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Asthma UpdateNEETA THAKUR MD, MPH ZUC KERBERG SAN FR ANCI SCO G ENERAL

UNIV ERSITY OF CAL IFOR NIA, SAN FR ANC ISCO

M AY 11, 2 018

Disclosure(s)Spouse employed by Roche/Genentech

Learning Objectives•To review updates in Asthma

• Screening• Categorizing • Treatment

• Non-pharmacologic therapies• Managing severe asthma and when to refer

•A paradigm switch: What are asthma phenotypes?

What is asthma?- Tightening of Airways- Airway Remodeling- Thick Mucus Production- Acute and Chronic Phases

- Wheezing- Coughing- Shortness of Breath

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What is asthma? Asthma can be effectively treated~ 80% managed in primary care

When asthma is well-controlled, patients can• Avoid troublesome symptoms• Need little or no reliever medication• Have productive, physically active lives• Have normal or near-normal lung function• Avoid serious asthma exacerbations

Does NOT equal symptom-free

Diagnosis

The diagnosis of asthma should be based on:◦ Characteristic symptom patterns ◦ Evidence of variable airflow limitation

◦ bronchodilator reversibility testing

Document evidence for the diagnosis◦ Preferably before starting controller treatment◦ Difficult to confirm diagnosis after treatment has been started

Diagnosis of asthma

GINA 2017 © Global Initiative for Asthma© Global Initiative for AsthmaGINA 2017, Box 1-1 (1/4)

Further history and tests for alternative

diagnosesNO

NO

Treat for alternative diagnosis

YES

YES

YES

YES

Patient with respiratory symptoms

Detailed history/ examination for asthma

Perform spirometry/PEF with

reversibility test

Treat for ASTHMA

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© Global Initiative for Asthma

YES

YES

© Global Initiative for AsthmaGINA 2017, Box 1-1 (1/4)

Perform spirometry/PEF with reversibility test

Patient with respiratory symptoms

Detailed history/ examination for asthma

Note: Each FEV1represents the highest of three reproducible measurements

FEV1

Flow (L/s)

Volume (L)

Normal

Asthma (after BD)

Asthma (before BD)

1 2 3 4 5

Is it Asthma?

• History of variable symptoms• Evidence of variable expiratory

airflow limitation • FEV1/FVC <70%• Diurnal variability• Bronchodilator response (12%)

• Physical Exam• Usually normal• Forced expiratory maneuver

© Global Initiative for Asthma© Global Initiative for AsthmaGINA 2017, Box 1-1 (1/4)

Repeat on another occasion or arrange other

tests. Confirms asthma diagnosis?

Consider trial of treatment for most likely

diagnosis? or refer for further investigations

NO

YES

NO

Further history and tests for alternative

diagnosesNO

NO

Treat for alternative diagnosis

YES

YES

YES

YES

Patient with respiratory symptoms

Detailed history/ examination for asthma

Perform spirometry/PEF with

reversibility test

Treat for ASTHMA

© Global Initiative for Asthma© Global Initiative for AsthmaGINA 2017, Box 1-1 (1/4)

Clinical urgency AND

other diagnoses unlikely

Empiric treatment with

ICS and prn SABAReview responseDiagnostic testing within 1-3 months

Repeat on another occasion or arrange other

tests. Confirms asthma diagnosis?

Consider trial of treatment for most likely

diagnosis? or refer for further investigations

NO

YES

NO

Further history and tests for alternative

diagnosesNO

NO

Treat for alternative diagnosis

YES

YES

YES

Patient with respiratory symptoms

Detailed history/ examination for asthma

Perform spirometry/PEF with

reversibility test

Treat for ASTHMA

YES

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Diagnosis of asthma – symptoms

GINA 2017

Increased probability:• More than one type of symptom

Symptoms worse at night/early AM• Symptoms vary (time and in

intensity)• Symptoms are triggered

Decreased probability:• Isolated cough with no other

respiratory symptoms• Chronic production of sputum• Shortness of breath associated with

dizziness, light-headedness or peripheral tingling

• Chest pain• Exercise-induced dyspnea with

noisy inspiration (stridor)

Treatment

The control-based asthma management cycle

GINA 2017, Box 3-2

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

Assessing Asthma ControlAsthma Control Test

- Free, quick

- Age-based questionnaire

- Follow over time

- Use to guide treatment

- Cut-point to know: 20

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Non-Pharmacological Interventions

I’ve got 3 inhalers, they all work the same?

