asthma management phenotype based approach

Asthma Management

Phenotypes based approach

Gamal Rabie Agmy, MD, FCCP Professor of chest Diseases, Assiut university

Asthma is a heterogeneous disease, usually

characterized by chronic airway inflammation.

It is defined by the history of respiratory

symptoms such as wheeze, shortness of breath,

chest tightness and cough that vary over time

and in intensity, together with variable expiratory

airflow limitation.

Definition of asthma

NEW!

GINA 2014

• Increased probability that symptoms are due to asthma if:

– More than one type of symptom (wheeze, shortness of breath, cough, chest tightness)

– Symptoms often worse at night or in the early morning

– Symptoms vary over time and in intensity

– Symptoms are triggered by viral infections, exercise, allergen exposure, changes in weather, laughter, irritants such as car exhaust fumes, smoke, or strong smells

• Decreased probability that symptoms are due to asthma if:

– Isolated cough with no other respiratory symptoms

– Chronic production of sputum

– Shortness of breath associated with dizziness, light-headedness or peripheral tingling

– Chest pain

– Exercise-induced dyspnea with noisy inspiration (stridor)

Diagnosis of asthma – symptoms

GINA 2014

• Confirm presence of airflow limitation

– Document that FEV1/FVC is reduced (at least once, when FEV1 is low)

– FEV1/ FVC ratio is normally >0.75 – 0.80 in healthy adults, and >0.90 in children

• Confirm variation in lung function is greater than in healthy individuals

– The greater the variation, or the more times variation is seen, the greater probability that the diagnosis is asthma

– Excessive bronchodilator reversibility (adults: increase in FEV1 >12% and >200mL; children: increase >12% predicted)

– Excessive diurnal variability from 1-2 weeks’ twice-daily PEF monitoring (daily amplitude x 100/daily mean, averaged)

– Significant increase in FEV1 or PEF after 4 weeks of controller treatment

– If initial testing is negative:

• Repeat when patient is symptomatic, or after withholding bronchodilators

• Refer for additional tests (especially children ≤5 years, or the elderly)

Diagnosis of asthma – variable airflow

limitation

GINA 2014, Box 1-2

© Global Initiative for Asthma

Time (seconds)

Volume

Note: Each FEV1 represents the highest of

three reproducible measurements

Typical spirometric tracings

FEV1

1 2 3 4 5

Normal

Asthma

(after BD)

Asthma

(before BD)

Flow

Volume

Normal

Asthma

(after BD)

Asthma

(before BD)

GINA 2014

• Physical examination in people with asthma

– Often normal

– The most frequent finding is wheezing on auscultation, especially on

forced expiration

• Wheezing is also found in other conditions, for example:

– Respiratory infections

– COPD

– Upper airway dysfunction

– Endobronchial obstruction

– Inhaled foreign body

• Wheezing may be absent during severe asthma exacerbations (‘silent

chest’)

Diagnosis of asthma – physical examination

GINA 2014

GINA 2014, Box 1-1 © Global Initiative for Asthma

NEW!

Asthma Pathology

Asthma is a chronic inflammatory disease associated with airway

hyperresponsiveness (AHR), short-term consequences…

Airway obstruction

and symptoms by:

Bronchoconstriction

Mucus plugs

Mucosal edema Inflammatory cell

infiltration/activation

Remodelling:

Increased vascularity

Epithelial cell disruption

Increased airway smooth

muscle mass

(hyperplasia)

Reticular basement membrane thickening

…and long-term consequences

Bousquet J et al. Am J Respir Crit Care Med 2000;161:1720–1745;

Beckett PA et al. Thorax 2003;58:163–174

Asthma Inflammation

Asthma Timeline

◙ For revealing the complexity and the

heterogeneity of this disease, asthma patients

were grouped into subtypes called phenotypes.

◙ Term ‘phenotype’ describes subtypes of

asthma focused on ‘clinically observable

characteristics’ of a disease.

Therefore, there are many ‘definitions’ for asthma phenotypes,

many of which are related to differences in symptoms and

severity rather than to differences in underlying mechanisms. but

this kind of subtyping does little to help understand prognosis

and target therapy.

When a link can be made between clinical characteristics and

molecular pathways, the term endotype can be introduced

to describe distinct subtypes with a defining etiology and

consistent pathobiologic mechanisms.

The definition of a true phenotype (or endotype)

requires an underlying pathobiology with

identifiable biomarkers and genetics .

Gene-expression profiling allows definition of

expression signatures to characterize patient

subgroups, predict response to treatment, and

offer novel therapies.

Asthma Endotypes: categories

1. TH2-associated asthma

– Allergic asthma

– Early-onset allergic asthma

– Late-onset persistent eosinophilic asthma

– Aspirin exacerbated airway disease (AERD)

– Exercise induced asthma

2. Non Th2-associated asthma

– Obesity-related asthma

– Neutrophilic asthma

– Smoking asthma



– Allergic asthma








– Smoking asthma

TH2-associated asthma

Allergic asthma (Virus induced asthma)

Asthma Phenotypes: categories


– Allergic asthma








– Smoking asthma


Early-onset allergic asthma

• Clinical characteristics :

– This group of asthmatic patients developed their

disease in childhood, and maintained their symptoms

into adulthood. . The majority of early-onset allergic

asthma is mild but that an increasing complexity of

immune processes leads to greater severity.

– Most people with asthma are likely to have this

phenotype.

– Positive skin prick tests, specific IgE antibodies in

serum, eosinophilia in the peripheral blood.



• Genetics:

– Early-onset allergic patients commonly have a family

history of asthma, suggesting a genetic component.

– Several Th2 cytokine SNPs

– Higher numbers of mutations in TH2-related genes

(IL4, IL13, IL4Rα ) associated with greater severity of

disease.

• Biomarkers:

– Positive SPT, elevated IgE/elevated FeNO

– Th2 cytokines IL-4 ,IL-5 , IL-9, IL-13, and periostin

measured in sputum, BAL, serum and bronchial

biopsies.



• Treatment responses:

– Corticosteroid-responsive.

– Th2 Targeted therapy:

– Anti IgE (omalizumab)in Severe allergic asthma.

– Anti–IL-13( lebrikizumab) in Allergic asthma with

dominant IL-13 activation . Surrogate marker

predicting better response is high circulating levels of

periostin.

– Inhaled IL-4Rα antagonist. Surrogate marker

predicting better response is IL-4 receptor a

polymorphism.



– Allergic asthma








– Smoking asthma


Late-onset persistent eosinophilic asthma

• Clinical characteristics:

– The majority of this group develops disease in adult

life, often in the late 20s to 40s.

– Severe from onset, Severe exacerbations with

persistent sputum eosinophilia (>2%), despite

corticosteroid therapy.

– less clinical allergic responses( non atopic) than

early-onset asthma.

– It is often associated with sinus disease.



• Genetics:

– Few patients in this group have a family history of

asthma.

– little is known regarding the genetics of adult onset

persistent asthma.



• Biomarkers:

– Lung eosinophilia. Persistent sputum eosinophilia (≥2%)

– The lack of clinical allergy in this phenotype suggests that

the TH2 process differs from and is probably more

complex than the one associated with the early-onset

allergic phenotype but the presence of IL-13 and IL-5 in

the lower airways confirm Th2 pathway.

– Some individuals show sputum neutrophilia intermixed

with their eosinophilic process. This mixed inflammatory

process implies that there are interactions of additional

immune pathways with TH2 immunity, including

activation of pathways related to IL-33 and IL-17 .

– Elevations in FeNO




– persistent eosinophilia in late-onset disease inspite of

ICS implies that the TH2 process in this type of asthma is

refractory to corticosteroids but high systemic doses of

corticosteroids are generally able to overcome this

refractoriness in late-onset asthma.

– IL-5 targeted therapy may show much better efficacy in

this endotype, compared in early-onset allergic asthma

patients, as IL-5 dependent eosinophilia may be more

important in this potential endotype. (decreasing

exacerbations and systemic corticosteroid requirements)

– IL-4 and IL-13 targeted therapy pathway.



– Allergic asthma








– Smoking asthma


Aspirin exacerbated airway disease (AERD)

• AERD is probably a subendotype or a similar endotype.

It is an acquired condition on top of an intrinsic or less

frequently allergic asthma and thus, despite its peculiar

sensitivity to NSAIDs, still has major overlap with these

conditions.

• Clinical characteristics :

– AERD is frequently progressive severe asthma starts

late in life and is associated with eosinophilia and

sinus disease Polyposis.

– Response to aspirin challenge

• Genetics :

– LT-related gene polymorphisms.

– Gene-expression study identified upregulation of

periostin a potent regulator of fibrosis and

collagen deposition has also been identified in

polyps of and in airway epithelial cells of patients

with AIA.

– Overexpression of periostin has been associated

with accelerated cell growth and

angiogenesis(subtype).

• Biomarkers:

– high cysteinyl leukotriene level.



• Treatment responses :

– Many patients require systemic corticosteroids to

control their sinusitis and asthma.

– Leukotriene modifiers especially 5-LO inhibitors

can have a robust impact on the AERD subset.

– Downregulation of periostin after treatment of

asthmatic patients with corticosteroids suggests that

normalization of periostin expression is a part of the

therapeutic effects of corticosteroids. This opens a

possibility of specifically targeting periostin in future

therapies for nasal polyps and asthma





– Allergic asthma








– Smoking asthma


– Exercise induced asthma refers to asthma whose

symptoms are experienced primarily after exercise.

