Bronchial Asthma Updates

Asthma Updates

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

Definition of Asthma

A chronic inflammatory disorder of the airways

Many cells and cellular elements play a role

Chronic inflammation is associated with airway hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing

Widespread, variable, and often reversible airflow limitation

Source: Peter J. Barnes, MD

Asthma Inflammation: Cells and Mediators


Mechanisms: Asthma Inflammation


Asthma Inflammation: Cells and Mediators

Smooth Muscle

Dysfunction

Airway

Inflammation

• Inflammatory Cell

Infiltration/Activation

• Mucosal Edema

• Cellular Proliferation

• Epithelial Damage

• Basement Membrane

Thickening

• Bronchoconstriction

• Bronchial Hyperreactivity

• Hypertrophy/Hyperplasia

• Inflammatory Mediator

Release

Symptoms/Exacerbations

Asthma Pathobiology

Pathology of Asthma

Factors that Exacerbate Asthma

Allergens

Respiratory infections

Exercise and hyperventilation

Weather changes

Sulfur dioxide

Food, additives, drugs

Factors that Influence Asthma

Development and Expression

Host Factors

Genetic

- Atopy

- Airway

hyperresponsiveness

Gender

Obesity

Environmental Factors

Indoor allergens

Outdoor allergens

Occupational sensitizers

Tobacco smoke

Air Pollution

Respiratory Infections

Diet

Is it Asthma?

Recurrent episodes of wheezing

Troublesome cough at night

Cough or wheeze after exercise

Cough, wheeze or chest tightness after exposure to airborne allergens or pollutants

Colds “go to the chest” or take more than 10 days to clear

90% of the asthma problem is not seen:

The inflammation!!!

Bronchospasm= 10%

When this disappears…

Have we eliminated this?

Symptoms

Underlying

disease

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

Estimate Comparative Daily Dosages for

Inhaled Glucocorticosteroids by Age

Drug Low Daily Dose (g) Medium Daily Dose (g) High Daily Dose (g)

> 5 y Age < 5 y > 5 y Age < 5 y > 5 y Age < 5 y

Beclomethasone 200-500 100-200 >500-1000 >200-400

>1000 >400

Budesonide

200-600 100-200

600-1000 >200-400 >1000 >400

Budesonide-Neb

Inhalation Suspension

250-500 >500-1000 >1000

Ciclesonide 80 – 160 80-160 >160-320 >160-320 >320-1280 >320

Flunisolide 500-1000 500-750 >1000-2000 >750-1250 >2000 >1250

Fluticasone 100-250 100-200 >250-500 >200-500 >500 >500

Mometasone furoate 200-400 100-200 > 400-800 >200-400 >800-1200 >400

Triamcinolone acetonide 400-1000 400-800 >1000-2000 >800-1200 >2000 >1200

Asthma is a complex disease or a syndrome that includes

several disease variants.

The term asthma, like „arthritis‟, equates to a definition of

grouped clinical and physiological characteristics. These

characteristics could identify syndromes, phenotypes or even

multiple diseases rather than a single disease.

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.

By The study of wenzel ,et al 2013 Combining clinical, statistical

and molecular approaches two broad emerging “endotypes” have

been defined.

Traditionally asthma has been thought to be a Th2-associated

disease. There is strong evidence supporting a TH2-high phenotype

in up to 50% of people with asthma of any severity, yet 50% show

no evidence for this immune process.

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

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.


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)

L-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

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 .

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

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

Lötvall et al.2011 proposed endotyping asthma into six classes

depending on several parameters used to define an endotype.

Aspirin sensitive asthma

Allergic asthma (adults)

Severe late-onset hypereosinophilic

ABPM

API-positive preschool wheezer

Asthma in cross country skiers

Lotvall J et al JACI 2011

Agache,etal 2o12

The principle of personalized or individualized medicine is to

'bring the right drug to the right patient at the right dose', such

that therapeutic efficacy is maximized and the side effects are

kept to a minimum.

The consideration of disease endotypes in treatment design

should be able to bridge the present era of treating asthma

based on family history, patient characteristics and laboratory

test, to the future era of personalized medicine where

treatment scheme will be based on individual biological data

such as genomic, proteomic and metabolic profiles.

