bronchial asthma and asthma control

Bronchial Asthma &Asthma

Control

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

Source: Peter J. Barnes, MD

Asthma Inflammation: Cells and Mediators

Airway inflammation in asthma

Asthmatic Normal

P Jeffery, in: Asthma, Academic Press 1998

Airway mucosal oedema

P Howarth

Epithelial damage


Smooth muscle hyperplasia


Basement membrane thickening


Asthma Phenotypes and Endotypes

◙ 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.

Th2-associated asthma

These patients are characterized by atopy,

eosinophilic inflammation and favorable response

to corticosteroids.

Early-onset allergic asthma

Late-onset persistent eosinophilic asthma

Exercise induced 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.

Late-onset persistent eosinophilic asthma


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.

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

Aspirin exacerbated airway disease

(AERD)

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


• 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 .

Exercise induced asthma

Biomarkers:

• Th2 cytokines and cysteinyl leukotriene

Genetics:

• No distinct genetic factors .


• Leukotriene modifiers high LTE4/FENO ratio is Surrogate

marker predicting better response.

• IL-9 targeted therapy has been shown effective on patients

of this group, which implies that Th2 immunity is involved in

the pathophysiology of EIA.

The lack of efficacy of Th2 targeted therapy suggests that a

subgroup of asthma develops in the absence of Th2 immunity.

Little is understood about the non Th2 asthma and its related

molecular elements.

• Obesity-related asthma

• Neutrophilic asthma

• Smoking asthma

Non Th2-associated 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.

, ..

Clinical characteristics :

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.

Clinical characteristics and biomarkers:

It remains controversial whether neutrophilia is an independent driving

component, a synergistic factor with eosinophilia or just a consequence of

corticosteroid therapy.

Still unclear whether this represents a unique form of asthma or just a

different stage of severity or persistent bacterial colonization or infection of

the airways on the background of a previously eosinophilic asthma.

Airway pathophysiology in neutrophilic asthma is characterized by (fixed)

airflow limitation more trapping of air, thicker airway walls (as

measured by CT) .

Novel mechanisms implicated in the pathogenesis of

noneosinophilic asthma involve the activation of innate immune

responses with a possible role of bacteria, viruses.

Neutrophilia can also co-exist with eosinophilia, and this identifies

the people with the most severe asthma and emphasizes the

complexity of the immunobiology of severe asthma in which

multiple different innate and adaptive immune pathways and cells

may have roles.

Impaired nuclear recruitment of histone deacetylase (HDAC).

The role of TH17 immunity

Biomarkers:

IL-8, IL-17A, LTB4, and possibly IL-32.

IL-1 and TNF-α pathways are upregulated and associated with

neutrophilic inflammation in a sputum gene-expression study.

low levels of FeNO.


Corticosteroids are less effective in patients of this subgroup.

Macrolide antibiotics may have some efficacy on neutrophilic

asthma, By modulating the innate immune response in the

lung, by reducing the expression of neutrophilic markers .

Restoration of HDAC 2 nuclear recruitment with theophylline.

Anti-TNF-α responsive( infliximab )

The efficacy of IL-17 targeted therapy in this subtype of

asthma awaits evidence from ongoing clinical trials.

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.

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.

The intensity of the colors represents the range of severity; the relative sizes

of the subcircles suggest relative proportions of affected individuals

• 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

Diagnosis of asthma – symptoms

GINA 2014

• 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

• 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

Functional assessment

Variability

– PEFR chart at home (useful in diagnosis and monitoring, diurnal variation ≥ 20 % or improvement of 60L/min or ≥ 20 % after bronchodilator administration suggests asthma).

Reversibility

– Spirometry before and after B2 agonist (an increase in FEV1 of ≥ 12% and ≥ 200 ml after administration of bronchodilator indicates reversible airflow limitation consistent with asthma).