EIA is a milder form of TH2 asthma.

– Consistent with a relationship to TH2 processes, EIA

common in atopic athletes and high percentages of

eosinophils and mast cells and their mediators .

• Biomarkers:

– Th2 cytokines and cysteinyl leukotriene

• Genetics:

– No distinct genetic factors .


Exercise induced asthma

Benefits of LTRAs in Activity-Induced Asthma

• Leukotrienes are important mediators of exercise-triggered

asthma episodes.1

• Both the LTRA montelukast and the LABA salmeterol

provide benefit in terms of chronic symptom control.2,3

– Montelukast may provide better bronchoprotection against

exercise-triggered asthma.4,5

– SABA rescue therapy may be more effective postexercise.2

Slide 49

LTRAs=leukotriene receptor antagonists; LABA=long-acting β-agonist; SABA=short-acting β-agonist.

1. O’Byrne PM. Am J Respir Crit Care Med. 2000;161:S68–S72. 2. Storms W et al. Respir Med. 2004;98:1051–1062. 3. Wilson AM et al.

Chest. 2001;119(4):1021–1026. 4. Villaran C et al. J Allergy Clin Immunol. 1999;104(3, pt 1):547–553. 5. Edelman JM et al. Ann Intern Med. 2000;

132(2):97–104.


Exercise induced asthma

Ann Allergy Asthma Immunol 2010

Study Design1

E=exercise challenge.

1. Fogel RB et al. Ann Allergy Asthma Immunol. 2010;104:511–517.

(n=78) Montelukast 5 mg + placebo for salmeterol

Salmeterol 50 µg twice daily + placebo for montelukast

(154) Fluticasone

100 µg twice daily

–4

Week

6 10 0 4

Active Treatment Run-In Active Treatment Washout

E

Fluticasone

100 µg twice daily

(n=76) Salmeterol 50 µg twice daily + placebo for montelukast

Montelukast 5 mg + placebo for salmeterol

E E

Slide 51

Efficacy End Points1

Minutes Postchallenge This article was published in the Annals of Allergy, Asthma & Immunology, 104, Fogel RB, Rosario N, Aristizabal G, et al, Ef fect of montelukast or

salmeterol added to inhaled f luticasone on exercise-induced bronchoconstriction in children, 511–517, ©2010 American College of Allergy, Asthma &

Immunology.

AUC0–20 min=area under the curve for the f irst 20 minutes af ter exercise; FEV1=forced expiratory volume in 1 second.


Slide 52

Mean

Perc

en

tag

e C

han

ge

Fro

m P

rech

all

en

ge

0 5 10 15 20 25 30 35 50

End of exercise, start of spirometry

–30

–20

–10

0

10

Exerc

ise C

halle

nge

β-agonist use 1st 2nd

Return to within 5% of the preexercise baseline FEV1

20

Time to recovery to within 5% of the preexercise baseline FEV1

AUC0–20 min

Max % fall in FEV1

Slide 52

Montelukast Provided Better Bronchoprotection After Exercise Than Salmeterol1

Mean

± S

D M

axim

um

%

Fall

in

FE

V1

Slide 53

SD=standard deviation; FEV1=forced expiratory volume in 1 second; LS=least squares. aOn a background of inhaled f luticasone.


Maximum % Fall in FEV1 (Primary End Point)

Slide 53

LS mean difference:

–3.3% (P=0.009)

Salmeterola

(n=144)

–10.6 ± 12.2

–13.8 ± 12.5

–20

0

–10

–15

–5

Montelukasta

(n=144)

Montelukast Maintained Bronchoprotective Effects After Exercise Challenge1

Mean

± S

E %

Ch

an

ge

Fro

m P

rech

all

en

ge

This article was published in the Annals of Allergy, Asthma & Immunology, 104, Fogel RB, Rosario N, Aristizabal G, et al, Ef fect of montelukast or

salmeterol added to inhaled f luticasone on exercise-induced bronchoconstriction in children, 511–517, ©2010 American College of Allergy, Asthma &

Immunology.

FEV1=forced expiratory volume in 1 second; SE=standard error.


Minutes Postchallenge

Pre-

challenge 0 5 10 15 20 25 30 35 50

Montelukast (n=144)

Salmeterol (n=144)

–15

–10

–5

0

10

5

Short-acting β-agonist rescue

Change in FEV1 Over Time

Slide 54

Montelukast Reduced the Extent and Duration of Bronchoconstriction1

Slide 55

AUC0–20 min=area under the curve for the f irst 20 minutes af ter exercise; FEV1=forced expiratory volume in 1 second; LS=least squares; SD=standard deviation.


AUC0–20 min for FEV1 Following Exercise Challenge

Mean

± S

D A

UC

0–

20

min

,

% •

min

Salmeterol (n=144)

0

Montelukast (n=144)

LS mean difference:

–52.7% (P=0.006)

116.0

168.8

250

100

50

150

Slide 55

200

Montelukast Reduced the Time to Recovery1

M

ed

ian

Tim

e, m

in

Slide 56

FEV1=forced expiratory volume in 1 second; LS=least squares.


Time to Recovery to Within 5% of Preexercise FEV1

Salmeterol (n=142)

Montelukast (n=141)

LS Mean Difference: 1.3

(P=0.04)

Slide 56

0

5.9

11.1

14

6

2

10

4

8

12

Children Remained More Responsive to SABA Rescue With Montelukast1

Slide 57

SABA=short-acting β-agonist; FEV1=forced expiratory volume in 1 second; LS=least squares.


Average % Change in FEV1 Following First SABA Use

Slide 57

Avera

ge %

Ch

an

ge i

n F

EV

1

Fro

m P

reexerc

ise B

aseli

ne

Salmeterol (n=144)

0

Montelukast (n=144)

LS mean difference:

3.8% (P<0.001)

6.5

2.7

8

4

2

6

10

Summary and Conclusions

• In a study of children aged 6 to 14 years receiving an ICS

for the treatment of persistent asthma (N=154):

– Montelukast provided superior bronchoprotection

compared with LABA therapy.

– Children remained more responsive to SABA rescue while

on montelukast compared with LABA therapy.

• Montelukast + an ICS may provide better protection against

exercise-triggered asthma than a LABA + an ICS.

ICS=inhaled corticosteroid; LABA=long-acting β-agonist; SABA=short-acting β-agonist.


Slide 58

Montelukast Activity-Induced Asthma Study (6–14 years)

Summary

Adapted from Kemp JP et al J Pediatr 1998;133(3):424-428; Data on file, MSD.

Clinical Benefits

Reduced the Extent of EIB

Reduced the Duration of EIB

Reduced the Recovery Time From EIB

Tolerability

As Placebo



– Allergic asthma








– Smoking asthma

• Whether obesity is a driving component in asthma

development or a mere confounder or comorbidity of its

presence remains controversial.

• It is likely that obesity differentially impacts asthma that

develops early in life, as compared to later in life, being a

more prominent independent contributor in later onset

disease.

• So a distinct obesity-related asthma phenotype seems to

occur only in non-TH2 asthma.

Non TH2-associated asthma

Obesity related Asthma


– Patients in this group are commonly women, obese,

late onset (mid-40s), less allergic (obesity is neither a

risk factor for atopy nor a risk factor for allergic

asthma).with a high burden of symptoms.

• Biomarkers:

– High expression of non Th2 mediators such as tumor

necrosis factor (TNF)-a, IL-6 .

– Hormones of obesity, such as adiponectin, leptin,

and resistin either alone or in association with

increased oxidative stress.

– Elevations in an endogenous inhibitor of iNOS,

asymmetric dimethyl arginine (ADMA).

– lower amounts of FeNO, fewer eosinophils.




– Patients of this subgroup usually respond poorly to

corticosteroids.

– Bariatric surgery induced weight loss was associated

with profound improvements in lung function and

symptoms in obese asthma.

– However, the effect of weight loss on bronchial hyper

responsiveness was only shown in late-onset,

nonallergic (non-Th2) asthma patient, consistent with

late onset obese asthma being a separate endotype.

This is further supported by the increase in ADMA in

association with worsening severity and control in

late onset obese asthma only.





– Allergic asthma








– Smoking asthma

• Smoking has a complex relationship with asthma. It is

associated with deteriorating lung function and

resistance to corticosteroids.

• Smoking asthma has been associated with neutrophilia

in lung tissue.

• It is unknown if smoking asthma is a subtype of

neutrophilic asthma or an independent endotype . Since

not all smoking asthma is accompanied by neutrophilia,

it is more likely that there is only a partial overlap

between neutrophilic asthma and smoking asthma.


Smoking asthma

• Some reports have suggested that smoking is

associated with elevated total IgE and that active

smoking may increase the risk of sensitization to

workplace allergens.

• However, little is understood regarding the role of

genetics, biomarkers or pathobiology.

• FeNO levels are decreased by smoking and could help

to differentiate asthmatic subjects from non-asthmatic

subjects.

• Treatment responses

– Quitting smoking

– Restoration of HDAC 2 nuclear recruitment with

theophylline.


Smoking asthma


Smoking asthma

Rationale for Targeting Leukotrienes in Patients With Asthma Who Smoke

Does Smoking Affect Leukotriene Production

in Subjects Without Asthma?

LTE4=leukotriene E4.

