G IN A: Lobal I'a've For Sthma

G lobal

IN i'a've for
A sthma
© Global Initiative for Asthma
Burden of asthma
•  Asthma is one of the most common chronic diseases worldwide
with an es'mated 300 million affected individuals
•  Prevalence is increasing in many countries, especially in children
•  Asthma is a major cause of school and work absence
•  Health care expenditure on asthma is very high
–  Developed economies might expect to spend 1-‐2 percent of total
health care expenditures on asthma.
–  Developing economies likely to face increased demand due to
increasing prevalence of asthma
–  Poorly controlled asthma is expensive
–  However, investment in preven'on medica'on is likely to yield cost
savings in emergency care
GINA 2015
Prevalence of asthma in children aged
13-14 years
© Global
GINA 2015 Appendix Box A1-1; figure provided by Initiative for Asthma
R Beasley © Global Initiative for Asthma
Definition and diagnosis of
asthma
GINA Global Strategy for Asthma

Management and Prevention 2015
This slide set is restricted for academic and educa'onal purposes only.
Use of the slide set, or of individual slides, for commercial or promo'onal
purposes requires approval from GINA.

What is known about asthma?
•  Asthma is a common and poten'ally serious chronic
disease that can be controlled but not cured
•  Asthma causes symptoms such as wheezing, shortness of
breath, chest 'ghtness and cough that vary over 'me in
their occurrence, frequency and intensity
•  Symptoms are associated with variable expiratory airflow,
i.e. difficulty breathing air out of the lungs due to
–  Bronchoconstric'on (airway narrowing)
–  Airway wall thickening
–  Increased mucus
•  Symptoms may be triggered or worsened by factors such as
viral infec'ons, allergens, tobacco smoke, exercise and
stress
GINA 2015
What is known about asthma?
•  Asthma can be effec'vely treated
•  When asthma is well-‐controlled, pa'ents can
ü Avoid troublesome symptoms during the day and night
ü Need liVle or no reliever medica'on
ü Have produc've, physically ac've lives
ü Have normal or near-‐normal lung func'on
ü Avoid serious asthma flare-‐ups (also called exacerba'ons,
or severe aVacks)
GINA 2015
Defini'on of asthma
Asthma is a heterogeneous disease, usually characterized by
chronic airway inflamma'on.

It is defined by the history of respiratory symptoms such as
wheeze, shortness of breath, chest 'ghtness and cough that vary
over 'me and in intensity, together with variable expiratory
airflow limita'on.
GINA 2015
Diagnosis of asthma
•  The diagnosis of asthma should be based on:
–  A history of characteris'c symptom paVerns
–  Evidence of variable airflow limita'on, from
bronchodilator reversibility tes'ng or other tests
•  Document evidence for the diagnosis in the pa'ent’s
notes, preferably before star'ng controller treatment
–  It is o[en more difficult to confirm the diagnosis a[er
treatment has been started
•  Asthma is usually characterized by airway
inflamma'on and airway hyperresponsiveness, but
these are not necessary or sufficient to make the
diagnosis of asthma.
GINA 2015
Patient with
respiratory symptoms
Are the symptoms typical of asthma?
YES
Detailed history/examination
for asthma
History/examination supports
asthma diagnosis?
YES
Perform spirometry/PEF
with reversibility test
Results support asthma diagnosis?
YES
Treat for ASTHMA
GINA 2015, Box 1-1 (1/4) ©

© Global
Global Initiative
Initiative for
for Asthma
Asthma
Patient with
NO
YES
for asthma
asthma diagnosis?
Further history and tests for
NO alternative diagnoses
YES Alternative diagnosis confirmed?
YES YES
Treat for ASTHMA Treat for alternative diagnosis
GINA 2015, Box 1-1 (2/4) ©

© Global
Global Initiative
Initiative for
for Asthma
Asthma
Patient with
NO
YES
for asthma
asthma diagnosis?
Repeat on another
NO
occasion or arrange
NO
YES other tests
Confirms asthma diagnosis?
YES NO YES
Consider trial of treatment for

most likely diagnosis, or refer
for further investigations
GINA 2015, Box 1-1 (3/4) ©

© Global
Global Initiative
Initiative for
for Asthma
Asthma
Patient with
NO
YES
for asthma
asthma diagnosis?
Clinical urgency, and
other diagnoses unlikely
Repeat on another
NO
occasion or arrange
NO
YES other tests
Confirms asthma diagnosis?
Empiric treatment with YES NO YES

