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Page 1: Asthma updates
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Asthma Updates

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

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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

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Source: Peter J. Barnes, MD

Asthma Inflammation: Cells and Mediators

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Source: Peter J. Barnes, MD

Mechanisms: Asthma Inflammation

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Source: Peter J. Barnes, MD

Asthma Inflammation: Cells and Mediators

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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

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Pathology of Asthma

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Factors that Exacerbate Asthma

Allergens

Respiratory infections

Exercise and hyperventilation

Weather changes

Sulfur dioxide

Food, additives, drugs

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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

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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

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90% of the asthma problem is not seen:

The inflammation!!!

Bronchospasm= 10%

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When this disappears…

Have we eliminated this?

Symptoms

Underlying

disease

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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

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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

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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.

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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.

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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.

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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.

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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.

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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

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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 .

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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.

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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. .

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Inhaled IL-4Rα antagonist . Surrogate marker predicting

better response is IL-4 receptor a polymorphism.

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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.

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Genetics:

Few patients in this group have a family history of asthma.

little is known regarding the genetics of adult onset persistent

asthma.

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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

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Treatment responses:

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.

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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

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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.

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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

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Clinical characteristics:

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 .

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Biomarkers:

Th2 cytokines and cysteinyl leukotriene

Genetics:

No distinct genetic factors .

Treatment responses:

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.

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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

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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.

, ..

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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.

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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.

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Treatment responses:

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.

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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) .

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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

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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.

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Treatment responses:

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.

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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.

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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.

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The intensity of the colors represents the range of severity; the relative sizes of the subcircles suggest relative proportions of affected individuals

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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

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Lotvall J et al JACI 2011

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Agache,etal 2o12

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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.

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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.

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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

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The Asthma–Chronic Obstructive

Pulmonary Disease Overlap

Syndrome (ACOS)

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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

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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.

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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.

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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.

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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 .

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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

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Levels of severity of acute asthma exacerbations

Management of acute asthma. Thorax 2012

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

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Levels of severity of acute asthma exacerbations

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

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)

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Levels of severity of acute asthma exacerbations

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

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:

•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

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Levels of severity of acute asthma exacerbations

Management of acute asthma. Thorax 2012

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:

•PEF <33% best or predicted

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

Moderate asthma exacerbation

• Increasing symptoms • PEF >50-75% best or predicted

• No features of acute severe asthma

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Levels of severity of acute asthma exacerbations

Management of acute asthma. Thorax 2012

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:

•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

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

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Initial assessment – the role of symptoms, signs and measurements

Management of acute asthma. Thorax 2012

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.

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Initial assessment – the role of symptoms, signs and measurements

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

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.

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Initial assessment – the role of symptoms, signs and measurements

Management of acute asthma. Thorax 2012

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 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%.

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Initial assessment – the role of symptoms, signs and measurements

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

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 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 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%.

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Initial assessment – the role of symptoms, signs and measurements

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

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 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 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)

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

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Initial assessment – the role of symptoms, signs and measurements

Management of acute asthma. Thorax 2012

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 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 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)

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

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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

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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

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

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Childhood asthma phenotypes: - transient early wheezers - wheeze sometime during first year of life; risk factors include prematurity, history of parental smoking during pregnancy, and passive exposure to tobacco smoke; such patients do not respond to inhaled bronchodilators or inhaled corticosteroids (ICS); wheezing tends to remit as child’s airway gets larger (between ages 2-3 yr) - nonatopic wheezers - 0 to 6 yr of age; wheeze associated exclusively with viral infection; usually no eczema or family history; wheezing tends to remit by 6 yr of age - atopic wheezers - past 5 yr of age, allergic - have positive blood and skin testing to inhalant allergens; tend to present within 2 to 3 yr of age, and continue to wheeze; wheezing not related to URTI

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URTI

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A 2012 study described 2 "new" phenotypes for young children with wheezing: 1-"boys atopic multiple-trigger" and 2-"girls nonatopic uncontrolled wheeze". JACI, 2012.

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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

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Positive API = 10 times more likely to have persistent asthma.

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Cough-variant asthma

Chronic, persistent cough - without wheezing - may be the only manifestation of asthma. More than 60% bronchial obstruction is

needed to produce wheezing - asthma can occur without wheezing - spirometry is required for diagnosis.

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.

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