1. Fauler J et al. Eur J Clin Invest. 1997;27:43–47.

Correlation of LTE4 Excretion With Cigarette Smoking1

No. of Cigarettes Smoked Per Day

Uri

na

ry E

xc

reti

on

of

LT

E4,

nm

ol/

mo

l c

rea

tin

ine

1

10

20 30 40 50 60 70 80

100

0

(r=0.92, P<0.001)

(n=30)

Does Smoking Affect Leukotriene Production

in Patients With Asthma?

Slide 69

LTE4=leukotriene E4.

1. Gaki E et al. Respir Med. 2007;101:826–832.

LTE4/Creatinine Concentration Ratios in Smoking and Nonsmoking Asthma

Patients1 LT

E4/C

rea

tin

ine

, p

g/m

g

300

250

200

150

100

50

0

P<0.0001

Asthma

Smoking

(n=20)

Nonsmoking

(n=20)

Effect of Montelukast for treatment of asthma in cigarette

smokers

Slide 70

J Allergy Clin Immunol 2013

Study Goal and Design

Montelukast 10 mg once daily (n=347)

Fluticasone propionate 250 µg twice daily (n=336)

Placebo (n=336)

Single-blind

placebo

run-in period Washout

Day –31 Day –21 Day 1 Day 30 Day 90 Day 180

Period I Period II

Goal: To evaluate the effect of montelukast vs placebo (primary) and

medium-dose fluticasone (secondary) in asthma patients who smoke

Slide 71

Key Inclusion/Exclusion Criteria

• Inclusion

– Male or female, aged 18 to 55 years

– History of chronic asthma ≥1 year

– Evidence of reversible airway obstruction (increase in FEV1 ≥12%

following

β-agonist administration)

– Cigarette smoker of 0.5 to 2 packs per day (≤30 pack-year history)

– Weekly average ≥2 puffs/day β-agonist during run-in period

Slide 72

FEV1=forced expiratory volume in 1 second; COPD=chronic obstructive pulmonary disease.

Key Inclusion/Exclusion Criteria

• Exclusion

– History of COPD

– History of intubation for asthma, acute asthma therapy in an

emergency department/urgent care/office setting within 1 month,

or hospitalization for asthma within 3 months of the beginning of

run-in

– Any active, acute, or chronic pulmonary disorder (other than

asthma), or active, clinically significant sinus infection

– Unresolved signs and symptoms of upper respiratory tract

infection within 3 weeks

of the beginning of run-in

– Prohibited medications (prior to screening visit)

Slide 73

FEV1=forced expiratory volume in 1 second; COPD=chronic obstructive pulmonary disease.

Primary and Secondary Efficacy

End Points

• Primary

– Percentage of asthma-control days, defined as a day

with none of the following:

♦ Unscheduled visit for asthma care to an office,

emergency department, or hospital setting

♦ Use of >2 puffs of β-agonist

♦ Use of other asthma rescue medication

♦ Nocturnal awakenings

• Secondary

– Average change from baseline in mean daytime

symptom score

– Change from baseline in average AM peak expiratory

flow rate

Slide 74

Tertiary Efficacy End Points

• Changes in lung function

– FEV1

– PM PEFR

• Changes in parameters of asthma control

– Average daily number of β-agonist puffs

– Average nighttime symptom score

– Asthma-free daysa

– Asthma attacks/time to first attackb

– Discontinuations due to asthma

• Other

– Eosinophil count FEV1=forced expiratory volume in 1 second; PEFR=peak expiratory f low rate.

aAsthma-free day def ined as a day with no unscheduled visit for asthma care to an of f ice, emergency department, or hospital setting; no use of

β-agonist; no use of other rescue medication; and no nocturnal awakening. bAsthma attack def ined as the occurrence of an unscheduled visit to the doctor’s office or emergency department, hospitalization, or treatment

with oral, intravenous, or intramuscular corticosteroids.

Slide 75

Safety Profile End Points

• Clinical Adverse Experiences

– Overall adverse experiences (primary)

– Serious adverse experiences

– Drug-related adverse experiences

– Discontinuations due to adverse experiences

Slide 76

Significant improvements in the mean percentage

of days with asthma control in both groups

Slide 77 J Allergy Clin Immunol 2013;

Patients with a smoking history of >11 pack years

tended to show more benefit with montelukast

Slide 78 J Allergy Clin Immunol 2013;

Key Conclusion

• Evidence suggests that corticosteroids have reduced efficacy for

treatment of asthma in smokers. Because smoking induces cysteinyl

leukotriene production, treatment with Singulair might be helpful in

this population.

• Both montelukast and fluticasone were superior to placebo in this

population; the difference between the 2 treatments was not

statistically significant.

• Patients with a smoking history of less than 11 pack years tended to

show more benefit with fluticasone, whereas those with a smoking

history of greater than 11 pack years tended to show more benefit

with montelukast

Slide 80


GINA Global Strategy for Asthma

Management and Prevention 2014

This slide set is restricted for academic and educational purposes

only. Use of the slide set, or of individual slides, for commercial or

promotional purposes requires approval from GINA.

Assessment of asthma


GINA assessment of asthma control

GINA 2014, Box 2-2A


GINA assessment of asthma control

GINA 2014, Box 2-2B


Assessment of risk factors for poor asthma outcomes

Risk factors for exacerbations include:

• Ever intubated for asthma

• Uncontrolled asthma symptoms

• Having ≥1 exacerbation in last 12 months

• Low FEV1 (measure lung function at start of treatment, at 3-6 months

to assess personal best, and periodically thereafter)

• Incorrect inhaler technique and/or poor adherence

• Smoking

• Obesity, pregnancy, blood eosinophilia

GINA 2014, Box 2-2B








• Smoking


Risk factors for fixed airflow limitation include:

• No ICS treatment, smoking, occupational exposure, mucus

hypersecretion, blood eosinophilia








• Smoking


Risk factors for fixed airflow limitation include:

• No ICS treatment, smoking, occupational exposure, mucus

hypersecretion, blood eosinophilia

Risk factors for medication side-effects include:

• Frequent oral steroids, high dose/potent ICS, P450 inhibitors


How?

Asthma severity is assessed retrospectively from the level of

treatment required to control symptoms and exacerbations

When?

Assess asthma severity after patient has been on controller

treatment for several months

Severity is not static – it may change over months or years, or as

different treatments become available

Categories of asthma severity

Mild asthma: well-controlled with Steps 1 or 2 (as-needed SABA or

low dose ICS)

Moderate asthma: well-controlled with Step 3 (low-dose ICS/LABA)

Severe asthma: requires Step 4/5 (moderate or high dose

ICS/LABA ± add-on), or remains uncontrolled despite this treatment

Assessing asthma severity

GINA 2014







Treating asthma to control

symptoms and minimize risk


Choosing between controller options – population-level decisions

Choosing between treatment options at a population level

e.g. national formularies, health maintenance organisations, national guidelines

The ‘preferred treatment’ at each step is based on:

Efficacy

Effectiveness

Safety

Availability and cost at the population level

based on group mean data for symptoms, exacerbations

and lung function (from RCTs, pragmatic studies and

observational data)

NEW!

GINA 2014, Box 3-3 (1/2) Provided by H Reddel


Start controller treatment early

For best outcomes, initiate controller treatment as early as possible

after making the diagnosis of asthma

Indications for regular low-dose ICS - any of:

Asthma symptoms more than twice a month

Waking due to asthma more than once a month

Any asthma symptoms plus any risk factors for exacerbations

Consider starting at a higher step if:

Troublesome asthma symptoms on most days

Waking from asthma once or more a week, especially if any risk

factors for exacerbations

If initial asthma presentation is with an exacerbation:

Give a short course of oral steroids and start regular controller

treatment (e.g. high dose ICS or medium dose ICS/LABA, then step

down)

Initial controller treatment for adults, adolescents and children 6–11 years

GINA 2014, Box 3-4 (1/2)

NEW!


Step 1 – as-needed inhaled short-acting beta2-agonist (SABA)

*For children 6-11 years, theophylline is not recommended, and preferred Step 3 is medium dose ICS

**For patients prescribed BDP/formoterol or BUD/formoterol maintenance and reliever therapy

GINA 2014, Box 3-5, Step 1


Step 2 – low-dose controller + as-needed inhaled SABA





Step 3 – one or two controllers + as-needed inhaled reliever





Step 4 – two or more controllers + as-needed inhaled reliever





Step 5 – higher level care and/or add-on treatment





Low, medium and high dose inhaled corticosteroids

Adults and adolescents (≥12 years)

This is not a table of equivalence, but of estimated clinical comparability

Most of the clinical benefit from ICS is seen at low doses

High doses are arbitrary, but for most ICS are those that, with prolonged use,

are associated with increased risk of systemic side-effects

Inhaled corticosteroid Total daily dose (mcg)

Low Medium High

Beclometasone dipropionate (CFC) 200–500 >500–1000 >1000

Beclometasone dipropionate (HFA) 100–200 >200–400 >400

Budesonide (DPI) 200–400 >400–800 >800

Ciclesonide (HFA) 80–160 >160–320 >320

Fluticasone propionate (DPI or HFA) 100–250 >250–500 >500

Mometasone furoate 110–220 >220–440 >440

Triamcinolone acetonide 400–1000 >1000–2000 >2000

GINA 2014, Box 3-6 (1/2)


Low, medium and high dose inhaled corticosteroids

Children 6–11 years

This is not a table of equivalence, but of estimated clinical comparability

Most of the clinical benefit from ICS is seen at low doses

High doses are arbitrary, but for most ICS are those that, with prolonged use, are

associated with increased risk of systemic side-effects

Inhaled corticosteroid Total daily dose (mcg)

Low Medium High

Beclometasone dipropionate (CFC) 100–200 >200–400 >400

Beclometasone dipropionate (HFA) 50–100 >100–200 >200

Budesonide (DPI) 100–200 >200–400 >400

Budesonide (nebules) 250–500 >500–1000 >1000

Ciclesonide (HFA) 80 >80–160 >160

Fluticasone propionate (DPI) 100–200 >200–400 >400

Fluticasone propionate (HFA) 100–200 >200–500 >500

Mometasone furoate 110 ≥220–<440 ≥440

Triamcinolone acetonide 400–800 >800–1200 >1200

GINA 2014, Box 3-6 (2/2)

Levels of Asthma Control

Characteristic Controlled

(All of the following)

Partly controlled (Any present in any week)

Uncontrolled

Daytime symptoms None (2 or less /

week)

More than

twice / week

3 or more

features of

partly

controlled

asthma present in

any week

Limitations of

activities None Any

Nocturnal

symptoms /

awakening

None Any

Need for rescue /

“reliever” treatment

None (2 or less /

week)

More than

twice / week

Lung function

(PEF or FEV1) Normal

< 80% predicted or

personal best (if

known) on any day

Exacerbation None One or more / year 1 in any week


How often should asthma be reviewed?