ICS and prn SABA
Review response
Consider trial of treatment for
Diagnostic testing most likely diagnosis, or refer
within 1-3 months for further investigations
GINA 2015, Box 1-1 (4/4) ©

© Global
Global Initiative
Initiative for
for Asthma
Asthma
Diagnosis of asthma – symptoms
•  Increased probability that symptoms are due to asthma if:
–  More than one type of symptom (wheeze, shortness of breath, cough, chest
'ghtness)
–  Symptoms o[en worse at night or in the early morning
–  Symptoms vary over 'me and in intensity
–  Symptoms are triggered by viral infec'ons, exercise, allergen exposure,
changes in weather, laughter, irritants such as car exhaust fumes, smoke, or
strong smells
•  Decreased probability that symptoms are due to asthma if:
–  Isolated cough with no other respiratory symptoms
–  Chronic produc'on of sputum
–  Shortness of breath associated with dizziness, light-‐headedness or peripheral
'ngling
–  Chest pain
–  Exercise-‐induced dyspnea with noisy inspira'on (stridor)
GINA 2015
Diagnosis of asthma – variable airflow
limita'on
•  Confirm presence of airflow limita'on
–  Document that FEV1/FVC is reduced (at least once, when FEV1 is low)
–  FEV1/ FVC ra'o is normally >0.75 – 0.80 in healthy adults, and
>0.90 in children
•  Confirm varia'on in lung func'on is greater than in healthy individuals
–  The greater the varia'on, or the more 'mes varia'on is seen, the greater
probability that the diagnosis is asthma
–  Excessive bronchodilator reversibility (adults: increase in FEV1 >12% and
>200mL; children: increase >12% predicted)
–  Excessive diurnal variability from 1-‐2 weeks’ twice-‐daily PEF monitoring (daily
amplitude x 100/daily mean, averaged)
–  Significant increase in FEV1 or PEF a[er 4 weeks of controller treatment
–  If ini'al tes'ng is nega've:
•  Repeat when pa'ent is symptoma'c, or a[er withholding bronchodilators
•  Refer for addi'onal tests (especially children ≤5 years, or the elderly)
GINA 2015, Box 1-‐2

Typical spirometric tracings
Volume Flow
Normal
FEV1
Asthma
(a[er BD)
Normal
Asthma
(before BD) Asthma
(a[er BD)
Asthma
(before BD)
1 2 3 4 5 Volume
Time (seconds)
Note: Each FEV1 represents the highest of
three reproducible measurements
GINA 2015 © Global Initiative for Asthma

Diagnosis of asthma – physical
examina'on
•  Physical examina'on in people with asthma
–  O[en normal
–  The most frequent finding is wheezing on ausculta'on,
especially on forced expira'on
•  Wheezing is also found in other condi'ons, for example:
–  Respiratory infec'ons
–  COPD
–  Upper airway dysfunc'on
–  Endobronchial obstruc'on
–  Inhaled foreign body
•  Wheezing may be absent during severe asthma
exacerba'ons (‘silent chest’)
GINA 2015
Assessment of asthma


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
func'on
2.  Treatment issues
–  Check inhaler technique and adherence
–  Ask about side-‐effects
–  Does the pa'ent have a wriVen asthma ac'on plan?
–  What are the pa'ent’s aotudes and goals for their asthma?
3.  Comorbidi'es
–  Think of rhinosinusi's, GERD, obesity, obstruc've sleep apnea,
depression, anxiety
–  These may contribute to symptoms and poor quality of life
GINA 2015, Box 2-‐1

GINA assessment of symptom control
A. Symptom control Level of asthma symptom control

Well- Partly Uncontrolled
In the past 4 weeks, has the patient had:
controlled controlled
•  Daytime asthma symptoms more
than twice a week?
Yesq Noq
•  Any night waking due to asthma?
Yesq Noq None of 1-2 of 3-4 of

•  Reliever needed for symptoms* these these these
more than twice a week?
*Excludes reliever taken before exercise, because many people take this rou'nely
Yesq Noq
This classifica'on
•  Any activity limitation is the same as the GINA 2010-‐12 assessment
due to asthma?
of ‘current control’, except that lung func'on now appears only
Yesq Noq in the assessment of risk factors
GINA 2015, Box 2-‐2A © Global Initiative for Asthma

GINA assessment of symptom control
Level of asthma symptom control
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
GINA 2015 Box 2-‐2B (1/4) © Global Initiative for Asthma