Ok…well I will use a spacer, that works?

True or False

True or FalseFalse

False

The who, what, where, when, and why of inhalers?

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How they work

Metered Dosed Inhalers (MDI)

Soft Mist InhalersDry Powder

InhalersNebulizer

Aerosol PRODUCED for you – breath slowly

You CREATE aerosol –breath forcefully

Provide hands-on inhaler skills trainingChoose

• Choose an appropriate device before prescribing • Avoid multiple different inhaler types if possible

Provide hands-on inhaler skills trainingChoose

• Choose an appropriate device before prescribing • Avoid multiple different inhaler types if possible

Check

• Check technique at every opportunity

“Can you show me how you use your inhaler?”• Identify errors with a device-specific checklist

Provide hands-on inhaler skills trainingChoose

• Choose an appropriate device before prescribing • Avoid multiple different inhaler types if possible

Check

• Check technique at every opportunity• Identify errors with a device-specific checklistCorrect

• Give a physical demonstration to show how to use the inhaler correctly

Confirm

• Can you demonstrate correct technique for the inhalers you prescribe?

• Re-check inhaler technique frequently (4-6 weeks)

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Why? When combined with self-monitoring and regular medical review, action plans are highly effective in reducing asthma mortality and morbidity

All patients should have a written asthma action plan

◦ Recognize and Respond◦ Individualized: medications, level of

asthma control and health literacy◦ Based on symptoms and/or PEF

The action plan should include: ◦ Usual asthma medications◦ When/how to increase reliever and

controller or start OCS◦ How to access medical care if

symptoms fail to respond

Pharmacological Interventions

Choosing between controller options Decisions for individual patientsUse shared decision-making with the patient/parent/carer to discuss the following:

1. Preferred treatment for symptom control and for risk reduction2. Patient characteristics (phenotype)

• Does the patient have any known predictors of risk or response? (e.g. smoker, history of exacerbations, blood eosinophilia)

3. Patient preference• What are the patient’s goals and concerns for their asthma?

4. Practical issues• Inhaler technique - can the patient use the device correctly after training?• Adherence: how often is the patient likely to take the medication?• Cost: can the patient afford the medication?

GINA 2017, Box 3-3 (2/2)

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Step-wise Management

STEP 1

PREFERRED CONTROLLER

CHOICE

Other controller

options

RELIEVER As-needed short-acting beta2-agonist (SABA)As-needed SABA or low dose ICS/formoterol

Consider low dose ICS

Low dose ICS

STEP 2

STEP 3

STEP 4

STEP 5

Low dose ICS/LABA

Leukotriene receptor antagonists (LTRA),

Low dose theophylline

Med/high dose ICS,Low dose ICS+LTRA

(or + theophylline)

Med/high ICS/LABA

Add tiotropium, High dose ICS + LTRA (or + theophylline)

Refer for add-on

treatment e.g.

tiotropium, anti-IgE, anti-IL5

Add low dose OCS

Where to start? Based on symptoms & severityWhen to go UP or DOWN? Based on control

Step-wise Management

STEP 1

PREFERRED CONTROLLER

CHOICE

Other controller

options

RELIEVER As-needed short-acting beta2-agonist (SABA)As-needed SABA or low dose ICS/formoterol

Consider low dose ICS

Low dose ICS

STEP 2

STEP 3

STEP 4

STEP 5

Low dose ICS/LABA

Leukotriene receptor antagonists (LTRA),

Low dose theophylline

Med/high dose ICS,Low dose ICS+LTRA

(or + theophylline)

