case of 46 year old male with asthma...

Case of 46 year old male with asthma comorbidities

History (1)

• A 46 year old male, with past medical history significant for allergic rhino conjunctivitis, GERD (gastro esophageal reflux), hiatal hernia, OSA (obstructive sleep apnea) and a former smoker (20 pack year history) presents with an 8 month history of cough.

• He describes the cough as dry during daytime, but productive of clear sputum at night, often causing nocturnal awakenings.

• It is associated with chest tightness, wheezing, shortness of breath at rest and dyspnea on exertion (< 1 flight of stairs).

• At times he would feel chest pain prior to the onset of the cough, which he attributes to GERD.

Case available at: https://www.thoracic.org/professionals/clinical-resources/asthma-center/cases/asthma-comorbidities.php

https://www.thoracic.org/professionals/clinical-resources/asthma-center/cases/asthma-comorbidities.php

History (2)

• The patient feels that triggers of the cough include exercise, pollens, reflux symptoms and weather changes. Medications used in the past to treat these symptoms include inhaled combination ICS/LABA, which have provided poor relief of symptoms, and has since been discontinued.

• The patient has no contributing family history of asthma.



Physical exam and lab test result

Physical Exam

• No wheezing or other significant findings on exam. BMI of 32.4

Lab

• Initial spirometry showed reversible obstructive physiology, FEV1/FVC 0.64, FEV1 1.9L (60% predicted), and post-bronchodilator, the FEV1 increases to 2.2L (390cc, 15%).

• His skin prick testing showed positive wheal/flare reactions to dust mite, cat dander, tree, grass and weed pollens.



What should be assessed next for this patient? a. Asthma control

b. Treatment issues

c. Comorbidities

d. All of the above

Polling Question #1

Assessment of asthma

1. Asthma control - two domains• Assess symptom control over the last 4 weeks

• Assess risk factors for poor outcomes, including low lung function

2. Treatment issues• Check inhaler technique and adherence

• Ask about side-effects

• Does the patient have a written asthma action plan?

• What are the patient’s attitudes and goals for their asthma?

3. Comorbidities• Think of rhinosinusitis, GERD, obesity, obstructive sleep apnea, depression, anxiety

• These may contribute to symptoms and poor quality of life

GINA assessment of asthma controlA. Symptom control

In the past 4 weeks, has the patient had:Well-

controlled

Partly

controlled

Uncontrolled

• Daytime asthma symptoms more

than twice a week? Yes No

None of these1-2 of

these

3-4 of

these

• Any night waking due to asthma? Yes No

• Reliever needed for symptoms*

more than twice a week? Yes No

• Any activity limitation due to asthma? Yes No

B. Risk factors for poor asthma outcomes

• Assess risk factors at diagnosis and periodically

• Measure FEV1 at start of treatment, after 3 to 6 months of treatment to record the patient’s personal best, then

periodically for ongoing risk assessment

ASSESS PATIENT’S RISKS FOR:

• Exacerbations

• Fixed airflow limitation

• Medication side-effects

Level of asthma symptom control

Assessment of risk factors in poor asthma outcomeRisk factors for exacerbations include:

• Ever intubated for asthma

• Uncontrolled asthma symptoms

• Having ≥1 exacerbation in last 12 months

• Low FEV1 (measure lung function at start of treatment, at 3-6 months to assess personal best, and periodically

thereafter)

• Incorrect inhaler technique and/or poor adherence

• Smoking

• Elevated FeNO in adults with allergic asthma

• Obesity, pregnancy, blood eosinophilia

Risk factors for fixed airflow limitation include:

• No ICS treatment, smoking, occupational exposure, mucus hypersecretion, blood eosinophilia

Risk factors for medication side-effects include:

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

What is the right treatment for this patient?a. As needed SABA

b. Low dose ICS + as needed SABA

c. Low dose ICS/LABA + as needed SABA

d. Med/High dose ICS/LABA + as needed SABA

Polling Question #2

The control based asthma management cycle

Diagnosis

Symptom control & risk factors

(including lung function)

Inhaler technique & adherence

Patient preference

Asthma medications

Non-pharmacological strategies

Treat modifiable risk factors

Symptoms

Exacerbations

Side-effects

Patient satisfaction

Lung function

Inflammation plays a key role in the pathophysiology

of asthma

© 2018 GSK Group of Companies

Bousquet J et al. Am J Respir Crit Care Med 2000 May;161(5):1720-45. Syslová K et al. (2012). Determination of Biomarkers in Exhaled Breath Condensate:

