Case Study

Case Study

Gamal Rabie Agmy, MD, FCCP

Professor of chest Diseases, Assiut university

Patient Details

A 20 years old male.

Smoking Status: Ex-smoker

His weight is 100 Kg.

Occupation: Student

His grandfather died with asthma 4 years ago.

Past respiratory history

Age at onset of symptoms – Childhood

Hospitalizations – He was admitted on three occasions.

Life threatening attacks/ICU admissions/ventilated: 1 ICU intervention

4

Patient Details (cont.’):

Cannot socialize with friends.

Patient’s lifestyle was restricted.

Unable to participate in any sport

Gained weight due to lack of physical activity.

He misses up to 50% of college lectures due to asthma

Shortness of breath prevented him from using public transport

The patient is very depressed as a consequence of his asthma.


He has daytime symptoms as breathlessness and coughing 2 to 3 times per week.

He uses his rescue treatment around 5 to 6 times per week.

He wakes up on the early morning 3 to 4 times per week due to coughing and chest tightness.

He is poorly controlled on maximum doses of inhaled medications

Despite of taking his medications regularly, He is still uncontrolled with poor quality of life.


Clinical Findings:

Clinical findings:

Reversibility test ＞ 12% FEV1 improvement.

FEV1= 52% predicted.

Serum Eosinophil count 630 /mm3 .

Allergic status

Positive skin prick test to grass, cat, dog.

Total serum IgE 175 IU/ml.

9

Respiratory Medications (include unsuccessful trials):

Maximum dose ICS/LABA fixed combination twice daily.

Tried Leukotriene modifiers and discontinued

Theophylline.

Salbutamol when needed.

Medications’ effects

Mood swings

Tachycardia

Nausea

11

Questions

Guided by the clinical presentation of this patient, what is your provisional diagnosis for this case? Why?

Severe Asthma Definitions (cont.’):

Continuing signs of inadequate control in the presence of nearly continuous use of oral steroids or of maximal doses of inhaled corticosteroids. (SARP)1.

One or more acute exacerbations within the past year despite treatment with at least maximum recommended doses of inhaled corticosteroids. (ENFUSOMA)2.

Postgrad Med J. 2008 Mar;84(989):115-20 SARP: The Severe Asthma Research Program

ENFUSOMA: European Network for Understanding Mechanisms of Severe Asthma

Definition of The American Thoracic Society (ATS) for severe asthma:

Definition requires that at least one major criterion and two minor criteria are met in the same patient.

Major characteristics:

Treatment with continuous or near continuous (≥50% of year) oral corticosteroids.

Need for treatment with high-dose inhaled corticosteroids.

Lancet. 2006 Aug 26;368(9537):780-93

Definition of The American Thoracic Society for severe asthma (cont.’): Minor Characteristics:

Need for additional daily treatment with a controller medication (e.g. Long-acting β agonist, theophylline, or leukotriene antagonist)

Asthma symptoms needing short-acting β agonist use on a daily or near-daily basis

One or more urgent care visits for asthma per year

Three or more oral steroid bursts per year

Near-fatal asthma event in the past

Lancet. 2006 Aug 26;368(9537):780-93

International ERS/ATS Guidelines on Definition, Evaluation and Treatment of Severe Asthma

December 2013

When a diagnosis of asthma is confirmed and comorbidities have been addressed, severe asthma is defined as “asthma which requires treatment with high dose inhaled corticosteroids (ICS) plus a second controller (and/or systemic CS) to prevent it from becoming “uncontrolled” or which remains “uncontrolled“ despite this therapy.”

Definition of Severe Asthma

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 Pathophysiology

19

FCƹR1

Cƹ3

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

Questions


What are the risk factors that associated with this case?

Risk factors associated with this case

Medical History

Family history

Risk Factors & Associated Characteristics of

Severe Asthma

Risk Factors:

In most cases, multiple factors are responsible for

difficult-to-treat asthma.

Many of the risk factors that contribute to disease chronicity are also triggers of worsening asthma and exacerbations, indicating complex interactions with the environment.

Lancet. 2006 Aug 26;368(9537):780-93

Risk Factors (cont.’):

ENFUMOSA is among several studies that have found higher concentrations of neutrophils in induced sputum or bronchoscopic biopsy specimens from patients with severe asthma than in samples from patients with mild-to-moderate asthma.

This neutrophil predominant inflammation is significant because corticosteroids may protect these cells from undergoing apoptosis.

Postgrad Med J. 2008 Mar;84(989):115-20

1-Neutrophils


The genetics of asthma is a growing focus of interest, with a number of mutations having been associated with increased asthma risk.