This study present video-assisted thoracoscopic biopsy

findings from 10 patients, previously diagnosed with severe

asthma and meeting criteria for asthma. Pathobiologically,

these patients have evidence for asthmatic small airway

inflammation and infrequent nonnecrotizing granulomas with

interstitial inflammation. This distinct pathobiology in addition

to their response to cytotoxic agents suggests that these

patients represent a newly described disease, which we term

asthmatic granulomatosis.

Sally E. Wenzel1, Catherine A. Vitari1, Manisha Shende2, Diane C. Strollo3,

Allyson Larkin4, and Samuel A. Yousem5 Am J Respir Crit Care Med Vol 186, Iss. 6, pp 501–507, Sep 15, 2012

Asthmatic Granulomatosis A Novel Disease with Asthmatic and

Granulomatous Features

The Asthma–Chronic Obstructive

Pulmonary Disease Overlap

Syndrome (ACOS)

The Spanish COPD guidelines propose

four COPD phenotypes that determine

differential treatment: nonexacerbator

with emphysema or chronic bronchitis,

mixed COPD–asthma, exacerbator with

emphysema and exacerbator with

chronic bronchitis

ACOS

ACOS

The mixed COPD–asthma phenotype was

defined as an airflow obstruction that is not

completely reversible accompanied by

symptoms or signs of an increased

reversibility of the obstruction.[7] In other

guidelines, these patients are described as

'patients with COPD and prominent asthmatic

component' or as asthma that complicates

COPD.

ACOS

*Two major criteria (FEV1 >15% and >400 ml

after bronchodilator or sputum eosinophils or

history of asthma) and

*Two minor criteria (elevated total IgE or

history of atopy or FEV1 >12% and >200 ml

after bronchodilator) are recommended.

ACOS

*Asthma with partially reversible airflow obstruction

– that is, based on change in FEV1 with

bronchodilators – with or without emphysema or

reduced carbon monoxide diffusing capacity (DLco)

to <80% predicted;

*COPD with emphysema accompanied by

reversible or partially reversible airflow obstruction,

with or without environmental allergies or reduced

DLco.

ACOS

The following major criteria for ACOS:

a physician diagnosis of asthma and COPD in the

same patient, history or evidence of atopy, for

example, hay fever, elevated total IgE, age 40 years

or more, smoking >10 pack-years,

postbronchodilator FEV1 <80% predicted and

FEV1/FVC <70%.

Minor criteria:

A ≥15% increase in FEV1 or ≥12% and ≥200 ml

increase in FEV1 postbronchodilator treatment with

albuterol .

Do oral Beta Blockers Really

Exacerbate Asthma?

Recent investigations suggest BB therapy may actually improve asthma. A 2002 meta-analysis found no significant adverse effects of beta-blocker therapy in people with mild-to-moderate asthma, and in fact, bronchodilator response increased with chronic beta-blocker treatment. Thorax 2011;66:502-507.

http://www.sciencedirect.com/science/article/pii/S1094553907000673

http://annals.org/article.aspx?articleid=715759



http://thorax.bmj.com/content/66/6/502.abstract










72

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

73

Levels of severity of acute asthma exacerbations


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

74


Management of acute asthma. Thorax 2003; 58 (Suppl I): i1-i92


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)

75






•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

76







•SpO2 <92% •PaO2 <8 kPa •normal PaCO2 (4.6-60 kPa)




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

77







•SpO2 <92% •PaO2 <8 kPa •normal PaCO2 (4.6-6.0 kPa)




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

78

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.

79



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.

80





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%.

81







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%.

82








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

83








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

Radiographic Signs of Pneumomediastinum

Subcutaneous emphysema

Thymic sail sign

Pneumoprecardium

Ring around the artery sign

Tubular artery sign

Double bronchial wall sign

Continuous diaphragm sign

Extrapleural sign

Air in the pulmonary ligament

Pediatric Asthma Not all wheezing is asthma

Wheezing occurrences in children:

- single episode in 30% to 50% of children

before 5 yr of age

- 40% who wheeze before 3 yr of age continue

at 6 yr (“persistent wheezers”)

- 50% of infants who wheeze once will wheeze

again within several months

Wheezing in Children - Phenotypes

Childhood asthma phenotypes

Childhood asthma phenotypes

*A 2012 study described 2 "new" phenotypes for

young children with wheezing: "boys atopic

multiple-trigger" and "girls nonatopic uncontrolled

wheeze". JACI, 2012.