A Perspective Way in Bronchial Asthma Diagnostics, Bronchial Asthma - Emerging Therapeutic Strategies, Dr. Elizabeth Sapey (Ed.), InTech

11

Inflammatory cell activation

(mast cells / macrophages)

Inflammatory

mediator releaseRelease of cytokines

and growth factorsTissue repair

and

remodelling

Smooth muscle and

mucus gland

proliferation

Airway

remodelling

Chronic inflammation

(exacerbations)

Acute inflammation

(Symptoms – bronchoconstriction)

Normal airway

Increased

bronchial

hyperreactivity

Epithelial

sheddingMucus secretion /

bronchoconstrictionVascular

permeability +

oedema

Pollutants

Bacteria

Viruses

Triggers

Th2High inflammation

– Eosinophyl is key effector of Th2 inflammation

– Sputum eosinophilia is a feature in up to 80% of

corticosteroid naive and 50% of corticosteroid treated

asthmatics.

– IL-4, IL-5,IL-9,IL-13 are critical to the regulation of

eosinophilic inflammation.

Th2low inflammation

– Th2low inflammation is mediated predominantly by non-

eosinophilic Th1 and Th17 pathway.

– Some asthmatics can switch between Th2 and Th17

inflammation profiles.

– Th17 cells produce IL-17A,IL-17F and IL-22.

Russel RJ, Brightling C Clin Science 2017;131:1723-1735

Insert your date / confidentiality text here4x3 core presentation 12

Airway inflammation

Step wise approach

Other

controller

options

RELIEVER

STEP 1 STEP 2STEP 3

STEP 4

STEP 5

Low dose ICS

Consider low

dose ICS Leukotriene receptor antagonists (LTRA)

Low dose theophylline*

Med/high dose ICS

Low dose ICS+LTRA

(or + theoph*)

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

Low dose

ICS/LABA**

Med/high

ICS/LABA

PREFERRED

CONTROLLER

CHOICE

Refer for add-on

treatment e.g.

tiotropium,*

anti-IgE, anti-IL5*

As-needed SABA or low dose ICS/formoterol#

Add tiotropium*

High dose ICS

+ LTRA

(or + theoph*)

Add low dose OCS

Management

• The patient was resumed on high dose ICS/LABA (Fluticasone/Salmeterol)

• Intranasal steroid spray was prescribed for his rhinitis.



Salmeterol Fluticasone combination improve patient quality of life and reduce symptom and exacerbation

15

Patients achieve near normal QoL with SFC vs. FP

This was a 1-year, stratified, randomised, double-blind, parallel-group study (n=3421 randomised) in patients (≥12 to <80 years) with persistent asthma who received either SFC (50/100

μg bid) and SFC (50/250 μg bid) up to a maximum of SFC (50/500 μg bid) or FP (100 μg bid) and FP (250 μg bid) up to a maximum of FP (500 μg bid).

AQLQ, Asthma Quality of Life Questionnaire; FP, fluticasone propionate; ICS, inhaled corticosteroid; SFC, salmeterol/fluticasone propionate combination; QoL Quality of life

The same results were first published in Bateman et al. Am J Respir Crit Care Med. 2004;170:836-844. This graph has been independently created by GSK from the original. 16

0

20

40

60

80

% p

ati

en

ts a

ch

ievin

g A

QL

Q

sc

ore

26

Quality of life for patients achieving a near-maximal (6)or maximum (7) AQLQ score

SFC

FP

Stratum 3

(moderate-dose ICS)

FP n=345 SFC n=346

Stratum 2

(low-dose ICS)

FP n=331 SFC n=339

Stratum 1

(steroid-naive)

FP n=275 SFC n=282

p=ns p<0.001p<0.005

A significantly higher percentage of patients achieving AQLQ score ≥6

for SFC versus FP in Stratums 2 and 3

More patients achieved guideline defined asthma control

was significantly greater with SFC versus FP

FP, fluticasone propionate; SFC, salmeterol/fluticasone propionate combination.

17

The odds of achieving well-controlled/totally controlled asthma at the same or lower dose of ICS for

SFC vs. FP in Stratum 1 increased by at least 40% (well-controlled: p=0.003; totally controlled:

p<0.001) and was more than double in both Stratum 2 (well-controlled and totally controlled: p<0.001)

and Stratum 3 (well-controlled and totally controlled: p<0.001).

The same results were first published in Bateman et al. Am J Respir Crit Care Med. 2004;170:836-844. These graphs have been independently created by GSK from the original.