Assessment of risk factors for poor asthma
outcomes
Risk 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
•  Obesity, pregnancy, blood eosinophilia
GINA 2015, Box 2-2B (2/4) © Global Initiative for Asthma

outcomes
•  Smoking
Risk factors for fixed airflow limitation include:
•  No ICS treatment, smoking, occupational exposure, mucus
hypersecretion, blood eosinophilia

outcomes
•  Smoking
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

The role of lung func'on in asthma
•  Diagnosis
–  Demonstrate variable expiratory airflow limita'on
–  Reconsider diagnosis if symptoms and lung func'on are discordant
•  Frequent symptoms but normal FEV1: cardiac disease; lack of fitness?
•  Few symptoms but low FEV1: poor percep'on; restric'on of lifestyle?
•  Risk assessment
–  Low FEV1 is an independent predictor of exacerba'on risk
•  Monitoring progress
–  Measure lung func'on at diagnosis, 3-‐6 months a[er star'ng treatment
(to iden'fy personal best), and then periodically
–  Consider long-‐term PEF monitoring for pa'ents with severe asthma or
impaired percep'on of airflow limita'on
•  Adjus'ng treatment?
–  U'lity of lung func'on for adjus'ng treatment is limited by between-‐visit
variability of FEV1 (15% year-‐to-‐year)
GINA 2015
Assessing asthma severity
•  How?
–  Asthma severity is assessed retrospec'vely from the level of
treatment required to control symptoms and exacerba'ons
•  When?
–  Assess asthma severity a[er pa'ent has been on controller treatment
for several months
–  Severity is not sta'c – it may change over months or years, or as
different treatments become available
•  Categories of asthma severity
–  Mild asthma: well-‐controlled with Steps 1 or 2 (as-‐needed SABA or low
dose ICS)
–  Moderate asthma: well-‐controlled with Step 3 (low-‐dose ICS/LABA)
–  Severe asthma: requires Step 4/5 (moderate or high dose ICS/LABA ±
add-‐on), or remains uncontrolled despite this treatment
GINA 2015
Treating asthma to control
symptoms and minimize risk


Goals of asthma management
•  The long-‐term goals of asthma management are
1.  Symptom control: to achieve good control of symptoms
and maintain normal ac'vity levels
2.  Risk reducAon: to minimize future risk of exacerba'ons,
fixed airflow limita'on and medica'on side-‐effects
•  Achieving these goals requires a partnership between
pa'ent and their health care providers
–  Ask the pa'ent about their own goals regarding their
asthma
–  Good communica'on strategies are essen'al
–  Consider the health care system, medica'on availability,
cultural and personal preferences and health literacy
GINA 2015
Trea'ng to control symptoms and
minimize risk
•  Establish a pa'ent-‐doctor partnership
•  Manage asthma in a con'nuous cycle:
–  Assess
–  Adjust treatment (pharmacological and
non-‐pharmacological)
–  Review the response
•  Teach and reinforce essen'al skills
–  Inhaler skills
–  Adherence
–  Guided self-‐management educa'on
•  WriVen asthma ac'on plan
•  Self-‐monitoring
•  Regular medical review
GINA 2015
The control-‐based asthma
management cycle
Diagnosis
Symptom control & risk factors
(including lung function)
Inhaler technique & adherence
Patient preference
Symptoms
Exacerbations
Side-effects
Patient satisfaction
Lung function
Asthma medications
Non-pharmacological strategies
Treat modifiable risk factors
GINA 2015, Box 3-2

Choosing between controller options –
population-level decisions
Choosing between treatment options at a population level
e.g. national formularies, health maintenance organisations, national guidelines
The ‘preferred treatment’ at each step is based on:

§  Efficacy
based on group mean data for symptoms, exacerba'ons and lung
§  Effec'veness func'on (from RCTs, pragma'c studies and observa'onal data)
§  Safety
§  Availability and cost at the popula'on level
GINA 2015, Box 3-‐3 (1/2) Provided by H Reddel © Global Initiative for Asthma
Choosing between controller options –
individual patient decisions
Decisions for individual patients
Use shared decision-‐making with the pa'ent/parent/carer to discuss the following:
1.  Preferred treatment for symptom control and for risk reduc'on
2.  Pa'ent characteris'cs (phenotype)
•  Does the pa'ent have any known predictors of risk or response?
(e.g. smoker, history of exacerba'ons, blood eosinophilia)
3.  Pa'ent preference
•  What are the pa'ent’s goals and concerns for their asthma?
4.  Prac'cal issues
•  Inhaler technique -‐ can the pa'ent use the device correctly a[er training?
•  Adherence: how o[en is the pa'ent likely to take the medica'on?
•  Cost: can the pa'ent afford the medica'on?
GINA 2015, Box 3-‐3 (2/2) Provided by H Reddel © Global Initiative for Asthma
Ini'al controller treatment for adults,
adolescents and children 6–11 years
•  Start controller treatment early
–  For best outcomes, ini'ate controller treatment as early as possible a[er
making the diagnosis of asthma
•  Indica'ons for regular low-‐dose ICS -‐ any of:
–  Asthma symptoms more than twice a month
–  Waking due to asthma more than once a month
–  Any asthma symptoms plus any risk factors for exacerba'ons
•  Consider star'ng at a higher step if:
–  Troublesome asthma symptoms on most days
–  Waking from asthma once or more a week, especially if any risk factors for
exacerba'ons
•  If ini'al asthma presenta'on is with an exacerba'on:
–  Give a short course of oral steroids and start regular controller treatment (e.g.
high dose ICS or medium dose ICS/LABA, then step down)
GINA 2015, Box 3-‐4 (1/2)

Ini'al controller treatment
•  Before star'ng ini'al controller treatment
–  Record evidence for diagnosis of asthma, if possible
–  Record symptom control and risk factors, including lung
func'on
–  Consider factors affec'ng choice of treatment for this pa'ent
–  Ensure that the pa'ent can use the inhaler correctly
–  Schedule an appointment for a follow-‐up visit
•  A[er star'ng ini'al controller treatment
–  Review response a[er 2-‐3 months, or according to clinical
urgency
–  Adjust treatment (including non-‐pharmacological treatments)
–  Consider stepping down when asthma has been well-‐
controlled for 3 months
GINA 2015, Box 3-‐4 (2/2)

Stepwise approach to control asthma
symptoms
and reduce risk
Diagnosis
Patient preference
Symptoms
Exacerbations
Asthma medications
Side-effects
Non-pharmacological strategies
Patient satisfaction
Treat modifiable risk factors
Lung function
STEP 5
STEP 4
PREFERRED STEP 3 Refer for

STEP 1 STEP 2 add-on
CONTROLLER
treatment
CHOICE Med/high e.g.
ICS/LABA anti-IgE
Low dose
Low dose ICS ICS/LABA*
Other
Consider low Leukotriene receptor antagonists (LTRA) Med/high dose ICS Add tiotropium# Add tiotropium#
controller dose ICS Low dose theophylline* Low dose ICS+LTRA High dose ICS Add low dose
options (or + theoph*) + LTRA OCS
(or + theoph*)
RELIEVER As-needed short-acting beta2-agonist (SABA) As-needed SABA or

low dose ICS/formoterol**
• Provide guided self-management education (self-monitoring + written action plan + regular review)
REMEMBER
• Treat modifiable risk factors and comorbidities, e.g. smoking, obesity, anxiety
TO...
• Advise about non-pharmacological therapies and strategies e.g. physical activity, weight loss, avoidance of
sensitizers where appropriate
• Consider stepping up if … uncontrolled symptoms, exacerbations or risks, but check diagnosis, inhaler
technique and adherence first
• Consider stepping down if … symptoms controlled for 3 months + low risk for exacerbations.
Ceasing ICS is not advised.
GINA 2015, Box 3-5 (1/8) © Global Initiative for Asthma

Stepwise management -‐
pharmacotherapy Diagnosis
Patient preference
Symptoms
Exacerbations
Side-effects Asthma medications
Patient satisfaction Non-pharmacological strategies
Lung function Treat modifiable risk factors
STEP 5
STEP 4
*For children 6-11 years,
STEP 3 Refer for theophylline is not
PREFERRED STEP 1 STEP 2 add-on
CONTROLLER recommended, and preferred
CHOICE treatment Step 3 is medium dose ICS
Med/high
e.g. **For patients prescribed BDP/
ICS/LABA
Low dose anti-IgE formoterol or BUD/ formoterol
Low dose ICS ICS/LABA* maintenance and reliever
therapy
Other Consider low Leukotriene receptor antagonists (LTRA) Med/high dose ICS Add tiotropium# Add # Tiotropium by soft-mist
controller dose ICS Low dose theophylline* Low dose ICS+LTRA High dose ICS tiotropium#
+ LTRA Add low inhaler is indicated as add-on
options (or + theoph*)
(or + theoph*) dose OCS treatment for adults
(≥18 yrs) with a history of
As-needed short-acting beta2-agonist (SABA) As-needed SABA or
RELIEVER exacerbations
GINA 2015, Box 3-5 (2/8) (upper part)