*Toward a definition of asthma phenotypes in

childhood: early viral wheezers, multitrigger

wheezers (MTWs), and nonatopic uncontrolled

wheezers (NAUWs). Some children have “allergic

bronchitis” rather than “asthma”. JACI, 2012.

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.

Guidelines National Heart, Lung, and Blood Institute (NHLBI) guidelines

for diagnosis and management of asthma

Key concepts: - severity dictates therapy

- - distinction between intermittent and persistent asthma

- - "rule of 2s”

- - 4 levels of asthma severity - intermittent; 3 sublevels of

persistent

- - inhaled corticosteroids (ICS) preferred for all levels of

persistent asthma

- - use of asthma action plans

- - spirometry recommended

Rule of 2s

- if symptoms are present for more than 2 days per

week or for more than 2 nights per month, asthma

categorized as persistent.

- Within this category, disease must be classified as

mild, moderate, or severe. However, as severity of

asthma not constant, must monitor patients for

changes; as severity changes, therapy should

change too.

- The category of “mild intermittent” asthma was

eliminated in the 2007 guidelines - now it is just called

“intermittent” asthma.

- impairment - refers to symptoms

- - risk - refers to likelihood that the patient will eventually

have exacerbation of asthma and present to emergency

department (ED) or hospital, or need course of oral

corticosteroids

- - control - refers to the level of patient’s asthma control

The concepts of “impairment”, “risk”, and “control” were

introduced in the 2007 guidelines:

Classification of asthma severity

- impairment domain - daytime and nighttime symptoms

(rule of 2's), use of short-acting beta-agonist (SABA),

interference with normal activities

- - risk domain - number of exacerbations per year (if more

than 2, daily controller medication is needed). Increased

risk is conferred by parental history of asthma or history of

eczema.

- Childhood Asthma Control Test (ACT) is validated down to

age 4 yr. Adult ACT questionnaire should be used for

teenagers (cutoff age is 11 years).

Treatment steps

- step 1 - SABA as needed –

- step 2 - low-dose ICS monotherapy vs. leukotriene receptor

antagonist (LTRA)

- - step 3 - low-to-medium dose ICS plus long-acting beta-

agonist (LABA)

- - step 4 - high-dose ICS therapy plus LABA and (if needed)

systemic corticosteroids. Omalizumab (Xolair; anti-IgE

antibody) is prescribed before placing patient on daily oral

corticosteroids.

“Rule of 2s” to determine level of control

- daytime symptoms more than 2 days/wk

- rescue β2 -agonist use more than 2 times per week

- nighttime symptoms more than 2 nights/mo

- more than 2 rescue β2-agonist canisters/yr

Step Down or Step Up

When to step down therapy? If patient is well-controlled for

3 mo, consider stepping down therapy.

When to step up therapy? If the patient is not well-

controlled, step up therapy and re-evaluate in 2 to 6 wk. If the

patient is very poorly controlled, step up therapy 2 steps,

consider short course of steroids, and reassess in 2 wk.

When to consider long-term ICS treatment

- positive API and more than 3 wheezing episodes in

previous 12 mo lasting more than 1 day and affecting

sleep

- consistent requirement for SABA treatment (more than

2 times/wk, on average, over 1-2 mo); 2 exacerbations in

6 mo requiring oral corticosteroids

Treatmnt

Inhaled corticosteroid

Relative binding affinity for glucocorticoid receptor (GR):

mometasone = fluticasone > budesonide > triamcinolone.

Relative anti-inflammatory potency: mometasone =

fluticasone > budesonide = beclomethasone >

triamcinolone.

Severe asthma - differential diagnosis and management

Treating to Maintain Asthma Control

Stepping up treatment in response to loss of control

Use of a combination rapid and long-acting inhaled β2-agonist (e.g., formoterol) and an inhaled glucocorticosteroid (e.g., budesonide) in a single inhaler both as a controller and reliever is effecting in maintaining a high level of asthma control and reduces exacerbations (Evidence A)

Doubling the dose of inhaled glucocortico-steroids is not effective, and is not recommended (Evidence A)

Difficult Asthma

Other terminology

• Severe asthma

• Difficult to control asthma

• Difficult to treath asthma

• Refractory asthma

• Steroid resistant asthma

• Unstable asthma

• Life threatening asthma

• Definition

• Factors that could be preventing a

normal response to asthma medication

• Phenotypes

• Risk Factors

Severe - Difficult Asthma

Definition - ERS Task Force

• ‘failure to achieve asthma

control when maximally

recommended doses of

inhaled therapy are

prescribed for at least 6 -

12 months’