Provocative Testing

– Exercise

– Cold dry air

– Methacholine

1. Peak flow measurement

Clinical follow up of asthma

2. FEV1 measurement

Clinical follow up of asthma

Patterns of Abnormality

Upper Airway Obstruction low PEF relative to FEV1

Recorded Predicted SR %Pred

FEV 1 2.17 2.27 -0.3 96

FVC 2.68 2.70 0.0 99

FEV 1%FVC 81 76 0.7 106

PEF 2.95 5.99 -3.4 49

FEV 1 /PEF 12.3

Discordant PEF and FEV1

High PEF versus FEV1 = early interstitial lung disease (ILD)

Low PEF versus FEV1 = upper airway obstruction

Concordant PEF and FEV1

Both low in airflow obstruction, myopathy, late ILD

Upper Airway Obstruction

0 1 2 3 4 5 6

-6

-4

-2

0

2

4

6 Age 40 yrs

FVC 3.52 L 0.84 SR

FEV1 3.0 L 0.74 SR

PEF 4.57 L/s -2.18 SR

FEV/PEF = 10.9

Inspiratory

Expiratory

Flo

w in

L/s

Volume in Litres

FEV1 in mls

PEF in L/min > 8

• 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

Diagnosis of asthma – variable airflow

limitation

GINA 2014, Box 1-2

• 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

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

Spirometry Pre- & Post- Bronchodilator

MANAGEMENT OF ASTHMA – GENERAL

PRINCIPLES

• The long-term goals of asthma management are symptom control and risk reduction.

• The aim is to reduce the burden to the patient and their risk of exacerbations, airway

damage, and medication side-effects.

• The patient’s own goals regarding their asthma and its treatment should also be identified.

• Population-level recommendations about „preferred‟ asthma treatments represent the

best treatment for most patients in a population.

• Patient-level treatment decisions should take into account any individual characteristics or

phenotype that predict the patient‟s likely response to treatment, together with the patient‟s

preferences and practical issues such as inhaler technique, adherence, and cost.

References 1. GINA Updates 2014

HOW TO MANAGE ASTHMA?

Levels of Asthma Control (Assess patient impairment)

Characteristic Controlled

(All of the following)

Partly controlled (Any present in any week)

Uncontrolled

Daytime symptoms Twice or less

per week

More than

twice per 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

Twice or less

per week

More than

twice per week

Lung function

(PEF or FEV1) Normal

< 80% predicted or

personal best (if

known) on any day

The Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma (GINA) 2014.

Available from: http://www.ginasthma.org

http://www.ginasthma.org/

controlled

partly controlled

uncontrolled

exacerbation

LEVEL OF CONTROL

maintain and find lowest controlling

step

consider stepping up to

gain control

step up until controlled

treat as exacerbation

TREATMENT OF ACTION

TREATMENT STEPS REDUCE INCREASE

STEP

1 STEP

2 STEP

3 STEP

4 STEP

5

RE

DU

CE

IN

CR

EA

SE

© Global Initiative for Asthma

Stepwise management - pharmacotherapy

*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


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


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



GINA 2015 – changes to Steps 4 and 5


GINA 2015


**For patients prescribed BDP/formoterol or BUD/formoterol maintenance and reliever therapy # Tiotropium by soft-mist inhaler is indicated as add-on treatment for patients with a history of exacerbations;

it is not indicated in children <18 years.

Other controller

options

RELIEVER

STEP 1 STEP 2 STEP 3

STEP 4

STEP 5

Low dose ICS

Consider low dose ICS

Leukotriene receptor antagonists (LTRA) Low dose theophylline*

Med/high dose ICS Low dose ICS+LTRA

(or + theoph*)

As-needed short-acting beta2-agonist (SABA)

Low dose

ICS/LABA*

Med/high

ICS/LABA

Refer for add-on treatment e.g. anti-IgE

PREFERRED

CONTROLLER

CHOICE

Add tiotropium# High dose ICS + LTRA

(or + theoph*)

Add tiotropium# Add low dose OCS

As-needed SABA or low dose ICS/formoterol**

• 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


GINA assessment of asthma control

GINA 2014, Box 2-2B

GINA 2015 Asthma Control is still a problem

• Many studies describe discordance between the patient‟s and health provider‟s

assessment of the patient‟s level of asthma control.

• This does not necessarily mean that patients „over-estimate‟ their level of control

or „under-estimate ‟its severity, but that patients understand and use the word

„control‟ differently from health professionals, e.g. based on how quickly their symptoms resolve when they take reliever medication. 1

GINA 2015

Why Did GSK Conduct The GOAL Study??

The AIRE Survey 1999:

• First comprehensive, multinational survey assessing the level of Asthma Control among patients with asthma in Western Europe

• Provided an understanding of how well the goals of the GINA asthma guidelines were being met in Europe.

• 2803 patients interviewed by telephone from 7 European Countries:

France

Germany

Italy

Netherlands

Spain

Sweden

UK

.