Med/high ICS/LABA

Add tiotropium, High dose ICS + LTRA (or + theophylline)

Refer for add-on

treatment e.g. SLIT,

tiotropium, anti-IgE, anti-IL5

Add low dose OCS

How often should asthma be reviewed?Reassess every:• 1-3 months after treatment started, then every 3-12 months• After an exacerbation, within 1 week

Stepping up asthma treatment◦ Sustained step-up, for at least 2-3 months if asthma poorly controlled◦ Short-term step-up, for 1-2 weeks, e.g. with viral infection or allergen

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

Step UP or Step DOWNConsider stepping up if …

- Uncontrolled symptoms

- Exacerbations or risks

**First Check- Is this the right diagnosis?

- Inhaler technique

- Adherence first

Consider stepping down if …

- Symptoms controlled for 3 months - Low risk for exacerbations

*** Ceasing ICS is not advised.

SustainedVs.

Short-Term?25%

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Patients at increased risk of asthma-related death should be identified◦ Any history of near-fatal asthma requiring intubation and ventilation◦ Hospitalization or emergency care in last 12 months◦ Not currently using ICS, or poor adherence with ICS◦ Recent oral steroid use◦ Over-use of SABAs (more than 1 canister/month)◦ NO written asthma action plan◦ Psychiatric disease or psychosocial problems◦ Confirmed food allergy

Flag these patients for more frequent review

Identify patients at risk of asthma-related death

GINA 2017, Box 4-1

Identifying Severe/Refractory asthmaContinuous or near-continuous oral steroidsHigh-dose ICS

Additional daily controllerUse of SABA on a near-daily basisPersistent airway obstructionFEV1 < 80%Diurnal variation in PF ≥ 25%≥ 1 urgent care visit per year≥3 or more steroid bursts per yearPrompt deterioration with 25% reduction in steroid doseEpisode of near-fatal asthma

Minor(2)

Major(≥1)

ATS AJRCCM 2000; 162:2341-51

Asthma is a complex diseasePhenotypes

WENZEL NATURE MEDICINE VOLUME 18, PAGES 716–725 (2012)

Asthma Phenotypes

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Non-eosinophilicCh

ildho

od

Adul

t

Eosinophilic

Asthma Phenotypes

Dust mites Pollens

EosinophilsElevated in bronchial bx, induced sputum, or peripheral bloodCorticosteroid naïve patients: ≥2.7% (blood)Who has high Eos?o“Childhood-onset” and allergy to airborne allergens

Who does Not?o“Late-onset” non-atopic disease

Associated with?oPersistence on high-dose ICS or PO steroids associated with

symptomatic and exacerbation-prone disease

Non-eosinophilic

Child

hood

Adul

t

Eosinophilic

Asthma Phenotypes

Allergic Intrinsic

Dust mites Pollens

How do you identify this group?Total IgE

Sum of total IgESometimes reported as %total IgG (0.05% normal)60% of allergic asthma (includes HMW OA)Poor PPV and NPV compared to allergen-specific IgE

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Dust mites Pollens

How do you identify this group? Skin prick allergy testingFalse negatives:–OTC antihistamines (48 hours)–Allegra, Clarinex, Zyrtec and Astelin (Azelastin) nasal spray (5 days)–PO steroids (25 mg prednisone) (3 weeks)–High dose topical steroids (3 weeks)

Dust mites Pollens

How do you identify this group? Radioallergosorbant IgE (RAST)Allergen-specific IgELess sensitive and specific than skin testingRational starting point:–Specific HMW candidate antigen(s) (some LMW antigens)–Determine positive aeroallergen–Grasses, weeds, dust mites, molds–Low predictive value for food allergies

What’s the Asthma Phenotype?Occupational Asthma

Beckett W., et al., NEJM 2000

Occupational Asthma“Work-sensitized” (high MW >5000 daltons)

IgE-mediated “asthma with latency”