ERS Task Force: ERJ 1999;13:1198-6

Levels of asthma control GINA

2006

Characteristic

Controlled

(all of the

following)

Partly controlled

(any measure

present in any

week) Uncontrolled

Daytime symptoms None (twice or

less/week)

More than twice/week Three or more

features of

partly

controlled

asthma present

in any week

Limitations of

activities

None Any

Nocturnal

symptoms/awakenin

g

None Any

Need for

reliever/rescue

treatment

None (twice or

less/week)

More than twice/week

Lung function (PEF

or FEV1)

Normal <80% predicted or

personal best (if

known)

Exacerbations None One or more/year One in any

week

Definition - ATS

Major Criteria

Use of oral corticosteroids >50% of time

Continious use of high dose ICS

Minor Criteria

Requirement for daily treatment with LABA, theophilline or

LTRA

Daily asthma symptoms requiring rescue medication

Persistent airway obstruction, diurnal PEF variability >20%

>1 urgent care visits for asthma in the last year

>3 courses oral steroid bursts in the last year

Prompt deterioration with >25% reduction in oral or ICS dose

Near fatal asthma event in the past ATS- JACI 2000;106:1033-1042

• Definition


normal response to asthma medication

• Phenotypes

• Risk Factors


Factors that could be preventing a

normal response to asthma

medication

• Incorrect diagnosis

• Continuing exposure to sensitising

agents

• Unrecognised aggravating

comorbidities

• Non-compliance with therapy

Incorrect Diagnosis -

Alternative Diagnoses

• COPD

• Congestive heart failure

• Central airway obstruction

– Foreign body, tumour, sarcoidosis, tracheobronchomalacia

• Cystic fibrosis

• Recurrent pulmonary embolism

• Obstructive bronchiolitis

• Recurrent aspiration

• Vocal cord disfunction

• Allergic bronchopulmonary aspergillosis

• Churg-Strauss syndrome

Bel EH. Breathe 2006; 3:2; 129-139

Incorrect diagnosis : pseudo-

tm

Incorrect diagnosis :

tracheomalasia

Strategy for the diagnosis-1

• History of asthma development

(age of onset, atopy, response to treatment, smoking)

• Severity of disease

(exacerbations, hospitalisations, ICU admissions)

• Exogenous aggravating factors

(allergens, occupationnal agents, drugs, foods..)

• Endogenous aggrating factors

(Rhinosinusitis, GER, OSA, influence of menstruation, psychiatric disease..)

• Miscellaneous

(adherence, advers effect, psychosocial circumstances)

• Physical examination (specific points of attention)

(Body mass index, Nasal polypes, cardiac failure, adverse effects of treatment)

Strategy for the diagnosis:

Laboratory tests

• Peripheral blood

(ESR, blood count, tIgE, sIgE, T3, T4, TSH)

• Lung function

(spirometry, flow-volume, PEF variability, challenge tests, arterial blood gases)

• Radiology

(chest radiography, thorax CT or HRCT, sinus CT scans)

• Additional tests for comorbidities and alternative diagnoses

(nasal endoscopy, oesophageal pH or PPI, polysomnography, broncoscopy, D-dimer, ANCA, IgG againts aspergllus fumigatus….)

Bel EH. Breathe 2006; 3:2; 129-139

Continuing exposure to

sensitising agents

• Allergen exposure at

home

• Allergen or

occupationnal exposure

at work

• Drugs

• Dietary factors

- metabisulphite, salicylate,

food allergens

• Smoking

Bel EH. Breathe 2006; 3:2; 129-139

18%

73%

9%

56%

14%

30%

Allergic Sensitization

Patients with Severe Asthma

Grootendorst DC et al., AJRCCM 2000

Multiple allergies

Single allergy

Non-atopic

Early-onset asthma Late-onset asthma

Allergic Sensitization


Grootendorst DC et al., AJRCCM 2000

0

20

40

60

80

100

Pe

rce

nta

ge

of

ato

pic

pa

tie

nts

• ß-Blockers

Exposure to sensitizing drugs

• Aspirin and NSAIDS

• ACE inhibitors

-5

0

5

10

15

20

25

30

Placebo

Fluticasone

(1mg/day)