0

20

40

60

80

100

Pa

tie

nts

(%

)

Totally controlled

SFC

FP

Stratum 1FP n=544

SFC n=539

Stratum 2FP n=577

SFC n=583

Stratum 3FP n=567

SFC n=568

0

20

40

60

80

100

Pa

tie

nts

(%

)

Well-controlled (primary endpoint)

SFC

FP

Stratum 1FP n=544

SFC n=539

Stratum 2FP n=577

SFC n=583

Stratum 3FP n=567

SFC n=568

* **

**

**

**

**

Percentage of patients with well-controlled (primary endpoint) or totally controlled asthma

*p=0.039

**p<0.001

This was a 1-year, stratified, randomised, double-blind, parallel-group study (n=3421 randomised) in patients (≥12 to <80 years) with persistent

asthma who received either SFC (50/100 μg bid) and SFC (50/250 μg bid) up to a maximum of SFC (50/500 μg bid) or FP (100 μg bid) and FP (250

μg bid) up to a maximum of FP (500 μg bid).

SFC provided more symptom-free days and a lower risk of

severe exacerbations vs. FP alone

These are post-hoc results from a 1-year, stratified, randomised, double-blind, parallel-group study (n=3416 ITT) in patients (≥12 to <80 years) with persistent asthma who received either

SFC (50/100 μg bid) and SFC (50/250 μg bid) up to a maximum of SFC (50/500 μg bid) or FP (100 μg bid) and FP (250 μg bid) up to a maximum of FP (500 μg bid).

OR and CI based on proportional odds logistic regression analysis.

CI, confidence interval; FP, fluticasone propionate; ITT, intent to treat; OR, odds ratio; SFC, salmeterol/fluticasone propionate combination

These figures were first published in Woodcock et al. Prim Care Respir J. 2007;16:155-161. These graphs have been independently created by GSK from the original. 18

SFC vs FP: †p=0.005; ± p<0.001; §p=0.025

0

10

20

30

40

50

60

70

80

90

100

Me

dia

n %

sym

pto

m-f

ree

da

ys

Weeks 1 to 52

Stratum 3

(moderate-dose ICS)

FP n=579

SFC n=576

Stratum 2

(low-dose ICS)

FP n=578

SFC n=585

Stratum 1

(steroid-naive)

FP n=550

SFC n=548

OR 1.30§

(96% CI: 1.08, 1.84)OR 2.06±

(96% CI: 1.66, 2.58)

OR 1.78±

(95% CI: 1.43, 2.21)

0

0.01

0.02

0.03

0.04

0.05

0.06

0.07

Me

an

ex

ac

erb

ati

on

rate

pe

r p

ati

en

t p

er

ye

ar

SFC FP

Stratum 3

(moderate-dose ICS)

FP n=579

SFC n=576

Stratum 2

(low-dose ICS)

FP n=578

SFC n=585

Stratum 1

(steroid-naive)

FP n=550

SFC n=548

Daytime symptoms Severe exacerbations

p=0.014

p=0.993

p=0.007

Regular maintenance dose v. Single maintenance and reliever therapy (SMART)

19

Outcome Maintenance and

reliever therapy

n/N

Regular maintenance

dosing (at a higher ICS

dose)

Odds Ratio

(95% CI)

P-value for

overall effect

Heterogeneity

Patients with

exacerbations requiring

oral steroids

342/4202

8.1%

516/4894

10.5%

0.75

[0.65, 0.87]

Z=3.85;

p=0.00012I2=0%

Patients with severe

exacerbations

(hospitalisation or ER

visit)

118/3321

3.6%

225/4447

5.1%

0.72

[0.57, 0.90]

Z=2.83;

p=0.0047

I2=0%

Patients with serious

adverse events

176/4215

4.2%

213/4915

4.3%

0.92

[0.74, 1.13]

Z=0.82;

p=0.41

I2=0%

Regular maintenance dosing vs. single maintenance and reliever therapy: Effects on exacerbations (4 studies)

• Data from double-blind randomized clinical trials

The same results were first published in Kew K et al. Cochrane Database Syst Rev 2013;Issue 12:CD009019. This graph has been independently created by GSK from the original. –20

• ICS: inhaled corticosteroid; LABA: long-acting β2-agonist; SABA: short-acting β2-agonist; ER: emergency room

Favours maintenance and reliever therapy Favours regular maintenance dosing

1.0 2.0 5.00.50.2

Outcome Maintenance and

reliever therapy

(n/N)

Regular

maintenance dosing

(n/N)

Odds Ratio

(95% CI)

P-value for

overall effect

Heterogeneity

Patients with

exacerbations

requiring oral

steroids

257/4433

5.8%

304/4408

6.9%

0.83

[0.70, 0.98]