Stepwise management –
addi'onal components
• Provide guided self-management education

REMEMBER
• Treat modifiable risk factors and comorbidities
TO...
• Advise about non-pharmacological therapies and strategies
• Consider stepping up if … uncontrolled symptoms, exacerbations or risks,
but check diagnosis, inhaler technique and adherence first
• Consider stepping down if … symptoms controlled for 3 months
+ low risk for exacerbations. Ceasing ICS is not advised.
GINA 2015, Box 3-5 (3/8) (lower part)

Step 1 – as-‐needed inhaled short-‐
ac'ng
beta2-‐agonist (SABA)
STEP 5
STEP 4
STEP 3 Refer for

PREFERRED STEP 1 STEP 2
CONTROLLER add-on
CHOICE treatment
Med/high e.g.
ICS/LABA anti-IgE
Low dose
Other Consider low Med/high dose ICS Add tiotropium# Add

Leukotriene receptor antagonists (LTRA) tiotropium#
controller dose ICS Low dose ICS+LTRA High dose ICS
Low dose theophylline* Add low
options (or + theoph*) + LTRA
(or + theoph*) dose OCS

*For children 6-11 years, theophylline is not recommended, and preferred Step 3 is medium dose ICS
**For patients prescribed BDP/formoterol or BUD/formoterol maintenance and reliever therapy
# Tiotropium by soft-mist inhaler is indicated as add-on treatment for patients with a history of
exacerbations; it is not indicated in children <18 years.
GINA 2015, Box 3-5, Step 1 (4/8)
Step 1 – as-‐needed reliever inhaler
•  Preferred op'on: as-‐needed inhaled short-‐ac'ng
beta2-‐agonist (SABA)
–  SABAs are highly effec've for relief of asthma symptoms
–  However …. there is insufficient evidence about the
safety of trea'ng asthma with SABA alone
–  This op'on should be reserved for pa'ents with
infrequent symptoms (less than twice a month) of short
dura'on, and with no risk factors for exacerba'ons
•  Other op'ons
–  Consider adding regular low dose inhaled cor'costeroid
(ICS) for pa'ents at risk of exacerba'ons
GINA 2015
Step 2 – low-‐dose controller + as-‐
needed
inhaled SABA
STEP 5
STEP 4
STEP 3 Refer for

CONTROLLER add-on
CHOICE treatment
Med/high e.g.
ICS/LABA anti-IgE
Low dose
Other Consider low Leukotriene receptor antagonists (LTRA) Med/high dose ICS Add tiotropium# Add
tiotropium#
controller dose ICS Low dose theophylline* Low dose ICS+LTRA High dose ICS
options + LTRA Add low
(or + theoph*)

GINA 2015, Box 3-5, Step 2 (5/8)
Step 2 – Low dose controller + as-‐
needed SABA
•  Preferred op'on: regular low dose ICS with as-‐needed inhaled SABA
–  Low dose ICS reduces symptoms and reduces risk of exacerba'ons and
asthma-‐related hospitaliza'on and death
•  Other op'ons
–  Leukotriene receptor antagonists (LTRA) with as-‐needed SABA
•  Less effec've than low dose ICS
•  May be used for some pa'ents with both asthma and allergic rhini's, or if pa'ent
will not use ICS
–  Combina'on low dose ICS/long-‐ac'ng beta2-‐agonist (LABA)
with as-‐needed SABA
•  Reduces symptoms and increases lung func'on compared with ICS
•  More expensive, and does not further reduce exacerba'ons
–  IntermiVent ICS with as-‐needed SABA for purely seasonal allergic asthma
with no interval symptoms
•  Start ICS immediately symptoms commence, and con'nue for
4 weeks a[er pollen season ends
GINA 2015
Step 3 – one or two controllers +
as-‐needed inhaled reliever
STEP 5
STEP 4
STEP 3 Refer for

CONTROLLER add-on
CHOICE treatment
Med/high e.g.
ICS/LABA anti-IgE
Low dose
Other Consider low Med/high dose ICS Add tiotropium# Add