1-3 months after treatment started, then every 3-12 months

During pregnancy, every 4-6 weeks

After an exacerbation, within 1 week

Stepping up asthma treatment

Sustained step-up, for at least 2-3 months if asthma poorly controlled

• Important: first check for common causes (symptoms not due to asthma, incorrect inhaler technique, poor adherence)

Short-term step-up, for 1-2 weeks, e.g. with viral infection or allergen

• May be initiated by patient with written asthma action plan

Day-to-day adjustment

• For patients prescribed low-dose ICS/formoterol maintenance and reliever regimen*

Stepping down asthma treatment

Consider step-down after good control maintained for 3 months

Find each patient’s minimum effective dose, that controls both symptoms and exacerbations

Reviewing response and adjusting treatment

GINA 2014

*Approved only for low dose beclometasone/formoterol and low dose budesonide/formoterol

The underline cause of Asthma is the

inflammation…

Does the ICS based therapy is enough?

Airway Inflammation Persisted

Despite Corticosteroid Use

ICS=inhaled corticosteroids; OCS ± ICS=received oral corticosteroids with or without ICS

Adapted from Louis R et al Am J Respir Crit Care Med 2000;161:9-16.

20,000

10,000

1,000

100

10

1

Eosinophil 103/g sputum

Control group

Mild to moderate

ICS low-dose (n=10)

ICS high-dose

(n=15)

OCS (n=10)

OCS ± ICS (n=7)

Severe asthma

p<0.01

p<0.001

p<0.001

p<0.01

In a clinical study of 74 patients

Leukotrienes

Other inflammatory mediators

This slide is an artistic rendition.

Adapted from Holgate ST, Peters-Golden M J Allergy Clin Immunol 2003;111(1 suppl):S1-S4; Holgate ST et al J Allergy Clin Immunol 2003;111(1 suppl):S18-S36; Henderson WR Jr et al Am J Respir Crit Care Med 2002;165:108-116; Peters-Golden M, Sampson AP J Allergy Clin Immunol 2003;111(1 suppl):S37-S42; Varner AE, Lemanske RF Jr. In Asthma and Rhinitis. Oxford, UK: Blackwell Science, 2000:1172-1185.

No Inflammation Inflammation Asthma

Leukotrienes: Important in Early Asthma

and Throughout the Disease

block

steroid- sensitive mediators

blocks the

effects of CysLTs

Inhaled steroids Montelukast

Montelukast Combined with a Steroid

Affects the Dual Pathways of Inflammation

The slide represents an artistic rendition.

Adapted from Peters-Golden M, Sampson AP J Allergy Clin Immunol 2003;111(1 suppl):S37-S42; Bisgaard H Allergy

2001;56(suppl 66):7-11.

Steroid-sensitive

mediators play a key role

in asthmatic inflammation

CysLTs play a key role in asthmatic

inflammation

Steroids do NOT inhibit CysLT formation in the airways of asthmatic patients

DUAL PATHWAY

Dual Pathways of Inflammation

SGA 2003-W-6701-SS

Downloaded from – www.singulair.ae Slide 102

Budesonide Turbuhaler 400–1600 µg qd

+ montelukast (n=326)

Budesonide Turbuhaler 400–1600 µg qd

+ placebo

(n=313)

qd = once daily

Inhaled short-acting beta2 agonists were permitted as needed.

Adapted from Vaquerizo MJ et al Thorax 2003;58:204-211.

CASIOPEA Study

Design

Period I

Weeks

Period II

Budesonide

Turbuhaler 400–1600 µg/day

V1

–2

V2

0

V2

4

V2

8

V5

16

http://www.singulair.ae/

SGA 2003-W-6701-SS


FEV1 = forced expiratory volume in one second


• Non-smoking asthmatic patients 18–70 years of age

• Prior treatment with a clinically stable dose of ICS

equivalent to budesonide 400–1600 µg/day

• FEV1 55% of predicted

• Reversible airway obstruction (12% increase

from baseline)

• Minimum total daytime asthma symptom score

of 64 (of possible 336)

• 1 puff/day of beta2 agonist

CASIOPEA Study

Inclusion Criteria


SGA 2003-W-6701-SS



CASIOPEA Study

Montelukast + Budesonide

Significantly Reduced Asthma-Exacerbation Days

4.8

3.1

Budesonide +

placebo

(n=308)

Montelukast +

budesonide

(n=317)

Median

percentage

of asthma-

exacerbation

days

5

4

3

2

1

0

35% p=0.03


SGA 2003-W-6701-SS



CASIOPEA Study


Significantly Increased Asthma-Free Days

42.3

66.1

Budesonide +

placebo

(n=308)

Montelukast +

budesonide

(n=317)

Median

percentage

of asthma-

free days

70

60

50

40

30

56% p=0.001


SGA 2003-W-6701-SS


*The percentage of patients who awoke during the night because of asthma


CASIOPEA Study


Significantly Reduced Nocturnal Awakenings

25.6

Least square

mean % of

patients

with nocturnal

awakenings*

35

30

25

20

32.2

20% p=0.01

Budesonide +

placebo

(n=308)

Montelukast +

budesonide

(n=317)


SGA 2003-W-6701-SS


*p = 0.05 vs. budesonide alone


CASIOPEA Study


Significantly Reduced Beta2-Agonist Use*

% change

from

baseline in

beta2-agonist

use

30

20

10

0

–10

–20

–30

–40

First 7 days in active treatment

Budesonide + placebo (n=313)

Montelukast + budesonide (n=326)

Basal 1 2 3 4 5 6 7

A more rapid onset of action

than budesonide + placebo


SGA 2003-W-6701-SS


CASIOPEA Study


Significantly Increased AM PEFR*

Tertiary endpoint: Morning PEFR

Mean adjusted by center and stratum

*p = 0.05 vs. budesonide alone


11.3

16.86

Budesonide + placebo (n=308)

Montelukast + budesonide

(n=317)

20

15

10

5

0

49% p=0.05

Least square

mean change

in morning

PEFR

(L/min)


Key Conclusion

SINGULAIR in combination with ICS represents an

essential tool to better treat the inflammation.

This approach has also proven to provide high

efficacy on asthma symptoms.

The efficacy of the SINGULAIR/ICS approach on

symptoms results from its superior efficacy on

inflammation, the underlying cause of asthma.

110

Epidemiologic Links between Allergic Rhinitis and Asthma

Many Patients with Asthma Have

Allergic Rhinitis

Adapted f rom Bousquet J et al J Allergy Clin Immunol 2001;108(suppl 5):S147–S334; Sibbald B, Rink E Thorax 1991;46:895–901; Leynaert B

et al J Allergy Clin Immunol 1999;104:301–304; Brydon MJ Asthma J 1996:29–32.

Up to 80%

of all asthmatic patients have allergic rhinitis

All asthmatic patients

111

One Airway, One Disease

Allergic Rhinitis and Asthma Share Common

Inflammatory Cells and Mediators

Adapted f rom Casale TB et al Clin Rev Allergy Immunol 2001;21:27–49; Kay AB N Engl J Med 2001;344:30–37.

Early-phase

response

Late-phase

response T cells

Inflammatory

mediators

Allergen

Cytokines

Preformed Mediators Cysteinyl leukotrienes

Prostaglandins

Platelet-activating factor

Eosinophils

Membrane-bound

IgE

Mast

cell

Drug Asthma AR

Asthma and AR

ICS – –

LABAs – –

Intranasal steroids

– –

Antihistamines

– –

Montelukast

Major Therapies At-A-Glance

ICS=inhaled corticosteroids; LABAs=long-acting beta2-agonists

Adapted f rom Flovent® prescribing information, GlaxoWellcome, Research Triangle Park, NC, 2000; Pulmicort Turbuhaler® prescribing

information, AstraZeneca, Wilmington, DE, 2003; Advair Diskus® prescribing information, GlaxoWellcome, Research Triangle Park, NC, 2004;

Serevent® prescribing information, GlaxoWellcome, Research Triangle Park, NC, 2000; Zyrtec® prescribing information, Pf izer Labs, New York,

NY, 2004; Allegra-D® prescribing information, Aventis Pharmaceuticals, Kansas City, MO, 2004; Flonase® prescribing information,

GlaxoWellcome, Research Triangle Park, NC, 2000; Beconase AQ® prescribing information, GlaxoWellcome, Research Triangle Park, NC, 2002.