Non-smokers (n=21)

Sputum Eos

% change 0 -1.8 *

**

Chalmers GW et al: Thorax 2002

Smoking and steroid responses in asthma

Smokers (n=17)

0 0

Smoking and response to oral steroids

Non-smokers (26) Ex-smokers (10) Current smokers (14)

0

100

200

300

p<0.01

NS

NS

Chaudhuri R et al: AJRCCM 2003

Prednisolone 40mg daily x 2 weeks

FEV1

-1

-0.8

-0.6

-0.4

-0.2

0

Δ A

sth

ma c

on

tro

l sco

re

NS

NS

p<0.001

Asthma control

Unrecognised aggravating

comorbidities

• Chronic rhinosinusitis

• Recurrent respiratory tract infections

• Gastro-oesophageal reflux

• Obstructive sleep apnea

• Psychological dysfunctioning

• Obesity

• Systemic diseases (thyrotoxicosis…)

Bel EH. Breathe 2006; 3:2; 129-139

Co-morbid factors in asthmatic patients

with frequent exacerbations

sleep

apnoea

psycho-

pathology

sinus

disease

gastric

reflux

recurrent

infections

0

25

50

75

100

Pre

vla

nece (

%)

p=0.04 p=0.01 p=0.03 p=0.03 p=0.10

ten Brinke A et al., ERJ 2005;26:812-

8.

Co-morbid factors in asthmatic patients with frequent exacerbations

1 co-morbid

factor

13%

2 co-morbid

factors

35%

3 co-morbid

factors

39%

4 co-morbid

factors

8%

5 co-morbid

factors

5%

ten Brinke A et al., ERJ 2005;26:812-8.

0

10

20

30

40

50

60

70

80

90

Premenstrual Exercise

Aspirin

Sinusitis

Rhinitis Stress

Mild

Severe *

*

*

*

*

Women

ENFUMOSA Study: ERJ 2003, 22:470-477

Co-morbid factors in severe asthma

Pasternack et al. J Allergy Clin Immunol 2005; 116: 1123-8

Reccurent infections in severe

asthma

Pasternack et al. J Allergy Clin Immunol 2005; 116: 1123-8

Reccurent infections in severe

asthma

Reccurent infections in severe asthma

Kraft M et al: Chest 2002

2

2.5

3 p<0.05

B/L Clari

PCR +

NS

B/L Clari

PCR -

PCR for Mycoplasma pneumoniae and Chlamydia pneumoniae

Clarithromycin 500mg b.d.

Non- compliance with therapy

• Psychological problembs

• Missed appointments

• Complexity of treatement

• Lack of insight into illness

• Inhalation technique

Bel EH. Breathe 2006; 3:2; 129-139

İnhaler cihaza uyumsuzluk

• Kullanımında hata

% 14 - 74

• Kullanmak istememe

% 31

Wilson A. Aerosol delivery system. In: Weiss EB, Stein M.(eds). Bronchial Asthma.1993:749-755

Osman LM et al. Thorax 1993, 48: 827-830

• Definition



medication

• Phenotypes

• Risk Factors


Difficult asthma phenotypes

• Unstable asthma (Brittle, Nocturnal, Premenstrual)

• Poor response to treatment (Steroid-dependent asthma, Steroid-resistant asthma)

• “Fixed” asthma

Brittle asthma

•Type I: wide variability in PEF despite maximum therapy

•Type II: sudden attack from normally well controlled asthma

Ayres J, Miles J, Barnes PJ: Thorax 1998

Nocturnal Asthma

• Nocturnal hyperreactivity with an increase 8-10 fold

• High PEF variability

Teraschima T: Chest 2002, Barnes PJ. ERJ 1998

Premenstrual asthma

• Worsening of asthma ~7days

premenstrually

• Recovers with menstruation

0 1 2 3 4wk

PEF

Beynon H et al: Lancet 1988

Systemic side effects

Mild Moderate

Severe

Inhaled steroids (µg)

100 400 1600

Resistant

Steroid dependent

Oral steroids

Asth

ma c

on

tro

l Spectrum of steroid

responsiveness

• Poor adherence

• Wrong diagnosis

• Dose too low

• Increased metabolism

(e.g. carbamazepine, rifampicin)