Leukotriene receptor antagonists (LTRA) tiotropium#
controller dose ICS Low dose ICS+LTRA High dose ICS
Low dose theophylline* Add low
options (or + theoph*) + LTRA

GINA 2015, Box 3-5, Step 3 (6/8) © Global Initiative for Asthma
Step 3 – one or two controllers +
as-‐needed i
•  Before considering step-‐up
nhaled reliever
–  Check inhaler technique and adherence, confirm diagnosis
•  Adults/adolescents: preferred op'ons are either combina'on low dose ICS/LABA
maintenance with as-‐needed SABA, OR combina'on low dose ICS/formoterol
maintenance and reliever regimen*
–  Adding LABA reduces symptoms and exacerba'ons and increases FEV1, while allowing
lower dose of ICS
–  In at-‐risk pa'ents, maintenance and reliever regimen significantly reduces exacerba'ons
with similar level of symptom control and lower ICS doses compared with other
regimens
•  Children 6-‐11 years: preferred op'on is medium dose ICS with
as-‐needed SABA
•  Other op'ons
–  Adults/adolescents: Increase ICS dose or add LTRA or theophylline (less effec've than
ICS/LABA)
–  Children 6-‐11 years – add LABA (similar effect as increasing ICS)
*Approved only for low dose beclometasone/formoterol and low dose budesonide/formoterol
GINA 2015
Step 4 – two or more controllers + UPDATED!

STEP 5
STEP 4
STEP 3 Refer for

CONTROLLER add-on
CHOICE treatment
Med/high e.g.
ICS/LABA anti-IgE
Low dose
tiotropium#
(or + theoph*)

GINA 2015, Box 3-5, Step 4 (7/8) © Global Initiative for Asthma
Step 4 – two or more controllers +
UPDATED!
•  Before considering step-‐up

–  Check inhaler technique and adherence
•  Adults or adolescents: preferred op'on is combina'on low
dose ICS/formoterol as maintenance and reliever regimen*,
OR
combina'on medium dose ICS/LABA with as-‐needed SABA
•  Children 6–11 years: preferred op'on is to refer for expert
advice
•  Other op'ons (adults or adolescents)
–  Tiotropium by so[-‐mist inhaler may be used as add-‐on therapy for
adult pa'ents (≥18 years) with a history of exacerba'ons
–  Trial of high dose combina'on ICS/LABA, but liVle extra benefit
and increased risk of side-‐effects
–  Increase dosing frequency (for budesonide-‐containing inhalers)
–  Add-‐on LTRA or low dose theophylline
GINA 2015
Step 5 – higher level care and/or UPDATED!
add-‐on treatment
STEP 5
STEP 4
STEP 3 Refer for

CONTROLLER add-on
CHOICE treatment
Med/high e.g.
ICS/LABA anti-IgE
Low dose
tiotropium#
(or + theoph*)

GINA 2015, Box 3-5, Step 5 (8/8)

Step 5 – higher level care and/or
add-‐on t reatment
UPDATED!
•  Preferred op'on is referral for specialist inves'ga'on and

considera'on of add-‐on treatment
–  If symptoms uncontrolled or exacerba'ons persist despite Step 4
treatment, check inhaler technique and adherence before referring
–  Add-‐on omalizumab (an'-‐IgE) is suggested for pa'ents with moderate or
severe allergic asthma that is uncontrolled on Step 4 treatment
•  Other add-‐on treatment op'ons at Step 5 include:
–  Tiotropium: for adults (≥18 years) with a history of exacerba'ons despite
Step 4 treatment; reduces exacerba'ons
–  Sputum-‐guided treatment: this is available in specialized centers; reduces
exacerba'ons and/or cor'costeroid dose
–  Add-‐on low dose oral cor'costeroids (≤7.5mg/day prednisone
equivalent): this may benefit some pa'ents, but has significant systemic
side-‐effects. Assess and monitor for osteoporosis
–  See Severe Asthma Guidelines (Chung et al, ERJ 2014) for more detail
GINA 2015
Low, medium and high dose inhaled
cor'costeroids
Adults and adolescents
Inhaled corticosteroid
(≥12 years)
Total daily dose (mcg)
Low Medium High
Beclometasone dipropionate (CFC) 200–500 >500–1000 >1000