COMPACT Study Design

Adapted f rom Price DB et al Thorax 2003;58:211–216.

Budesonide

400 µg

twice daily

Montelukast 10 mg once daily +

Budesonide 400 µg twice daily (n=448)

0 4 16

Period I

Run-in (4 weeks)

Single-blind

Period II

Active treatment (12 weeks)

Double-blind

1 8 12

Budesonide 800 µg twice daily +

Oral placebo montelukast (n=441)

Weeks

Subanalysis of Asthma Patients with Concomitant Allergic Rhinitis in COMPACT

Montelukast Provided Greater Improvements in Morning PEF in Asthma Patients with Concomitant Allergic Rhinitis

50

40

30

20

10

0

Change

from

baseline

(L/min, LS

meanSEM)

0 4 8 12 0 4 8 12

Montelukast (n=433)*

Budesonide (n=425)**

p<0.03

p=0.36

Weeks Weeks

Montelukast (n=216)*

Budesonide (n=184)**

*Montelukast 10 mg once daily + budesonide 400 µg twice daily; **Budesonide 800 µg twice daily

Adapted f rom Price DB et al. Presentation at the World Allergy Organization Biannual Meeting, September 2003, Vancouver, British Columbia,

Canada.

50

40

30

20

10

0

Proposed pathophysiologic mechanisms

of asthma exacerbated by sinusitis

Spread of inflammatory mediators and

chemotactic factors to lower airways triggers

sinobronchial reflex mechanism.

Stimulation of autonomic nervous system

causes acute bronchial hyperresponsiveness.

Bronchoconstrictive reflexes originating in

extrathoracic airway receptors are stimulated.

Proposed pathophysiologic mechanisms

of asthma exacerbated by sinusitis

Reversible partial beta-adrenergic blockade is enhanced.

Nasal congestion causes mouth-breathing, which leads to increased loss of water and heat in lower airways.

Depressed nitric oxide concentration promotes acute bronchial hyperresponsiveness.

Why isn’t his asthma getting

better????

Poor asthma control? - then look up the nose. The importance of co-morbid rhinitis in patients with asthma

Scadding G. and Walker S.

The Royal National Throat, Nose and Ear Hospital, London, UK,Primary Care Respiratory Journal 21(2):222-228 2012

Review the patient after 2–4 weeks

Improved

Continue or step-

down treatment for >1 month

Review diagnosis

Review compliance Query infections or other causes

Add or

increase INS dose

Rhinorrhea:

Add ipratropium

In preferred order - INS - H1 blockers or LTRA

Failure

Blockage: Add

decongestant or oral corticosteroid

If failure: refer to a specialist

ARIA Update 2008: INSs Are the Preferred

First-Line Therapy for Moderate/Severe PER1

Moderate/Severe Persistent

ARIA = Allergic Rhinitis and its Impact on Asthma; INS = intranasal corticosteroid; PER = persistent allergic rhinitis;

LTRA = leukotriene receptor antagonist. 1. Bousquet J et al. Allergy. 2008;63(suppl 86):8–160.

Characteristics of an Ideal INS : balancing efficacy, safety and preference

Rapid onset of action

High efficacy against all nasal symptoms

Once daily dosing schedule

Acceptable to patients

With low or absent local / systemic side-effects

Clin Exp All Rev 2002(2):32-37

Share Your Patient Concerns …..

122

NASONEX Rapid Onset of Action: Significant Total Symptom Relief Within Hours of a Single Dose in Patients With SAR

*P<0.05 vs placebo.

Berkowitz et al. Allergy Asthma Proc. 1999;20:167.

-8

-6

-4

-2

0

0 1 2 3 4 5 6 7 8 9 10 11 12

Hours after dosing

Mean

ch

an

ge f

rom

baselin

e

in t

ota

l sym

pto

m s

co

re

* * * * * * * *

NASONEX® 200 μg (n=119)

Placebo (n=116)

Change in Total Symptoms

5 hrs

123

Primary

Endpoint

70

60

40

50

0

30

20

10

Days

1–15

Days

16–30

Days

31–45

Days

46–60

Days

61–75

Days

76–90

Endpoint*

Me

an

re

du

cti

on

fro

m

ba

se

lin

e in

AM

/PM

TN

SS

, %

MFNS

Placebo

a

a

a a

a a a

aP<0.01 vs placebo.

*Endpoint was defined as the last patient visit or last diary interval for which the patient had non-missing data. Baseline values were MFNS = 7.0 and placebo = 7.1. MFNS = mometasone furoate nasal spray; PAR = perennial allergic rhinitis; TNSS = total nasal symptom score. 1. Mandl M et al. Ann Allergy Asthma Immunol. 1997;79:370–378.

MFNS in Adolescents/Adults With PAR:

Efficacy Results – TNSS1

124

Ch

an

ge

in

na

sa

l c

on

ge

sti

on

fro

m b

as

eli

ne

, %

-60

-50

-40

-30

-20

-10

0

Days

1–15

Days

16–30

Days

31–45

Days

46–60

Days

61–75

Days

76–90 Endpoint* Baseline

Placebo (n=184)

MFNS 200 µg once daily (n=181)

40%

33%

aP<0.05 vs placebo.

*Endpoint was defined as the last patient visit or last diary interval for which the patient had non-missing data. MFNS = mometasone furoate nasal spray; PAR = perennial allergic rhinitis .

1. Mandl M et al. Ann Allergy Asthma Immunol. 1997;79:370–378.

MFNS in Adolescents/Adults With PAR:

Efficacy Results – Nasal Congestion1

a

a

a

a a

a

a

0

10

20

30

40

50

60

Flunisolide Triamcinolone Beclomethasone Budesonide FP Fluticasone

furoate

Ciclesonide MF

INS Systemic Bioavailability1,a

aDifferences in safety between INSs are more theoretical than evidence-based, with the greatest concern being systemic

exposure and effects on adrenal function and growth in children. INS = intranasal corticosteroid; FP = fluticasone propionate; MF = mometasone furoate. 1. Derendorf H et al. Allergy. 2008;63:1292–1300.

<0.1%

Bio

ava

ila

bil

ity,

%

126

1-Year Therapy With MFNS Did Not Induce

Nasal Atrophy in Patients With PAR1,a

Nasal Biopsies Before MFNS Treatment After 12 Months of Treatment With

MFNS 200 µg/d

Disruption of epithelium

Eosinophil infiltration

Epithelium intact

No eosinophil infiltration

aThe clinical relevance of these data in the treatment of allergic rhinitis is not known.

MFNS = mometasone furoate nasal spray; PAR = perennial allergic rhinitis. 1. Minshall E et al. Otolaryngol Head Neck Surg. 1998;118:648–654.

127

MFNS: Effect on Serum Cortisol in Children

2–5 Years of Age Following 42 Days of Treatment1 S

eru

m c

ort

iso

l

(μg

/dL

– R

IA)

0

2

4

6

8

10

12

14

16

Mean serum cortisol concentration-time profile on Day 42 in children with AR

MFNS 100 μg once

daily (n=26)

Placebo once daily

(n=26)

6:00 AM 10:00 AM 2:00 PM 6:00 PM 10:00 PM 2:00 AM 6:00 AM

MFNS = mometasone furoate nasal spray; AR = allergic rhinitis; RIA = radioimmunoassay. 1. Cutler DL et al. Pediatr Asthma Allergy Immunol. 2006;19:146–153.

Wheezing in

Children

Adventitious Airway Sounds

Snoring

Stridor

Wheezing

Crepitations

Airway Diameter

Cause of Wheezing

Not from obstruction of small airways –

Surface area too large

From increased intrathoracic pressure +

decreased large airway pressure =

vibration of airway wall in large airways

(Generations 1-5)

Wheezing

Sign of lower (intra-thoracic) airway

obstruction

Small airways

Air Trapping

Hyperinflated chest

Barrel shaped

Loss of cardiac dullness

Liver pushed down

Hoover sign

Hoover Sign

Normal diagphragm movement

Hyperinflation = diaphragm flattened

Diaphragm contraction = paradoxical

inward movement of lower interrcostal

area during inspiration

Acute Wheezing

Asthma

Bronchiolitis

Foreign body

Bronchiolitis

136

What Is Bronchiolitis?