Z=2.18;

p=0.03

I2=0%

Patients with

exacerbations

requiring

hospitalisation

21/4433

0.5%

26/4408

0.6%

0.81

[0.45, 1.44]

Z=0.72;

p=0.47

I2=0%

Discontinuation

due to adverse

events (AEs)

88/4224

4.2%

31/4187

4.3%

2.85

[1.89, 4.30]

Z=4.98;

p=0.00001

I2=0%

Regular dosing versus single maintenance and reliever therapy vs. current best practice

* Current best practice

AE: adverse events; ICS: inhaled corticosteroid; OCS: oral corticosteroids; LABA: long-acting β2-agonist; SABA: short-acting β2-agonist

The same results were first published in Cates C et al. Cochrane Database Syst Rev 2013;Issue 4:CD007313. This graph has been independently created by GSK from the original.

21

Favours regular

maintenance

and reliever therapy

1.0 3.0 10.00.30.1

Favours regular maintenance dosing*

Data from open-label randomised controlled trials (13 trials)

Continued impact on asthma symptoms following single maintenance and reliever therapy: 7 clinical studies

Weighted averages for asthma control endpoints at baselineand during maintenance and reliever therapy

• On average, patients on maintenance and reliever therapy:• needed reliever at least once per day,

• experienced nocturnal symptoms every 7–10 nights,

• were asymptomatic <50% of the study time, and

• rate of severe asthma exacerbation was ~one in five patients per year

* Severe exacerbation in this study was extended beyond the usual clinical definition to include not only a hospital or emergency department stay, but also a short course of prednisone or a decrease in morning PEF≥ 30% from baseline on 2 or more consecutive days

Chapman KR et al. Thorax 2010;65:747-752.

Total number of patients receiving Budesonide/formoterol maintenance and reliever therapy

6,603

Study durations 6-12 months

Asthma control endpoints Baseline Treatment

Symptom-free days (%) 13.2% 46.0%

As-needed reliever use (inhalations/day) 2.18 0.92

Reliever-free days (%) 14.7% 56.1%

Nights with awakenings due to asthma (%) 27.7% 11.5%

Severe exacerbations* (events/patient/year) 0.22

22

This is a weekly control measure. GINA: Global Initiative for Asthma; Patients all had ≥ 1 exacerbation in previous year.1. The same results were first published in Bateman E et al. J Allergy Clin Immunol. 2010;125:600–608. This graph has been

independently created by GSK from the original. 2. GSK DoF RF/SFC/0030/17. 3. Global Strategy for Asthma Management

and Prevention, Global Initiative for Asthma (GINA) 2018,

23

After 1 year of single maintenance and reliever therapy: 17% of asthma patients achieved guideline-defined asthma control1,2

17

37

46

A retrospective analysis of data from 5 studies: 5246 patients on maintenanceand reliever therapy assessed according to GINA-derived3 asthma control

Total control

Uncontrolled

Partial control

44

29

21

This is a weekly control measure.

At baseline, all patients had uncontrolled asthma (GINA-defined); mean exacerbation rate 0.6 events in previous yearExacerbations: Asthma requiring hospitalization and/or course of oral steroids or antibiotics

1. The same results were first published in Bateman E et al. Eur Respir J 2007;29(1):56–63 and 2. Bateman E, et al. Am J Respir Crit Care Med 2004;170:836-44. This graph has been independently created by GSK from the original. 3. GSK DoF RF/SFC/0031/17. 4. Global Strategy for Asthma Management and Prevention,

Global Initiative for Asthma (GINA) 2018, available from www.ginasthma.org.24

The Gaining Optimal Asthma control (GOAL) study1-3: 585 patients with moderate asthmataking fluticasone/salmeterol assessed according to GINA-defined4 asthma control

Total control

Uncontrolled

Partial control

Patients with GINA-defined asthma control maintain it after 1 year of regular maintenance therapy

http://www.ginasthma.org/

-60

-40

-20

0

20

40

60

80

100C

han

ge f

rom

bas

elin

e (%

)

One year of single maintenance and reliever therapy increased bronchial inflammation vs. regular maintenance ICS/LABA dosing

Bid: twice-daily; Bud/form: budesonide/formoterol; neut: neutrophil; mono: monocytes; lymph: lymphocytes; ICS: inhaled corticosteroids; LABA: Long-acting β2-agonist

The same results were first published in Pavord I et al. J Allergy Clin Immunol 2009;123(5):1083–1089. These graphs has been independently created by GSK from the original.