Beclometasone dipropionate (HFA) 100–200 >200–400 >400
Budesonide (DPI) 200–400 >400–800 >800
Ciclesonide (HFA) 80–160 >160–320 >320
Fluticasone propionate (DPI or HFA) 100–250 >250–500 >500
Mometasone furoate 110–220 >220–440 >440
Triamcinolone acetonide 400–1000 >1000–2000 >2000
– This is not a table of equivalence, but of es'mated clinical comparability
– Most of the clinical benefit from ICS is seen at low doses
– High doses are arbitrary, but for most ICS are those that, with prolonged use, are
associated with increased risk of systemic side-‐effects
GINA 2015, Box 3-‐6 (1/2)

Reviewing response and adjus'ng
treatment
•  How o[en should asthma be reviewed?
–  1-‐3 months a[er treatment started, then every 3-‐12 months
–  During pregnancy, every 4-‐6 weeks
–  A[er an exacerba'on, within 1 week
•  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 infec'on or allergen
•  May be ini'ated by pa'ent with wriVen asthma ac'on plan
–  Day-‐to-‐day adjustment
•  For pa'ents prescribed low-‐dose ICS/formoterol maintenance and reliever regimen*
•  Stepping down asthma treatment
–  Consider step-‐down a[er good control maintained for 3 months
–  Find each pa'ent’s minimum effec've dose, that controls both symptoms and
exacerba'ons
GINA 2015
General principles for stepping down
controller treatment
•  Aim
–  To find the lowest dose that controls symptoms and exacerba'ons, and minimizes the risk of
side-‐effects
•  When to consider stepping down
–  When symptoms have been well controlled and lung func'on stable for
≥3 months
–  No respiratory infec'on, pa'ent not travelling, not pregnant
•  Prepare for step-‐down
–  Record the level of symptom control and consider risk factors
–  Make sure the pa'ent has a wriVen asthma ac'on plan
–  Book a follow-‐up visit in 1-‐3 months
•  Step down through available formula'ons
–  Stepping down ICS doses by 25–50% at 3 month intervals is feasible and safe for most pa'ents
–  See GINA 2015 report Box 3-‐7 for specific step-‐down op'ons
•  Stopping ICS is not recommended in adults with asthma
GINA 2015, Box 3-‐7

Trea'ng modifiable risk factors
•  Provide skills and support for guided asthma self-‐management
–  This comprises self-‐monitoring of symptoms and/or PEF, a wriVen asthma ac'on plan and
regular medical review
•  Prescribe medica'ons or regimen that minimize exacerba'ons
–  ICS-‐containing controller medica'ons reduce risk of exacerba'ons
–  For pa'ents with ≥1 exacerba'ons in previous year, consider low-‐dose ICS/formoterol
maintenance and reliever regimen*
•  Encourage avoidance of tobacco smoke (ac've or ETS)
–  Provide smoking cessa'on advice and resources at every visit
•  For pa'ents with severe asthma
–  Refer to a specialist center, if available, for considera'on of add-‐on medica'ons and/or
sputum-‐guided treatment
•  For pa'ents with confirmed food allergy:
–  Appropriate food avoidance
–  Ensure availability of injectable epinephrine for anaphylaxis
GINA 2015, Box 3-‐8
Non-‐pharmacological interven'ons
•  Avoidance of tobacco smoke exposure
–  Provide advice and resources at every visit; advise against exposure of children to
environmental tobacco smoke (house, car)
•  Physical ac'vity
–  Encouraged because of its general health benefits. Provide advice about exercise-‐induced
bronchoconstric'on
•  Occupa'onal asthma
–  Ask pa'ents with adult-‐onset asthma about work history. Remove sensi'zers as soon as
possible. Refer for expert advice, if available
•  Avoid medica'ons that may worsen asthma
–  Always ask about asthma before prescribing NSAIDs or beta-‐blockers
•  (Allergen avoidance)
–  (Not recommended as a general strategy for asthma)
•  See GINA Box 3-‐9 and online Appendix for details
This slide shows examples of interventions with high quality evidence

GINA 2015, Box 3-‐9
Indica'ons for considering referral,
where available
•  Difficulty confirming the diagnosis of asthma
–  Symptoms sugges'ng chronic infec'on, cardiac disease etc
–  Diagnosis unclear even a[er a trial of treatment
–  Features of both asthma and COPD, if in doubt about treatment
•  Suspected occupa'onal asthma
–  Refer for confirmatory tes'ng, iden'fica'on of sensi'zing agent,
advice about elimina'ng exposure, pharmacological treatment
•  Persistent uncontrolled asthma or frequent exacerba'ons
–  Uncontrolled symptoms or ongoing exacerba'ons or low FEV1 despite
correct inhaler technique and good adherence with Step 4
–  Frequent asthma-‐related health care visits
•  Risk factors for asthma-‐related death
–  Near-‐fatal exacerba'on in past
–  Anaphylaxis or confirmed food allergy with asthma
GINA 2015, Box 3-‐10 (1/2)