Bronchiolitis is acute inflammation of the airways, characterised by wheeze

Bronchiolitis can result from a viral infection

Respiratory Syncytial Virus (RSV) may be responsible for up to 90% of bronchiolitis cases in young children

Hall CB, McCarthy CA. In: Principles and Practice of Infectious Diseases 2000:1782-1801;

Panitch HB et al. Clin Chest Med 1993;14:715-731

137

RSV Is a Common Virus Causing

Bronchiolitis in Children

In a clinical study in Argentina, RSV was the most common virus isolated from a sample of children aged <5 years with acute lower respiratory infection

0.7% 6.5% 6.8% 7.8%

78.2%

RSV

Adenovirus

Parainfluenza

Influenza A

Influenza B

Carballal G et al. J Med Virol 2001;64:167-174

138

New viruses (Human

Metapneumovirus,

Bocca, Corona)

Chronic Wheezing

Thriving child – Happy wheezer

Child failing to thrive - Causes

Exclude other conditions

Structural problems: bronchoscopy

URTD : Polysomnography,

Esophageal disease: Barium swallow, pH probes, scopes and gram

Primary ciliary dyskinesia: nasal ciliary motility, Exhaled NO, EM, saccharine test

TB: mantoux, induced sputum/ gastric lavage/ BAL = Culture, microscopy & PCR

Bronchiectasis: HRCT scan, BAL

CF: sweat test, nasal potentials, genotypes

Systemic immune deficiency: Ig subtypes, lymphocytes & neutrophil function, HIV

Cardiovascular disease: echo, angiography

WHEEZING PHENOTYPES 12 Longitudinal birth cohorts

Original Tucson Group (Taussig L et al 1985)

Persistent

Atopic

Non Atopic

Transient

TRANSIENT WHEEZERS Commonest form of wheeze

Decrease lung function at birth

No airway hyper-responsiveness

Non Atopic

No immune responses to viruses

Resolves by 3 years

– Wheeze in first year – better outcome

– Wheeze 2-3 year – worse outcome due to maturity of immune system

Affected by : Teenage pregnancy & smoking

Male gender

Day care- infections

STRUCTURAL CONSIDERATIONS

Lung Growth: Fetal 8 years

Affected by:

Temperature & O2 tension

Nutrition & Smoking

Functional disorders eg CDH

Prematurity

Growth factors-Gene repair

Drugs (B2 agonist/ C/S)

Risk factors for COPD Mx: antioxidant, retinoids,MMPI

PERSISTENT NON

ATOPIC WHEEZER

Lung function abnormal at birth and

reduced in later life

Non Atopic

Airway hyper-responsiveness

Peak flow variability

RSV induced wheeze due to alteration

in airway tone

BETTER OUTCOME THAN ATOPIC

PERSISTENT WHEEZERS

OUTCOME OF INFANT WHEEZING

Low birth weight

Pregnancy smoking

Male Sex

Affluence

Atopy

Low maternal age (first born)

Infant wheeze

With viral infection alone With various precipitants

Remission in 80%

?? COPD in adults

Persistent asthma (with or without

evidence of atopy) in 50-60%

Asthma in Pre-School

Children

146

The Various Marches That Set Up Asthma

Asthma

The Atopic March

Wheezing Phenotypes

• Tuscon:

- Transient early wheezing

- Persistent early-onset wheezing

- Late-onset wheezing (Martinez FD, 1995)

• ERS Task-Force:

- Viral induced wheeze

- Multi-trigger wheeze (Brand PLP, 2008)

Outcome of wheeze in infancy

Martinez FD, et al. N Engl J Med 1995; 332: 133-138

Causes of Recurrent Wheezing in Infancy

Asthma

Multiple trigger wheeze

Episodic viral wheeze

Other

causes

Viruses and Asthma

Atopy

Asthma

Rhinovirus

RSV

Genes

Influenza

Features Suggestive of Asthma

• Wheezing more than 1x/ month (Evidence C)

• Activity-induced cough or wheeze (Evidence A)

• Cough at night (Evidence A)

• Absence of seasonal variation (Evidence B)

• Symptoms persisting after the age of 3 years (Evidence A)

• Symptoms worsening with certain exposures (Evidence B)

• Colds repeatedly going to the chest (Evidence B)

• Response to a bronchodilator (Evidence B)

• Response to a 10-day oral steroid course (Evidence B)

• Concomitant rhinitis, eczema or food allergies (Evidence B)

• Family history of allergy (Evidence B)

• Response to a bronchodilators in children under 5 (FEV>12%, PEFR> (FEV>12%, PEF>20% of pre-bronchodilators PEF) (Evidence A)

• Diurnal variation of PEF >20% with twice daily readings (Evidence A)

Asthma Prediction Index

Major Criteria

Family history of

asthma

Positive history of

atopic eczema

Positive SPT

Minor Criteria

Eosinophilia > 4%

Positive history of

allergic rhinitis

Wheeze without

viral infections

Asthma = 1 Major or 2 Minor

Castro-Rodriguez JA, Holberg CJ, Wright AL, Martinez FD.

A clinical index to def ine risk of asthma in young children with recurrent wheezing.

Am J Respir Crit Care Med. 2000;162(4 Pt 1):1403-6.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract&list_uids=11029352&query_hl=1&itool=pubmed_docsum



56% Asthmatic Children in Pretoria Atopic

Figure 1. Inhalant Allergens. % of positive tests

(Only 28 of 50 patients positive)

27%

21%9%2%5%

12%

19%5%

Bermuda grass

Grass mix

Tree mix

Cat epithelium

Dog dander

HDM

Cockroach

Horse

TREATING

WHEEZES

Treatment Options Pre-school Wheeze

Montelukast 7 - 14 days

Episodic wheeze

ICS or

LTRA

Multiple trigger wheeze

Mild

ICS + LABA

Persistent asthma

Moderate/Severe

Wheeze

If not responding – Stop Treatment and Review diagnosis







Diagnosis and management

of asthma in children

5 years and younger

GINA 2014


Features suggesting asthma in children ≤5 years

Feature Characteristics suggesting asthma

Cough Recurrent or persistent non-productive cough that may be worse at

night or accompanied by some wheezing and breathing difficulties.

Cough occurring with exercise, laughing, crying or exposure to

tobacco smoke in the absence of an apparent respiratory infection

Wheezing Recurrent wheezing, including during sleep or with triggers such as

activity, laughing, crying or exposure to tobacco smoke or air pollution

Difficult or heavy

breathing or

shortness of breath

Occurring with exercise, laughing, or crying

Reduced activity Not running, playing or laughing at the same intensity as other

children; tires earlier during walks (wants to be carried)

Past or family history Other allergic disease (atopic dermatitis or allergic rhinitis)

Asthma in first-degree relatives

Therapeutic trial with

low dose ICS and

as-needed SABA

Clinical improvement during 2–3 months of controller treatment and

worsening when treatment is stopped

GINA 2014, Box 6-2


Common differential diagnoses of asthma in children ≤5 years

Condition Typical features

Recurrent viral respiratory

infections

Mainly cough, runny congested nose for <10 days; wheeze

usually mild; no symptoms between infections

Gastroesophageal reflux Cough when feeding; recurrent chest infections; vomits easily

especially after large feeds; poor response to asthma

medications

Foreign body aspiration Episode of abrupt severe cough and/or stridor during eating or

play; recurrent chest infections and cough; focal lung signs

Tracheomalacia or

bronchomalacia

Noisy breathing when crying or eating, or during URTIs; harsh

cough; inspiratory or expiratory retraction; symptoms often

present since birth; poor response to asthma treatment

Tuberculosis Persistent noisy respirations and cough; fever unresponsive to

normal antibiotics; enlarged lymph nodes; poor response to BD

or ICS; contact with someone with TB

Congenital heart disease Cardiac murmur; cyanosis when eating; failure to thrive;

tachycardia; tachypnea or hepatomegaly; poor response to

asthma medications

GINA 2014, Box 6-3 (1/2)


Common differential diagnoses of asthma in children ≤5 years (continued)

Condition Typical features

Cystic fibrosis Cough starting shortly after birth; recurrent chest infections;

failure to thrive (malabsorption); loose greasy bulky stools

Primary ciliary dyskinesia Cough and recurrent mild chest infections; chronic ear infections

and purulent nasal discharge; poor response to asthma

medications; situs inversus (in ~50% children with this condition)

Vascular ring Respirations often persistently noisy; poor response to asthma

medications

Bronchopulmonary

dysplasia

Infant born prematurely; very low birth weight; needed prolonged

mechanical ventilation or supplemental oxygen; difficulty with

breathing present from birth

Immune deficiency Recurrent fever and infections (including non-respiratory); failure

to thrive

GINA 2014, Box 6-3 (2/2)


GINA assessment of asthma control in children ≤5 years

GINA 2014, Box 6-4 (1/2)


Risk factors for poor asthma outcomes in children ≤5 years

Risk factors for exacerbations in the next few months


• One or more severe exacerbation in previous year

• The start of the child’s usual ‘flare-up’ season (especially if autumn/fall)

• Exposures: tobacco smoke; indoor or outdoor air pollution; indoor allergens (e.g.

house dust mite, cockroach, pets, mold), especially in combination with viral infection

• Major psychological or socio-economic problems for child or family

• Poor adherence with controller medication, or incorrect inhaler technique

GINA 2014, Box 6-4B









Risk factors for fixed airflow limitation

• Severe asthma with several hospitalizations

• History of bronchiolitis









Risk factors for fixed airflow limitation

• Severe asthma with several hospitalizations

• History of bronchiolitis

Risk factors for medication side-effects

• Systemic: Frequent courses of OCS; high-dose and/or potent ICS

• Local: moderate/high-dose or potent ICS; incorrect inhaler technique; failure to protect

skin or eyes when using ICS by nebulizer or spacer with face mask


Control-based asthma management cycle in children ≤5 years

GINA 2014, Box 6-5


Stepwise approach to control symptoms and reduce risk (children ≤5 years)

GINA 2014, Box 6-5


Assess asthma control

Symptom control, future risk, comorbidities

Self-management

Education, inhaler skills, written asthma action plan, adherence

Regular review

Assess response, adverse events, establish minimal effective treatment

Other

(Where relevant): environmental control for smoke, allergens, indoor or

outdoor air pollution

Stepwise approach – key issues (children ≤5 years)

GINA 2014, Box 6-5


Step 1 (children ≤5 years) – as-needed inhaled SABA



Preferred option: as-needed inhaled SABA

Provide inhaled SABA to all children who experience wheezing

episodes

Not effective in all children

Other options

Oral bronchodilator therapy is not recommended (slower onset of

action, more side-effects)

For children with intermittent viral-induced wheeze and no interval

symptoms, if as-needed SABA is not sufficient, consider intermittent

ICS. Because of the risk of side-effects, this should only be

considered if the physician is confident that the treatment will be

used appropriately.