Several of these mutations, are associated with an increased likelihood that asthma will be severe.

One such example is a mutation in the promoter region of transforming growth factor b1 (TGF-b1)

TGF-b1 is a pro-fibrotic cytokine that induces secretion of extracellular matrix proteins and thus could contribute to airway remodelling.


2-Genetics


The frequency of this mutation in patients with severe asthma was twice as great as in those with mild asthma and more than five times as great as in control subjects


2-Genetics


Severe asthma is two to three times more common in women than in men,

At its inception in childhood, asthma is more common in boys, but during the early teenage years severe asthma becomes more common in girls than in boys and this pattern persists into adulthood.

The higher prevalence of adult-onset asthma and severe asthma in women than in men is probably the result of endocrine factors

Lancet. 2006 Aug 26;368(9537):780-93

3-Endocrine Factors:


Strong associations have been reported with the menstrual cycle, whereas in pregnancy asthma commonly improves, especially in the mid and late trimesters.

Thyrotoxicosis is a recognized endocrine factor leading to loss of asthma control.

Obesity is a newly recognized risk factor for both asthma and its severity, especially in women, with weight loss being accompanied by improved asthma control.

Lancet. 2006 Aug 26;368(9537):780-93

3-Endocrine Factors:

Risk Factors (cont):

The co-existence of chronic rhinitis, nasal polyposis, and sinusitis contribute to asthma severity.

Gastro-esophageal reflux is also commonly associated with chronic asthma both in adults and children, possibly related to the proximity of the organs and neural connections.

Lancet. 2006 Aug 26;368(9537):780-93

4-Comorbid Diseases:


Severe asthma has long been associated with psychological and psychiatric disorders, which are particularly strong risk factors for frequent emergency room visits and asthma mortality with depression, anxiety, panic or fear, and behavioral problems that adversely affect disease control.

Lancet. 2006 Aug 26;368(9537):780-93

5-Psychopathological Factors:


β blockers can lead to severe asthma that is refractory to β2-adrenoceptor agonists. Asthma is, therefore, a contraindication for this drug class.

Inhibitors of angiotensin converting enzyme and adenosine for cardiovascular diseases are also associated with deterioration of asthma.

However, aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) present the most common and difficult problems.

Aspirin intolerance has emerged as a prominent risk factor of severe asthma.

Lancet. 2006 Aug 26;368(9537):780-93

6-Adverse Drug Effects:

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










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

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

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 .

78

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

79

Levels of severity of acute asthma exacerbations


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

80




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)

81






•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

82







•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

83







•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

84

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.

85



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.

86





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%.

87


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





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%.

88


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






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

89








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

International ERS/ATS Guidelines on Definition,

Evaluation and Treatment of Severe Asthma

When a diagnosis of asthma is confirmed and comorbidities have been addressed, severe asthma is defined as “asthma which requires treatment with high dose inhaled corticosteroids (ICS) plus a second controller (and/or systemic CS) to prevent it from becoming “uncontrolled” or which remains “uncontrolled“ despite this therapy.”

Definition of Severe Asthma

Recommendation

CT chest

Sputum eosinophil count

Exhaled NO

Omalizumab

Methotrexate

Macrolide antibiotics

Antifungal agents

Bronchial thermoplasty

Questions



Guided by guidelines, what’s our Goal of managing this case?

GINA Goals For Asthma Management:

Achieve and maintain control of symptoms.

Maintain normal activity levels.

Prevent asthma mortality.

Maintain pulmonary function as close to normal.

Prevent asthma exacerbations.

Adapted from Global strategy for Asthma management and prevention guidelines 2012.

Goals for this case

Patient Goals

- Reduction in symptoms

- To improve quality of life.

- To complete college course.

HCP Goal

• Reduction in healthcare utilization

• Improvement in patient’s QoL.

• Reducing exacerbation frequency.

• Reduce the potential for repeated admissions

Questions




What is the classification for this case?

Level of Control:

Regarding the mentioned case:

He has daytime symptoms. (He misses college).

He has limitation of activities (Unable to participate in sports).

Regarding the nocturnal awakening. (He wakes up at the early morning) (3 to 4 times/week).

He uses his rescue treatment more than twice/week (5 to 6 times/week).

Lung function FEV1＜ 80% (FEV1 = 52%).

Levels of Asthma Control

Characteristics

Controlled

(All of the

following)

Partly controlled

(Any measure

present)

Uncontrolled

Daytime symptoms None (twice or

less/week)

More than

twice/week

Three or more

features of partly

controlled

asthma

Limitation of activities None Any

Nocturnal symptoms/

Awakening

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)

Assessment of current clinical control (preferably over 4 weeks)

Adapted from Global strategy for Asthma management and prevention guidelines 2012

Questions




What is the classification for this case?