25

Endobronchial

biopsiesMore

inflammation

Mast

cellsEosinophils

p<0.001

Regular maintenance dosing (bud/form 640/9 µg bid) (n=58)Maintenance and reliever regimen (bud/form 160/4.5 µg bid + 160/4.5 µg) (n=60)

-60

-40

-20

0

20

40

60

80

100

Induced sputum

Eosinophils

p<0.0038

Ch

ange

fro

m b

asel

ine

(%)

Less

inflammation

2.25 (2.08)

4.00 (2.00)

4.71 (2.5)

Unscheduled visits Mean (SD)

Regular medication is associated with an improvement in outcomes in asthma patients

Data from an observational primary care questionnaire-led study derived over a three year period in 176 patients with asthmaAQLQ: Asthma Quality of Life Questionnnaire; SD: standard deviation

Medication pattern

Regular, n=16

Symptom-directed, n=9

Low-dosing, n=7

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

Regular Symptom-directed Low-dosing

Mea

n A

QLQ

sco

re

AQLQ score (mean [SD])

3.87 (1.44)

n=7

3.99 (1.29)

n=9

4.6 (1.58)

n=18

The same results were first published in Greaves CJ et al. PCRJ 2005;14:99-105. This graph has been independently created by GSK from the original. 26

For patients with moderate-to-severe asthma, regular adherence was the most effective treatment strategy, resulting in numerically better asthma quality of life scores and significantly less (p<0.001) unscheduled visits (around two less visits per three-year period)

How long should we follow up the patient asthma control?a. 1 week

b. 4-6 weeks

c. 1 month

d. 1-3 months

Polling Question #3

Reviewing response and adjusting treatment

• How often should asthma be reviewed?• 1-3 months after treatment started, then every 3-12 months

• During pregnancy, every 4-6 weeks

• After an exacerbation, within 1 week

When to consider step down treatment?a. After good control maintained for 1 months

b. After good control maintained for 2 months

c. After good control maintained for 3 months

d. After good control maintained for 6 months

Polling Question #4

Reviewing response and adjusting treatment

• Stepping down asthma treatment• Consider step-down after good control maintained for 3 months

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

Case continued…

• Symptoms improved on six month follow-up and due to being well controlled he was stepped down to a medium dose ICS/LABA.

• With step down his symptoms worsened at next six month follow-up.



Should we resume the treatment to high dose ICS/LABA?a. Yes

b. No

Polling Question #5

Stepping up asthma treatment

• Sustained step-up, for at least 2-3 months if asthma poorly controlled• Important: first check for common causes (symptoms not due to asthma,

incorrect inhaler technique, poor adherence)

• Short-term step-up, for 1-2 weeks, e.g. with viral infection or allergen• May be initiated by patient with written asthma action plan

• Day-to-day adjustment• For patients prescribed low-dose ICS/formoterol maintenance and reliever

regimen*

Case continued …

• He was resumed at high dose ICS/LABA.

• At the next follow-up he voiced that the cough had improved, but he still had symptoms of chest tightness, dyspnea on exertion. He also described a sensation of lung burning. He added that he was experiencing frequent episodes of GERD, despite being on BID dosing of omeprazole.



What’s next for the patient?a. Check inhaler technique

b. Address treatment issues

c. Manage comorbidities

d. All of the above

Polling Question #6

Managing asthma with comorbidities

• Identify and manage comorbidities such as rhinosinusitis, obesity and gastro-esophageal reflux disease.

• Comorbidities may contribute to respiratory symptoms and impaired quality of life, and some contribute to poor asthma control

Case continued …

• The patient was referred to gastroenterology (GI) and cardiology. Cardiology ruled out CAD via stress testing and commented that chest tightness was likely related to his reflux.

• GI commented that the patient had gained an additional 20 lbs in the last year.

• They switched the patient to maximal dose of BID esomeprazole, encouraged him to lose weight and ordered eesophageal manometry, pH monitoring and an EGD.

• The patient improved marginally with weight loss



Case continued …

• He returned for follow-up 5 months after his procedure, his coughing was minimal, dyspnea was much improved and he reported no use of his as needed SABA. He was stepped down to medium dose ICS/LABA.

• The patient called 2 months later, reporting that he had no residual cough and enquired if he may stop his ICS/LABA.



Should we step down the ICS/LABA?a. Yes

b. No

Polling Question #7

Case continued …

• He was advised to continue current regimen until next follow-up, at which time we stepped down to low dose ICS/LABA.

• We ultimately discontinued his ICS/LABA due to resolution of cough, chest tightness and SOB. He continues on as needed SABA.



Thank you

case of 46 year old male with asthma...

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