AIRE= Asthma Insight and Reality in Europe

Why Did GSK Conduct The GOAL Study??

The AIRE Survey 1999:

.

100

95 %

Uncontrolled

5 %

Controlled

Only 5% of patients met all

the criteria for asthma control

as defined by GINA

This data is raising a

question:

“Are the Expectations of GINA regarding Asthma Control

realistic and achievable?”

Study design

“The Gaining Optimal Asthma controL (GOAL) study was a 1-year, stratified, randomized, double-blind, parallel-group study comparing step-wise increases of

salmeterol and fluticasone combined (SFC) with fluticasone propionate (FP)

alone in achieving composite measures of well - total asthma control as defined by the guidelines.”

• It included 3421 uncontrolled asthmatic patients.

• International Study including 44 countries

• Inclusion criteria:

.

Patients aged ≥12 years with ≥6-month history of asthma, and who did

not achieve 2 well-controlled weeks during the 4-week run-in period.

Smoking packs <10/year Reversibility of ≥15 % of FEV1

Use of LABA in the last 2 weeks prior to run-in

Acute asthma exacerbation requiring oral steroids in the last 4 weeks or hospitalization in the past 12 weeks

Treatment with systemic steroids in the past 12 weeks prior to run-in

Resp. Infection in the last 4 weeks prior run-in > 3 days PEF < 50 % predicted during run-in

•Exclusion criteria:

Study Endpoints

Primary endpoint:

• To determine the proportion of patients who achieved guideline defined asthma control on Fluticasone Propionate/Salmeterol compared with Fluticasone propionate

during phase I in 7 out of the 8 weeks assessment period in the stepping up phase

Secondary endpoint:

• To determine if the concept of total control is achievable or not

Study design Well Controlled Patients

Patients with a well-controlled week were defined

for having 2 or more of the following criteria:

Symptom score >1 on ≤2 days/week

(PEF) of ≥80% predicted every day

Rescue medication use on ≤2 days and ≤4 occasions/week.

“They couldn't take more than 4 puffs of their medication during a week and over 2 days”

Guideline Defined Asthma Control

Patients with a well-controlled week were defined for having all of the following:

No Night-time awakenings No Exacerbations No Emergency room visits No Adverse events leading to a change in

asthma treatment.

Well controlled asthma was achieved if the patient recorded 7 totally controlled weeks during the 8 assessment weeks.

Only 5% of patients met all the criteria for asthma control as defined by GINA

“

Asthma Symptom Control Level of Asthma Symptom Control

In the past 4 weeks,

has the patient had: Well Contolled

Partly

Contolled Uncontrolled

Daytime asthma

symptoms for more than

twice/week?

None of these 1-2 of these 3-4 of these

Any activity limitation due

to asthma?

Reliever medication for

symptoms needed more

than twice/week?

Any night waking due to

asthma?

GINA assessment of asthma control in adults,

adolescents and children 6-11 years (GINA 2015)


Study design Totally Controlled Patients

Patients with a totally controlled week were defined

as having all of the following:

(PEF) of ≥80% predicted each day

No Daytime symptoms

No Rescue medication use

No Night-time awakenings

No Exacerbations

No Emergency room visits

No Adverse events leading to a change in asthma treatment.

‼ Totally controlled asthma was achieved if the patient

recorded 7 totally controlled weeks during the 8 assessment weeks.

GOAL: Significantly more patients achieve

well-controlled asthma with SFC vs FP

Pa

tie

nts

wit

h w

ell-c

on

tro

lle

d a

sth

ma (%

)

SFC Phase II

SFC Phase I

FP Phase II

FP Phase I

75**

62**

78*

47

60

70

20

80

60

40

0 ICS-naïve

Stratum I

Low-dose ICS

Stratum II

Moderate-dose ICS

Stratum III

*p=0.003 vs FP; **p<0.001 vs FP; †p=0.039 vs FP.

SFC=salmeterol and fluticasone combined; FP=fluticasone propionate; ICS=inhaled corticosteroid.

71†

65 69**

52 51**

33

Adapted from Bateman ED, et al. Am J Respir Crit

Care Med 2004;170:836-44.