How can we manage this case?

Treatment Options

Maintain Treatment

Step 4


Treatment according To guidelines:


Treatment Steps

Step 1 Step 2 Step 3 Step 4 Step 5

Asthma education

Environmental control

As needed rapid-

acting β2-agonist As needed rapid-acting β2-agonist

Controller options

Select one Select one To step 3 treatment,

select one or more To step 4 treatment,

add either

Low-dose ICS Low-dose ICS plus LABA Medium- or high-dose

ICS plus LABA Oral corticosteroid

(lowest dose)

Leukotriene modifier Medium- or high-dose ICS Leukotriene modifier Anti-IgE treatment

Low-dose ICS plus

Leukotriene modifier Sustained release

Theophylline

Low-dose ICS plus sustained

release Theophylline

Reduce Increase

The Mentioned Case Is Classified As:

•Uncontrolled (According to the GINA classification for the level of control).

•GINA step 5 (according to the treatment steps).

•Allergic(Atopic) (+ve skin test to 2 allergens).

Despite of taking his medications even with high doses regularly he is:

Treatment Options

Maintain Treatment

Step 4

Oral Corticosteroids




Treatment Steps


Asthma education


As needed rapid-


Controller options



add either



(lowest dose)


Low-dose ICS plus


Theophylline



Reduce Increase

Side effects of Oral Corticosteroids?!

OCS are used sparingly due to a broad array of serious adverse events including:

• Bone fractures

• Osteoporosis

• Susceptibility to infections

• Hyperglycemia

• Obesity

• Psychiatric condition

• Hypertension

• Skin condition

• Adrenal insufficiency

• Ocular condition

• Non-Hodgkin lymphoma

• Deep vein thrombosis

• Cardiac condition

• Weakness

• Abnormal hair growth

• Gastric condition

• Impaired growth

S.C. Manson et al. Respiratory Medicine (2009) 103, 975-994

Not only do the identified adverse events have a strong negative impact on the health of patients, but they also have economic and societal consequences as well.



Steroid avoidance became a key focus

As the multi-faceted negative consequences of OCS therapy are becoming better understood, the drive to find OCS substitutes becomes more urgent

Steroid avoidance has become a key focus in the effective management of patients treated with OCS



Treatment Options

Maintain Treatment

Step 4

Oral Corticosteroids

Anti-IgE




Treatment Steps


Asthma education


As needed rapid-


Controller options



add either



(lowest dose)


Low-dose ICS plus


Theophylline



Reduce Increase

What Is Anti-IgE (Xolair®) Treatment?

Murine MAb Humanized IgG

Xolair®

Humanizing the anti-IgE monoclonal antibody: Xolair®

5% murine residues

Allergic inflammation:

Eosinophils and lymphocytes

Asthma exacerbation

Omalizumab Mechanism of Action in IgE Mediated Asthma

Perennial aeroallergens

Allergic mediators

Omalizumab

1-Binds to free IgE, reducing

cell-bound IgE

2-Reduces high-affinity

receptors

4-Reduces asthma exacerbations and

symptoms

B lymphocyte

Release of IgE

Mast cells Basophils

Plasma cell

3-Reduces mediator release

Omalizumab

IgE

Xolair (Omalizumab) binds to the region of IgE that interact with IgE receptors

C3

region

Xolair interrupts the allergic cascade by inhibiting the crosslinking of IgE by allergen fragments.

Indication

Indication:

Xolair Basic Prescribing Information

Dose And Administration

Dosage and Administration:

The appropriate dose and dosing frequency of Xolair® is determined by baseline immunoglobulin E (IgE) (IU/mL), measured before the start of treatment, and body weight (kg).

Prior to initial dosing, patients should have their IgE level determined for their dose assignment.

Xolair® Basic Prescribing Information

Dosage and Administration (cont):

For subcutaneous administration (every 2 or 4 weeks) only in the deltoid region of the arm.

Alternatively, the injections can be administered in the thigh if there is any reason precluding administration in the deltoid region of the arm.


Dosage and Administration (cont):

Do not administer by the intravenous or intramuscular route.

There is limited experience in the self administration of Xolair®.

Therefore, treatment is intended to be administered by a healthcare professional.


Dosing:


Treatment duration, monitoring and dose adjustments

In clinical trials there were reductions in asthma exacerbation events and rescue medication use with improvements in symptom scores during the first 16 weeks of treatment.

At 16 week after commencing Xolair® therapy patients should be assessed by their physicians for treatment effectiveness before further injections are administered.



