronchodilator (SABA)

Single Maintenance And Reliever Therapy (MART or SMART)

• ICS-formoterol ONLY

• It is non-inferior to daily dose ICS and can be used for BOTH controller and reliever (max dose 8 - 12 inhalation/day)

DO NOT USE _______ AS MONO-THERAPY IN ASTHMA!

LABA

Does symptom control of asthma directly translate to a low risk of adverse outcomes?

NO! They are independent each other since someone with great symptom control may have a high risk of adverse outcomes (Ex. Overuse of SABA) since symptoms may be treated without treating airway inflammation and symptoms may be explained by other conditions.

How often is lung function (FEV1) measured?

• At diagnosis or at start of treatment...

• Then, after 3 - 6 months of controller treatment to record personal best

• Periodically after that (q 1 - 2 years)

If an asthma patient has normal FEV1, but has frequent symptoms, what could it mean?

It is unlikely that asthma is uncontrolled, but it can be an alternative cause like cardiac disease, GERD, allergies, etc

When is a peak expiratory flow (PEF) measured?

• Short-term: treatment response, evaluate triggers, establish asthma action plan baseline

• Long-term: only recommended in patients with severe asthma

In the GINA guidelines, what is the time period that symptom control is assessed for?

The last 4 weeks

Asthma Severities

Categorized based on what treatment step the patient is on

• Mild

- As needed low dose ICS-formoterol (SMART)

- Low dose ICS plus a SABA

- Just because an asthma is mild, does not mean it is low risk

• Moderate

- Well controlled with Step 3 or Step 4

- Low/Medium-dose ICS LABA

• Severe

- Uncontrolled despite high dose ICS LABA

- Controlled with high dose ICS LABA +/- biologic therapy

- Exclude other causes inadequate treatment, adherence/technique, comorbidities

GINA Guidelines: Asthma Treatment Initiation (≥ 12 years)

Step 1: Infrequent asthma symptoms (≤ 2 days per week)

• Preferred Track (Track 1): Low dose ICS/formoterol PRN

• Alternative Treatment (Track 2): Low dose ICS taken whenever SABA is needed/used

Step 2: Asthma symptoms less than 3 - 5 days per week, with normal or mildly reduced lung function

• Preferred Track (Track 1): Low dose ICS/formoterol PRN

• Alternative Treatment (Track 2): Low dose ICS daily + SABA PRN

Step 3: Asthma symptoms most days (4 - 5 day per week) OR ≥1x/week nighttime awakening, or low lung function

• Preferred Track (Track 1): Low dose ICS/formoterol daily + PRN

• Alternative Treatment (Track 2): Medium dose ICS daily + SABA PRN OR Low dose ICS/LABA daily + SABA PRN

*ICS/SABA PRN

Step 4: Daily symptoms, ≥1x/week nighttime awakening, and low lung functionInitial asthma presentation severely uncontrolled or with an acute exacerbation

• Preferred Track (Track 1): Medium dose ICS/formoterol daily + PRN+/- oral corticosteroids

• Alternative Treatment (Track 2): Medium dose ICS/LABA daily + SABA PRN OR High dose ICS/LABA daily + SABA PRN +/- oral corticosteroids

*ICS/SABA PRN

Step-up Treatment

• Poor symptom control and frequent exacerbations

• Before initiating or stepping up, assess the following

– Technique, adherence, modifiable risk factors, comorbidities, appropriate diagnosis

• Day-to-day

– ICS/formoterol → adjust PRN doses (MAX: 8 - 12 doses)

• Short term (1-2 weeks)

– Viral infections, seasonal allergies

• Sustained (2-3 months) after excluding other possible causes & pt requires change in treatment

– Poor response to treatment

– If no response after 2-3 months, step down then step up to alternative therapy