Percentage of Patients who still had Guideline-defined

asthma control at the end of 52 weeks

FP

%

FP/Salmeterol

%

Stratum II 75% 83%

Stratum III 77% 77%

Patients that retained Control at the end of Phase II

Percentage of Patients who achieved total control in

phase I

FP/Salmeterol

%

FP

%

Stratum I 42%

P < 0.001 31%

Stratum II 32%

P < 0.001 20%

Stratum III 19%

P < 0.001 8%

0

Pa

tie

nts

wh

o w

ere

w

ell-c

on

tro

lle

d in

ph

as

e I

(%)

20

80

40

60

500µg bd

250µg bd

100µg bd

100µg bd

250µg bd

500µg bd

FP SFC

GOAL: More patients receiving SFC vs FP are well-

controlled, and at lower ICS doses

Adapted from Bateman ED, et al. Am J Respir Crit Care Med 2004;170:836-44.

Low-dose ICS patient types. Dose of FP indicated within figure. SFC=salmeterol and fluticasone combined; FP=fluticasone propionate; ICS=inhaled corticosteroid; bd=twice daily.

Stratum II

0

Pa

tie

nts

wh

o w

ere

w

ell-c

on

tro

lle

d in

ph

as

e I

(%)

20

80

40

60

500µg bd

250µg bd

250µg bd

500µg bd

FP SFC

GOAL: More patients receiving SFC vs FP are well-

controlled, and at lower ICS doses

Adapted from Bateman ED, et al. Am J Respir Crit Care Med 2004;170:836-44.

Low-dose ICS patient types. Dose of FP indicated within figure. SFC=salmeterol and fluticasone combined; FP=fluticasone propionate; ICS=inhaled corticosteroid; bd=twice daily.

Stratum III

30

50

250µg bd

250µg bd

81.5

74.2

55.9

76.6

51.0

29.9

0

10

20

30

40

50

60

70

80

90

ICS-naïve Low-dose ICS Moderate-dose ICS

**

GOAL: Significantly more symptom-free

days with SFC vs FP

* **

Woodcock AA, et al. Prim Care Resp J 2007;16:155-61.

Me

dia

n s

ym

pto

m-f

ree

da

ys

(%

)

*p=0.025 vs FP; **p<0.001 vs FP.

SFC=salmeterol and fluticasone combined; FP=fluticasone propionate; ICS=inhaled corticosteroid.

FP

SFC

271 Days

186 Days

204Days

109Days

*

*

*

0.2

0.4

0.7

0

0.1

0.3

0.6

0.5


FP

SFC

0.27

Mean

exacerb

ati

on

rate

per

pati

en

t p

er

year

GOAL: Significantly fewer exacerbations

with SFC vs FP

*p≤0.009 vs FP.

SFC=salmeterol and fluticasone combined; FP=fluticasone propionate;

ICS=inhaled corticosteroid.

Adapted from Bateman ED, et al. Am J Respir Crit Care Med

2004;170:836-44.

0.37

0.12 0.17

GOAL: Significantly more rescue medication-free days with

SFC vs FP

91.887.8

77.9

87.1

72.0

61.9

0

10

20

30

40

50

60

70

80

90

100


*

*

*

Me

dia

n re

sc

ue m

ed

icati

on

-fre

e d

ays

(%

)

*p<0.001 vs FP. SFC=salmeterol and fluticasone combined; FP=fluticasone propionate; ICS=inhaled corticosteroid. Woodcock AA, et al. Prim Care Resp J 2007;16:155-61.

FP

SFC

Asthma related Quality of Life

Using the Asthma quality of Life questionnaire:

• 32 Questions in 4 domains:

Activity limitations

Asthma Symptoms

Emotional functioning

Exposure to environmental stimuli

• Overall score

(mean of scores of 4 domains)

• Each scored on 7 point scale

(1= severe impairment; 7= no impairment)

GOAL: AQLQ scores reach near-maximal levels when

patients are totally or well controlled

5.4

6.16.6

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

Not well controlled

Well controlled

Totally controlled

Me

an

AQ

LQ

sc

ore

s

n=90 n=101 n=110

p<0.001 p<0.001

AQLQ=Asthma Quality of Life Questionnaire. Bateman ED, et al. Eur Respir J 2007;29:56-63.