• Relative resistance / Complete

resistance

Poor response to corticosteroids

0 1 2 weeks

Peak

flow CORTICOSTEROID-SENSITIVE

Peak

flow

0 1 2 weeks

CORTICOSTEROID-RESISTANT

Prednisolone 30-40 mg om

Corticosteroid-resistant asthma

moderate

asthma

n=13

severe asthma

n=15

Age (med.range) 49 (42-61) 47 (25-61)

Sex (m:f) 7:6 7:8

FEV1 (% pred) 88.6 (4.8) 72.7 (6.5)

Pepe C et al, J Allergy Clin Immunology 2005;116:544-9)

Fixed asthma


Fixed Asthma


(r = −0.58, P < .05).

Fixed Asthma

• Definition



medication

• Phenotypes

• Risk Factors


ENFUMOSA Study: Risk

factors • Female predominance

• Reduced influence of atopy on asthma phenotypes

• Exposure to aspirin as a risk factor

• Association with increased body mass index, especially in women

• A proportion of fixed airflow obstruction with increased residual volumes to total lung capacity ratio, suggesting the presence of structural changes

Eur Res J 22:470-477 (2003)

PARAPLU study, AJRCCM 2001;163:1093-1096

Severe Asthma is associated with Increased

Health Care Utilization

Health care utilization parameters

GP visits: 4 last yr

Chest physician visits: 4 last yr

Emergency visits: 2 last yr

Exacerbations: 2 last yr *

Hospital admissions: 2 last yr

Maintenance oral corticosteoids

Ever ICU admission

Ever mechanical ventilation

n

15

17

15

12/13

4

8

3

3

%

71.4

81.0

71.4

92.3

19.0

38.1

14.3

14.3

n

23

60

24

29/51

4

26

8

2

%

29.9

77.9

31.2

56.9

5.2

33.8

10.4

2.6

p-value

0.02

0.78

0.01

0.02

0.04

0.71

0.62

0.03

Cases (n=21) Non-cases (n=77)

Associated Factors of Airflow Obstruction

in


Adjusted OR*

7.7

3.9

3.3

1.9

1.7

1.7

1.5

1.4

1.3

0.8

(95% CI)

(2.4 – 25.1)

(1.2 – 13.0)

(1.2 – 9.0)

(0.8 – 4.8)

(0.8 – 3.6)

(0.8 – 3.7)

(0.6 – 3.6)

(0.5 – 4.0)

(0.6 – 2.9)

(0.4 – 1.9)

Sputum eosinophils 2%

PC20 histamine 1.0 mg/ml

Adult-onset of asthma

Exhaled NO 10 ppb

Reversibility FEV1 9%

Total IgE > 100 IE/ml

Blood eosinophil count > 450.106/l

Sputum neutrophils 64%

Ex-smoker

Atopic

*OR adjusted for age, gender, and asthma duration

PARAPLU-study, LUMC Leiden: AJRCCM 164:744-748 (2001)

Risk factors: FEV1 decline and Chlam

P.

0

50

100

150

Cp+ Cp+ Cp- Cp- Cp+ Cp- Cp+ Cp-

atopic atopic non-atopic non-atopic ______ ______ ______ ______

______________ ______________ childhood-onset adult-onset

Estim

ate

d lo

ss in

FE

V

1

(ml/yr)

PARAPLU-study, LUMC Leiden: JACI 2001;107:449-454

Risk Profile of Patients with Frequent

Asthma Exacerbations

Adjusted OR

10.8

6.9

4.9

3.7

3.4

2.8

1.9

0.7

0.6

0.6

0.5

0.4

0.2

(95% CI)

1.1 – 108.4

1.9 – 24.7

1.4 – 17.8

1.2 – 11.9

1.2 – 10.4

0.5 – 15.8

0.2 – 19.6

0.2 – 2.1

0.1 – 2.9

0.1 – 3.5

0.2 – 1.3

0.1 – 1.7

0.1 – 1.9

Psychological dysfunctioning

Recurrent respiratory tract infections

Gastro-oesophageal reflux

Severe chronic sinus disease

Obstructive sleep apnoea

Hormonal influences

Hyperthyroidism

Occupational sensitisers

Poor inhaler technique

Food allergens

Ongoing allergen exposure

Relative immune deficiency

Drugs

PARAPLU-study, LUMC Leiden: JACI 2001;107:449-454

154

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