“Irritant-induced” (low MW <5000 daltons)Non IgE-mediated “asthma without latency”Irritant asthmaReactive airways dysfunction syndrome (RADS)“Low-dose RADS”

“Work-exacerbated” (aggravated)> 250 workplace culprit substances

Estimated 16% of all adult onset asthma

Toren and Blanc 2009

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What do these have in common? When to do obstruction testing for Occupational Asthma?Preferably performed toward the end of a typical work week and within 24 hr of the occurrence of symptoms

Active panel patients with DMNon-eosinophilic

Occupational (non-sensitized)

Asthma Phenotypes

Child

hood

Allergic IntrinsicAdult

Eosinophilic

Occupational (sensitized)

What’s the Asthma Phenotype?

34 year old man

Persistent rhinitis at age 30, watery rhinorrhea

Cough, wheeze

Sudden acute event requiring ED visit

No previous history of asthma

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B. Ghorayeb, MD

Asthma-Exacerbated Asthma

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Aspirin-Exacerbated Asthma: diagnosisReferral to Specialist

•Exacerbation after ingestion of aspirin or other non-NSAIDs

•Starts with intractable nasal congestion and watery rhinorrhea

•Refractory to pharmacologic treatment (benefit with leukotriene inhibitors)

•Specific IgE tests negative

•Treatment may include desensitization to aspirin

Active panel patients with DMNon-eosinophilic

Child

hood Adult

EosinophilicAspirin

Cough variant

Air pollution

Asthma Phenotypes

Allergic Intrinsic

Occupational (sensitized)

Occupational (non-sensitized)

EIACigarette

Leiria, 2014

Obese Asthma Phenotype

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Active panel patients with DMNon-eosinophilic

Child

hood Adult

EosinophilicAspirin

Cough variant

Air pollution

Asthma Phenotypes

Allergic Intrinsic

Occupational (sensitized)

Occupational (non-sensitized)

EIACigarette

Infection-related

Obesity

Active panel patients with DMNon-eosinophilic

Child

hood Adult

EosinophilicAspirin

Cough variant

Air pollution

Asthma Phenotypes

Allergic Intrinsic

Occupational (sensitized)

Occupational (non-sensitized)

EIACigarette

Infection-related

Obesity

Exacerbation-prone

Treatment Options Based on Phenotypes

TARGETED AT Th2 (ALLERGIC) ASTHMA

Treatments based on Phenotypes -OmalizumabBest Candidates:

High IgE

Known Allergen

BMI

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Hanania Ann Intern Med 2011, Busse NEJM 2011

Treatments based on Phenotypes - Omalizumab

Asthma Exacerbations

25% reduction

IL-5: Key cytokine in eosinophil oDifferentiationoRecruitmentoActivationoSurvival

Best Candidates:o- High Eosinophilso- 2 or greater exacerbations/yro- On high dose ICS

Fulkerson Nature Review Drug Discovery 2013

Treatments based on Phenotypes – Anti-IL5/IL5R

MENSA trial (RCT), selected for high eosinophils, mod-high dose ICS

Treatments based on Phenotypes -Mepolizumab

Asthma Exacerbations and FEV1 at 32 Weeks.

Ortega NEJM 2014 (Sponsored by Glaxo-Smith Kline)

50% reduction

Side Effects and Adverse ReactionsOmalizumab

Anaphylaxis (must have epi-pen)◦ 0.1-0.2% ◦ Can occur as late as 1 year

? Malignancy (0.5 vs. 0.2% in RCT)◦ Longer observation trials underway

Pain and arthralgia

Injection site bruising/pain

Mepolizumab/Anti-IL5 Therapy

No observed risk of anaphylaxis

Muscle pain

Fatigue

Injection site bruising/pain

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In SummaryASTHMA IS COMPLEX!!!

But majority can be controlled in primary care

Look at multiple data points, including◦ Age◦ Patient specific data: BMI, occupation ◦ Triggers◦ Disease course◦ Biomarkers