Stratum II

Treatment – a stepwise approach

Each patient should be assigned to one of five treatment steps as per the GINA guidelines:

PREFERRED

CONTROLLER

CHOICE

Step 1 Step 2 Step 3 Step 4 Step 5

LOW DOSE ICS LOW DOSE

ICS/LABA

MED/HIGH

ICS/LABA

REFER FOR

EXPERT

INVESTIGATION

AND ADD-ON

THERAPY

e.g. ANTI-IgE

OTHER

CONTROLLER

OPTIONS

CONSIDER

LOW DOSE

ICS

LTRA

LOW DOSE

THEOPHYLLINE

MED/HIGH DOSE

ICS

LOW DOSE

ICS+LTRA

(or + theoph)

HIGH DOSE

ICS+LTRA

(or +

theoph)

ADD LOW

DOSE OCS

RELIEVER AS NEEDED SABA AS NEEDED SABA or

LOW DOSE ICS/FORMOTEROL


How is actually the SMART/MART approach

The asthma control outcomes in SMART-treated patients are poor; it has been reported

that only 17.1% of SMART-treated patients are controlled.

In seven trials of 6–12 months duration, patients using SMART:

have used quick reliever daily (weighted average 0.92 inhalations/day),

have awakened with asthma symptoms once every 7–10 days (weighted average 11.5% of nights),

have suffered asthma symptoms more than half of days (weighted average 54.0% of days) and

have had a severe exacerbation rate of one in five patients per year (weighted average 0.22 severe

exacerbations/patient/year).

Kenneth R Chapma.. Single maintenance and reliever therapy (SMART) of asthma: a critical appraisal. Kenneth R Chapman. Thorax doi:10.1136/thx.2009.128504 Review

Summary

• Guideline-defined control is achievable and sustainable in a significant

proportion of patients

• More patients achieve and maintain Guideline-defined control with

Fluticasone Propionate/Salmeterol than with ICS alone

• With Fluticasone Propionate/Salmeterol, more patients can achieve

Guideline-defined control:

Earlier

At a lower ICS dose

With more Symptom free days

With fewer exacerbations

With a better Quality of Life

• For Step 3/4: there are 2 preferred treatment options low dose

ICS/LABA- Low dose ICS/Formoterol

• SMART/MART approach is not indicated for less than 18 years

• Asthma control outcomes in SMART-treated patients are poor; it has

been reported that only 17.1% of SMART-treated patients are

controlled

• Considering a medication as maintenance and reliever therapy

confuses patients handle it as an “as needed= reliever”

treatment

Summary

• Recent recent ERS abstract suggests actual translation of SMART approach into clinical practice fails in a significant number of occasions. On the othe hand treating your patients with Seretide plus as needed SABA is extensively studied, reliable approach and is simple to follow

• Professor Jones:

“SMART/MART approach: no step up/step down approach to treat the patient according to his current condition, same treatment every day”

“There‟s evidence that SMART/MART approach delays the time for first exacerbation, however there‟s also lot of evidence stating that SMART/MART approach doesn‟t increase asthma control and as a consequence of that, it is unlikely to reduce exacerbations.”

“There‟s a lot of evidence that the step up approach achieves a very high level of control and the GOAL study at the end of 1 year nearly 70 % of patients achieved good control of their asthma versus only 17% on the SMART/ MART approach”

ERS on SMART: “1-2% of prescribers only wanted their patients to use SMART/MART approach. Interestingly, over half the patients were prescribes SABA as reliever + budesonide/formoterol combination which should have been used as a rescue therapy, not the SABA. This goes against the entire principal of the SMART/MART approach.

Summary

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.

140

Lessons learnt from studies of asthma deaths

Management of acute asthma. Thorax 2012

B Health care professionals must be aware that patients with severe asthma and one or more adverse psychosocial factors are at risk of death

Keep patients who have had near fatal asthma or brittle asthma under specialist supervision indefinitely

Respiratory specialist should follow up patients admitted with severe asthma for at least a year after admission

Many deaths from asthma are preventable – 88-92% of attacks requiring

hospitalisation develop over 6 hours

Factors include:

• inadequate objective monitoring

• failure to refer earlier for specialist advice

• inadequate treatment with steroids

141

Levels of severity of acute asthma exacerbations


Near fatal asthma Raised PaCO2 and/or requiring mechanical ventilation with raised

inflation pressures

142



Near fatal asthma Raised PaCO2 and/or requiring mechanical ventilation with

raised inflation pressures

Life threatening

asthma

Any one of the following in a patient with severe asthma:

• Altered conscious level • Exhaustion • Arrythmias

• Hypotension • Cyanosis

• Silent chest • Poor respiratory effort

• PEF <33% best or predicted

• SpO2 <92%

• PaO2 <8 kPa • “normal” PaCO2

(4.6–6.0 kPa)