Step 1 (children ≤5 years) – as-needed inhaled SABA

GINA 2014


Step 2 (children ≤5 years) – initial controller + as-needed SABA



Indication

Child with symptom pattern consistent with asthma, and symptoms not

well-controlled, or ≥3 exacerbations per year

May also be used as a diagnostic trial for children with frequent

wheezing episodes

Preferred option: regular daily low dose ICS + as-needed inhaled SABA

Give for ≥3 months to establish effectiveness, and review response

Other options depend on symptom pattern

(Persistent asthma) – regular leukotriene receptor antagonist (LTRA)

leads to modest reduction in symptoms and need for OCS compared

with placebo

(Intermittent viral-induced wheeze) – regular LTRA improves some

outcomes but does not reduce risk of exacerbations

(Frequent viral-induced wheeze with interval symptoms) – consider

episodic or as-needed ICS, but give a trial of regular ICS first

Step 2 (children ≤5 years) – initial controller + as-needed SABA

GINA 2014


Step 3 (children ≤5 years) – medium dose ICS + as-needed inhaled SABA



Indication

Asthma diagnosis, and symptoms not well-controlled on low dose

ICS

First check symptoms are due to asthma, and check adherence,

inhaler technique and environmental exposures

Preferred option: medium dose ICS with as-needed inhaled SABA

Review response after 3 months

Other options

Consider adding LTRA to low dose ICS (based on data from older

children)

Step 3 (children ≤5 years) – medium dose ICS + as-needed inhaled SABA

GINA 2014


Step 4 (children ≤5 years) – refer for expert assessment



Indication

Asthma diagnosis, and symptoms not well-controlled on medium

dose ICS

First check symptoms are due to asthma, and check adherence,

inhaler technique and environmental exposures

Preferred option: continue controller treatment and refer for

expert assessment

Other options (preferably with specialist advice)

Higher dose ICS and/or more frequent dosing (for a few weeks)

Add LTRA, theophylline or low dose OCS (for a few weeks only)

Add intermittent ICS to regular daily ICS if exacerbations are the

main problem

ICS/LABA not recommended in this age group

Step 4 (children ≤5 years) – refer for expert assessment

GINA 2014


This is not a table of equivalence

A low daily dose is defined as the dose that has not been associated

with clinically adverse effects in trials that included measures of safety

‘Low dose’ inhaled corticosteroids (mcg/day) for children ≤5 years

GINA 2014, Box 6-6

Inhaled corticosteroid Low daily dose (mcg)

Beclometasone dipropionate (HFA) 100

Budesonide (pMDI + spacer) 200

Budesonide (nebulizer) 500

Fluticasone propionate (HFA) 100

Ciclesonide 160

Mometasone furoate Not studied below age 4 years

Triamcinolone acetonide Not studied in this age group

GINA 2014, Box 6-6


Choosing an inhaler device for children ≤5 years

GINA 2014, Box 6-6

Age Preferred device Alternate device

0–3 years Pressurized metered dose

inhaler plus dedicated spacer

with face mask

Nebulizer with face mask

4–5 years

Pressurized metered dose


with mouthpiece

Pressurized metered dose


with face mask, or nebulizer

with mouthpiece or face mask

GINA 2014, Box 6-7


Initial assessment of acute asthma exacerbations in children ≤5 years

Symptoms Mild Severe*

Altered consciousness No Agitated, confused or drowsy

Oximetry on

presentation (SaO2)**

>95% <92%

Speech† Sentences Words

Pulse rate <100 beats/min >200 beats/min (0–3 years)

>180 beats/min (4–5 years)

Central cyanosis Absent Likely to be present

Wheeze intensity Variable Chest may be quiet

*Any of these features indicates a severe exacerbation

**Oximetry before treatment with oxygen or bronchodilator † Take into account the child’s normal developmental capability

GINA 2014, Box 6-8


Indications for immediate transfer to hospital for children ≤5 years

GINA 2014, Box 6-9

*Normal respiratory rates (breaths/minute): 0-2 months: <60; 2-12 months: <50; 1-5 yrs: <40

Transfer immediately to hospital if ANY of the following are present:

Features of severe exacerbation at initial or subsequent assessment

Child is unable to speak or drink

Cyanosis Subcostal retraction

Oxygen saturation <92% when breathing room air

Silent chest on auscultation

Lack of response to initial bronchodilator treatment

Lack of response to 6 puffs of inhaled SABA (2 separate puffs, repeated

3 times) over 1-2 hours

Persisting tachypnea* despite 3 administrations of inhaled SABA, even if the

child shows other clinical signs of improvement

Unable to be managed at home

Social environment that impairs delivery of acute treatment

Parent/carer unable to manage child at home


Initial management of asthma exacerbations in children ≤5 years

Therapy Dose and administration

Supplemental

oxygen

24% delivered by face mask (usually 1L/min) to maintain

oxygen saturation 94-98%

Inhaled SABA 2–6 puffs of salbutamol by spacer, or 2.5mg by nebulizer, every

20 min for first hour, then reassess severity. If symptoms

persist or recur, give an additional 2-3 puffs per hour. Admit to

hospital if >10 puffs required in 3-4 hours.

Systemic

corticosteroids

Give initial dose of oral prednisolone (1-2mg/kg up to maximum

of 20mg for children <2 years; 30 mg for 2-5 years)

GINA 2014, Box 6-10

Therapy Dose and administration

Supplemental

oxygen

24% delivered by face mask (usually 1L/min) to maintain

oxygen saturation 94-98%

Inhaled SABA 2–6 puffs of salbutamol by spacer, or 2.5mg by nebulizer, every

20 min for first hour, then reassess severity. If symptoms

persist or recur, give an additional 2-3 puffs per hour. Admit to

hospital if >10 puffs required in 3-4 hours.

Systemic

corticosteroids

Give initial dose of oral prednisolone (1-2mg/kg up to maximum

of 20mg for children <2 years; 30 mg for 2-5 years)

Additional options in the first hour of treatment

Ipratropium

bromide

For moderate/severe exacerbations, give 2 puffs of

ipratropium bromide 80mcg (or 250mcg by nebulizer) every

20 minutes for one hour only

Magnesium

sulfate

Consider nebulized isotonic MgSO4 (150mg) 3 doses in first

hour for children ≥2 years with severe exacerbation

Case 1

A 45-year-old man complains of nasal blockage and loss

of smell and taste. He is an asthmatic who has been well

controlled on ICS and LABA therapy. His past history is

significant for chronic rhinosinusitis and one previous hospital admission for asthma with intubation and

mechanical ventilation.

He was told following that admission that he was allergic

to Aspirin, which he had taken for a back pain. On physical examination his lungs are clear of wheeze.

The findings on nasal examination are seen

in this Figure

A. Leukotriene receptor antagonist.

B. A 3-week course of prednisone.

C. Inhaled topical nasal corticosteroid.

D. Allergen immunotherapy to relevant antigens.

E. Aspirin desensitization program.

The most appropriate treatment at this time is:

The patient under discussion has asthma and nasal

polyposis. The aim of therapy for nasal polyps is to restore

nasal patency, and this may return lost taste and smell and

restore sinus drainage.

Topical corticosteroids have been the drugs of choice for

many years as they have been shown to reduce the size of

small polyps and prevent or delay the recurrence of nasal

polyps after surgery. Oral corticosteroids are also very

effective for nasal polyps and in severe cases are preferred

for 3 weeks followed by prolonged topical therapy.

Oral and not topical corticosteroids are usually effective for

anosmia and therefore are preferred in this patient, making

option B correct and C incorrect. When corticosteroids are

not effective, surgery is unavoidable.

Having both asthma and nasal polyposis places a patient up

to a 40% risk of having or developing aspirin sensitivity,

otherwise known as aspirin intolerant asthma (AIA).

Nasal polyps are smooth gelatinous semitranslucent

structures that seem to be outgrowths of the nasal mucosa.

Most polyps arise from the ethmoid sinus and histologically

are a mass of edema fluid with an abundance of eosinophils

and other inflammatory cells such as mast cells,

lymphocytes, and neutrophils. Nasal polyposis is an non-

IgE mediated inflammatory condition and is often

associated with nonallergic rhinitis, aspirin sensitivity, and

nonallergic asthma.

Atopy is no more prevalent in patients with nasal polyps

than in the general population; therefore, option D would not

be an appropriate step in this patient.

Most patients with AIA have a long history of

perennial rhinitis, which begins in the third decade,

often after a viral illness. Over months to years

nasal polyps develop followed by the appearance

of moderately severe to severe asthma and aspirin

sensitivity.

After ingestion of aspirin or a nonsteroidal

antiinflammatory drug (NSAID), an acute asthma

exacerbation occurs, often accompanied by

rhinorrhea, periorbital edema, conjunctival

congestion, and occasionally flushing of the face.