Discontinuation of treatment generally results in a return to elevated free IgE levels and associated symptoms.


Total IgE levels are elevated during treatment and remain elevated for up to one year after the discontinuation of treatment.

Therefore, re-testing of IgE levels during Xolair® treatment cannot be used as a guide for dose determination.



Dose determination after treatment interruptions lasting less than one year should be based on serum IgE levels obtained at the initial dose determination.

Total serum IgE levels may be re-tested for dose determination if treatment with Xolair® has been interrupted for one year or more.

Doses should be adjusted for significant body weight Changes.



Clinical Outcomes

INNOVATE

INvestigatioN of Omalizumab in seVere Asthma TrEatment

Humbert M, et al. Allergy 2005 (60): 309-316

The INNOVATE Study

• The primary objective of the INNOVATE study was to evaluate the effect of add-on omalizumab on asthma exacerbations in patients with severe persistent asthma who were inadequately controlled despite GINA step 4 therapy, which comprises high-dose ICS plus LABA and additional controller medication if required

Objective


Study design

Screening

tests

(7 days)

28 weeks

Omalizumab (n=209) or placebo

(n=210) as

add-on to GINA step 4 therapy

Off

study

drug

Randomization

Run-in phase

(8 weeks)

Follow-up

(16 weeks)

A 28-week randomized double-blind, placebo-controlled study


Omalizumab

(n=209)

Placebo

(n=210)

1.2

1.0

0.8

0.6

0.4

0.2

0

Clin

ically

sig

nific

ant

asth

ma

exace

rbatio

n r

ate

Omalizumab significantly reduces clinically significant exacerbations

26%

p=0.042


0.68

0.91

Xolair® Significantly Reduces Severe Exacerbation Rate


Xolair® Significantly Reduces Emergency Visits Due to Asthma Worsening


Xolair® Significantly Improved Overall QoL & Across All Domains

49% improvement in Overall QoL with Omalizumab


49% 40% 55% 51% 49%

Omalizumab was well tolerated

The percentage of patients who experienced adverse events (AEs) was similar in both treatment groups.

- Omalizumab, 72.2%; placebo, 75.5%

Fewer serious AEs in the Omalizumab group.

- Omalizumab, 11.8%; placebo, 15.6%

AEs were generally mild or moderate in nature and of short duration.


Italian Real Life Experience

M. Cazzola et al, Respiratory Medicine (2010) 104, 1410-1416

Study Design

A 12-month, prospective observational trial conducted in a real-life setting evaluating the efficacy of omalizumab as an add-on treatment in 142 patients with uncontrolled severe persistent allergic asthma.

Data was collected at baseline, month 4, 8 and 12.

The evaluation performed at the end of the study (month 12). Patients treated with omalizumab for at least 4 months (n =130).


With Xolair®: Effective reduction of emergency visits and hospitalizations


p < 0.001


Pooled analysis of seven trials (24-52 weeks long) were included on common study efficacy variables.

With objective of testing the association between the effect of OMA on need for rescue bursts of systemic steroids (SB).

4308 patients were in the pooled analysis (2511 OMA, 1797 control)

145

Maykut R, et al. J Allergy Clin Immunol 2006;117(2):S10,39 (abstract).

Xolair® significantly reduces the need for systemic corticosteroid bursts: Pooled Analysis.

0.4

0.6

Ste

roid

bu

rsts

(m

ea

n)

Omalizumab

(n=2,511)

Control

(n=1,797)

0.8

0.6

0.4

0.2

0

p<0.001

Maykut R, et al. J Allergy Clin Immunol 2006;117(2):S10,39 (abstract).

Relative risk: –43.0%

Conclusion

Xolair® is indicated for adults and children (6 years and above) with moderate to severe persistent allergic asthma whose symptoms are inadequately controlled with ICS.1

Omalizumab significantly reduces clinically significant exacerbations. 2

Xolair® Significantly Reduces Severe Exacerbation Rate.2


Allergy 2005;60:309–16

Conclusion

Xolair® Significantly Reduces Emergency Visits Due to Asthma Worsening.2

Xolair® Significantly Improved Overall QoL & Across All Domains.2

Xolair® Effectively reduced emergency visits and hospitalizations.

Xolair® significantly reduced the need for systemic corticosteroid bursts

1-Allergy 2005;60:309–16

2- M. Cazzola et al, Respiratory Medicine (2010) 104, 1410-1416

3- Maykut R, et al. J Allergy Clin Immunol 2006;117(2):S10,39 (abstract).

Case Study

Health & Medicine

Transcript of Case Study