143




inflation pressures

Life threatening

asthma


•PEF <33% best or

predicted •SpO2 <92% •PaO2 <8 kPa

•normal PaCO2 (4.6-6.0 kPa)

•silent chest

•cyanosis •feeble respiratory

effort

•bradycardia

•dysrhythmia

•hypotension •exhaustion •confusion

•coma

Acute severe

asthma

Any one of:

• PEF 33-50% best or predicted

• respiratory rate 25/min • heart rate 110/min

• inability to complete sentences

in one breath

144




inflation pressures

Life threatening

asthma


•PEF <33% best or


•normal PaCO2 (4.6-60 kPa)

•silent chest


effort

•bradycardia

•dysrhythmia


•coma

Acute severe

asthma

Any one of:

•PEF 33-50% best or predicted

•respiratory rate 25/min •heart rate 110/min

•inability to complete sentences

in one breath

Moderate asthma

exacerbation

• Increasing symptoms

• PEF >50-75% best or predicted

• No features of acute severe

asthma

145




inflation pressures

Life threatening

asthma


•PEF <33% best or


•normal PaCO2 (4.6-6.0 kPa)

•silent chest


effort

•bradycardia

•dysrhythmia


•coma

Acute severe

asthma

Any one of:

•PEF 33-50% best or predicted

•respiratory rate 25/min •heart rate 110/min

•inability to complete sentences

in one breath

Moderate asthma

exacerbation

•Increasing symptoms

•PEF >50-75% best or predicted

•No features of acute severe

asthma

Brittle asthma • Type 1: wide PEF variability (>40% diurnal variation for >50% of

the time over a period >150 days) despite intense therapy

• Type 2: sudden severe attacks on a background of apparently

well-controlled asthma

146

Initial assessment – the role of symptoms, signs and measurements


Clinical features Clinical features can identify some patients with severe asthma,

eg severe breathlessness (including too breathless to complete

sentences in one breath), tachypnea, tachycardia, silent chest,

cyanosis, accessory muscle use, altered consciousness or

collapse.

None of these singly or together is specific. Their absence does not

exclude a severe attack.

147



Clinical features Clinical features, symptoms and respiratory and cardiovascular signs

helpful in recognising severe asthma, but none specific, and their absence does not exclude a severe attack

PEF or FEV1 Measurements of airway caliber improve recognition of the

degree of severity, the appropriateness or intensity of therapy, and

decisions about management in hospital or at home.

PEF or FEV1 are useful and valid measures of airway caliber. PEF is

more convenient in the acute situation.

PEF expressed as a percentage of the patient’s previous best value

is most useful clinically. PEF as a percentage of predicted gives

a rough guide in the absence of a known previous best value.

Different peak flow meters give different readings. Where possible

the same or similar type of peak flow meter should be used.

148





PEF or FEV1 Measurements of airway calibre improve recognition of severity and guide

hospital or at home management decisions. PEF is more convenient and cheaper than FEV1. PEF as % previous best value or % predicted most

useful

Pulse oximetry Measure oxygen saturation (SpO2) with a pulse oximeter to

determine the adequacy of oxygen therapy and the need for arterial

blood gas (ABG) measurement. The aim of oxygen therapy is to

maintain SpO2 94-98%.

149







useful

Pulse oximetry Necessary to determine adequacy of oxygen therapy and need for arterial

blood gas measurement. Aim of oxygen therapy is to maintain SpO2 92%

Blood gases

(ABG) Measure oxygen saturation (SpO2) with a pulse oximeter to

determine the adequacy of oxygen therapy and the need for arterial

blood gas (ABG) measurement. The aim of oxygen therapy is to

maintain SpO2 94-98%.

150







useful



Blood gases

(ABG)

Necessary for patients with SpO2 <92% or other features of life threatening

asthma

Chest X-ray Not routinely recommended in patients in the absence of: • suspected pneumomediastinum or

pneumothorax • suspected consolidation • life threatening asthma

• failure to respond to treatment

satisfactorily • requirement for ventilation

151







useful



Blood gases

(ABG)

Necessary for patients with SpO2 <92% or other features of life threatening

asthma

Chest X-ray Not routinely recommended in patients in the absence of: •suspected pneumomediastinum or

pneumothorax •suspected consolidation •life threatening asthma

•failure to respond to treatment

satisfactorily •requirement for ventilation

Systolic paradox Abandoned as an indicator of the severity of an attack

bronchial asthma and asthma control

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