Evidence suggests that by inhibiting the

cyclooxygenase (COX) pathway, aspirin and

NSAIDS divert arachadonic metabolism to the

lipoxygenase pathway which is involved in the

pathogenesis of this syndrome. Leukotriene

pathway modifiers such as the receptor

antagonists have shown to be effective

Leukotriene pathway pathway which is involved in the

pathogenesis of this syndrome. Leukotriene pathway

modifiers such as the receptor antagonists have shown to

be effective for asthma but not nasal polyps; therefore,

option A is not correct

Aspirin desensitization is done by giving small increasing

oral doses of aspirin over 2 to 3 days and then a daily dose

after a refractory period is reached. The asthma is improved

and the nasal inflammatory disease responds the best. This

procedure is ideal in those patients who have just had

surgical polypectomy, as it has been shown to delay the

recurrence of polyps for an average of 6 years.

It would not improve nasal patentcy in this patient;

therefore, option E is not correct. The addition of

nedocromil sodium is incorrect because there is no need to

“step up” her asthma therapy at this time.

oMr Samir a lifelong heavy smoker and asthmatic, the seventy year old Mr Samir is wheezing most days and always is short of breath. He is on regular combivent, beclomethasone 200mcg bd and intermittant salbutamol.

Case 2

oThe most likely diagnosis is Uncontrolled

Asthma.

but The COPD element should not be neglected in this patient with a high smoking index (old age and heavy smoker). It definitely has a share in his symptoms and airflow limitation.

What is the likely diagnosis?

A 46 year old man comes to your clinic for management of

his asthma. He takes high-dose inhaled corticosteroids

and a long-acting beta agonist, along with a leukotriene

inhibitor. His adherence and technique are perfect.

He still has symptoms of cough, wheezing, and chest

tightness that bother him most days and nights each

week. He is using albuterol daily. The symptoms persist

when he goes on vacation out of state.

Sputum culture is negative. IgE level is 3,600 ng/mL. His

primary doctor obtained imaging and a chest CT, which

are shown.

Case 3

What should be the next step? A. Schedule spirometry for next week to

guide step-up therapy.

B. Start omalizumab injections every 2

weeks.

C. Sweat chloride testing.

D. Skin testing for reactivity to Aspergillus

fumigatus.

E. HIV test.

Allergic bronchopulmonary aspergillosis (ABPA) is an

ongoing hypersensitivity reaction in response to

bronchial colonization by Aspergillus, and is a common

cause of poorly controlled asthma. Cystic fibrosis

patients are also often affected. Bronchial obstruction

by mucus and chronic inflammation can lead to

bronchiectasis and lung fibrosis with irreversible loss

of lung function.

Clinical features: Cough productive of sputum, frequent

"bronchitis"; often with dyspnea and wheezing.

Diagnosis:

By constellation of symptoms and objective

findings. "Classic" ABPA would include the

following:

Asthma history Immediate reactivity on skin prick with Aspergillus

antigens

Precipitating serum antibodies to A. fumigatus Serum total IgE concentration >1,000 ng/mL

Peripheral blood eosinophilia >500/mm3 Lung opacities on chest x-ray or chest HRCT

Central bronchiectasis present on chest CT

Elevated specific serum IgE and IgG to A. fumigatus

A skin test is the best first test, as it

is considered 100% sensitive (i.e., a

negative test rules out the condition).

A serum IgE < 1,000 or negative

precipitating antibodies also rule out

ABPA with high confidence.

Case 4

Your internal medicine colleague asks you about

a patient she is about to discharge home after a

hospitalization for asthma exacerbation. The

patient, takes a beta-blocker for coronary artery

disease and hypertension. Your colleague is

considering stopping the beta-blocker to avoid

any contribution to future asthma exacerbations,

but wants your opinion first.

What do you recommend?

A. Stop the beta blocker.

B. Continue the beta blocker.

C. Stop the beta blocker; order a stress test.

D. Continue the beta blocker; order an

echocardiogram.

Case 5

o Yusuf is 4 years old. He has had a persistant cough for

weeks that wakes him at night. “Every cold goes to his

chest” This is the fifth consultation for cough in the last

year. Only once has a wheeze been documented. His

father is known asthmatic.

1- What is the likely diagnosis? 2- What treatment would you give?

Self-fulfilling: Infant Wheezing

Phenotypes

• Never (51%)

• Transient (20%) – Wheeze 0-3, not at age 6

• Persistent (14%) – Wheeze 0-3 still present

age 6

• Late onset (15%) – Wheeze after age 3

Diagnosing Asthma in Young

Children – Asthma Predictive

Index

• > 4 episodes/yr of wheezing lasting more than 1 day affecting sleep in a child with one MAJOR or two MINOR criteria

• Major criteria

– Parent with asthma

– Physician diagnosed

atopic dermatitis

• Minor criteria

– Physician diagnosed

allergic rhinitis

– Eosinophilia (>4%)

– Wheezing apart from

colds

1Adapted from Castro-Rodriquez JA, et al. AJRCCM 2000; 162: 1403

Modified Asthma Predictive Index (API)

Cough-variant asthma

Cough-variant asthma presents as dry

cough at night. It worsens with exercise

(EIA) and nonspecific triggers (cold air).

Cough-variant asthma responds to asthma

therapy with ICS.

Cough-variant asthma is diagnosed with

pulmonary function testing (PFTs) with

response to bronchodilator. The most

common cause of chronic cough in children

is cough-variant asthma.

1- What is the likely diagnosis?

The likely diagnosis is Bronchial Asthma (childhood asthma): - Family history. - Symtoms (cough mainly at night, every cold goes to the chest). - Signs: chest wheeze.

Treatmnt

Severe asthma - differential diagnosis and management

Case 7 oA 30-year-old G2P1 pregnant woman at 15 weeks gestation presents to an outpatient clinic with worsening dyspnea over the preceding two weeks. Her past medical history is significant for asthma diagnosed in childhood, seasonal allergies, and gastroesophageal reflux disease (GERD) during her previous pregnancy. She notes that her asthma symptoms had been well-controlled on inhaled Budesonide/formoterol (160mcg/4.5mcg), Salbutamol MDI as needed, and a nasal steroid spray prior to pregnancy. However, she discontinued all of her medications when she learned that she was pregnant for fear that they might harm her baby.

oAt today’s visit she feels that she is unable to take a deep breath. She also describes one to two episodes of wheezing daily and night time cough two to three times per week. Warm air, dust, and exposure to cats seem to exacerbate her symptoms. oOn physical exam, the patient is in no acute distress. The lungs are clear to auscultation bilaterally.

1- Is the patient controlled?

2- Is asthma medications safe in pregnancy?

3- Treatment needed?

1- Is the patient controlled?

NO…… Breathlessness. Frequent nocturnal symptoms

(cough and wheezes).

2- Is asthma medications safe in pregnancy?

Yes, There is little evidence suggesting that medications used to treat asthma may harm the fetus. AND also Pregnant patients with asthma should be advised that the greater risk for their babies lies in poorly controlled asthma and most modern asthma medications are safe.

For this reason, using medications to obtain optimal asthma control is justified.

3- Treatment needed?

Asthma control was already achieved on this treatment: o Inhaled Budesonide/formoterol (160mcg/4.5mcg). o Salbutamol MDI as needed. o Nasal steroid spray. o It may be repeated with reassurance about the safety of the medications and regular follow up to assess asthma control.

o Sandra is 60 years old and has had asthma for 4 years. She

has attended today as she has a cough, She is short of breath

and getting disturbed nights.

o She is currently on regular salbutamol and beclomethasone 200mcg 2

puffs bd.

Discuss your therapeutic options?

Case 8

current medications: (medium dose ICS + rapid acting B₂ agonist as reliever) Therapeutic options: STEP UP the actual treatment: Add long acting B₂ agonist with ICS in a single inhaler. (+/-) sustained release theophylline or leukotriene modifier.

o A 22 years old male patient, non smoker, comes to

primary care clinic complaining of chronic cough for the

last 3 months, mainly at night, together with occasional

exertional dyspnea and chest wheezes.

o 1- How will you approach this case?

o 2- What is the basic functional assessment to be

proposed?

Case 9

1- How will you approach this case?

o A young patient with symptoms suggestive of airway

obstruction.

(bronchial asthma??)

Proper medical history is essential: - Family or past history of allergic diseases. - Risk factors and exposure to exacerbating factors. - detailed history concerning the pattern of symptoms.

Physical examination: (CHEST WHEEZES??)

- Order for functional assessment

2- What is the basic functional assessment to be proposed?

Spirometry before and after B₂ agonist to demostrate airway obstruction and to assess the reversibility.

o A 23 years old female patient with known bronchial asthma

since childhood experiences almost daily symptoms, her

sleep is disturbed because of asthma three times a week,

and she is not able to perform regular exercise. She’s been

prescribed daily ICS for six months and uses Salbutamol for

breakthrough wheezing, chest tightness and breathlessness.

oWhat are the management options?

Case 10

What are the management options?

o The patient is uncontrolled on her current treatment

Daily symptoms

Nocturnal symptoms>3 times/week

Limitations of activities

So……Stepping up…

Add long acting B₂ agonist to ICS.

Add leukotriene modifier.

+/- Sustained release theophylline.

Pattern of

uncontrolled

asthma

asthma management phenotype based approach

Health & Medicine

asthma pathology asthma

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definition of asthma

assiut university asthma

asthma management phenotypes

bd flow volume normal

intensity symptoms

chest tightness symptoms