Indica'ons for considering referral,
where available
•  Significant side-‐effects (or risk of side-‐effects)
–  Significant systemic side-‐effects
–  Need for oral cor'costeroids long-‐term or as frequent courses
•  Symptoms sugges'ng complica'ons or sub-‐types of asthma
–  Nasal polyposis and reac'ons to NSAIDS (may be aspirin
exacerbated respiratory disease)
–  Chronic sputum produc'on, flee'ng shadows on CXR (may be
allergic bronchopulmonary aspergillosis)
•  Addi'onal reasons for referral in children 6-‐11 years
–  Doubts about diagnosis, e.g. symptoms since birth
–  Symptoms or exacerba'ons remain uncontrolled
–  Suspected side-‐effects of treatment, e.g. growth delay
–  Asthma with confirmed food allergy
GINA 2015, Box 3-‐10 (2/2)

Inves'ga'ons in pa'ents with severe
asthma
•  Confirm the diagnosis of asthma
–  Consider alterna've diagnoses or contributors to
symptoms, e.g. upper airway dysfunc'on, COPD, recurrent
respiratory infec'ons
•  Inves'gate for comorbidi'es
–  Chronic sinusi's, obesity, GERD, obstruc've sleep apnea,
psychological or psychiatric disorders
•  Check inhaler technique and medica'on adherence
•  Inves'gate for persistent environmental exposure
–  Allergens or toxic substances (domes'c or occupa'onal)
GINA 2015, Box 3-‐14 (1/2)

Management of severe asthma
•  Op'mize dose of ICS/LABA
–  Complete resistance to ICS is rare
–  Consider therapeu'c trial of higher dose
•  Consider low dose maintenance oral cor'costeroids
–  Monitor for and manage side-‐effects, including osteoporosis
•  Add-‐on treatments without phenotyping
–  Tiotropium -‐ reduces exacerba'ons (adults with history of exacerba'ons)
–  Theophylline, LTRA – limited benefit
•  Phenotype-‐guided treatment
–  Sputum-‐guided treatment to reduce exacerba'ons and/or steroid dose
–  Severe allergic asthma: suggest add-‐on an'-‐IgE treatment (omalizumab)
–  Aspirin-‐exacerbated respiratory disease: consider add-‐on LTRA
•  Non-‐pharmacological interven'ons
–  Consider bronchial thermoplasty for selected pa'ents
–  Comprehensive adherence-‐promo'ng program
•  For detailed guidelines, see Chung et al, ERJ 2014
GINA 2015, Box 3-‐14 (2/2)
Asthma flare-ups
(exacerbations)


Defini'on and terminology
•  A flare-‐up or exacerba'on is an acute or sub-‐acute worsening
of symptoms and lung func'on compared with the pa'ent’s usual
status
•  Terminology
–  ‘Flare-‐up’ is the preferred term for discussion with pa'ents
–  ‘Exacerba'on’ is a difficult term for pa'ents
–  ‘AVack’ has highly variable meanings for pa'ents and clinicians
–  ‘Episode’ does not convey clinical urgency
•  Consider management of worsening asthma as a con'nuum
–  Self-‐management with a wriVen asthma ac'on plan
–  Management in primary care
–  Management in the emergency department and hospital
–  Follow-‐up a[er any exacerba'on
GINA 2015
Iden'fy pa'ents at risk of asthma-‐
related death
•  Pa'ents at increased risk of asthma-‐related death should
be iden'fied
–  Any history of near-‐fatal asthma requiring intuba'on and
ven'la'on
–  Hospitaliza'on or emergency care for asthma in last 12 months
–  Not currently using ICS, or poor adherence with ICS
–  Currently using or recently stopped using OCS
•  (indica'ng the severity of recent events)
–  Over-‐use of SABAs, especially if more than 1 canister/month
–  Lack of a wriVen asthma ac'on plan
–  History of psychiatric disease or psychosocial problems
–  Confirmed food allergy in a pa'ent with asthma
•  Flag these pa'ents for more frequent review
GINA 2015, Box 4-‐1

WriVen asthma ac'on plans
•  All pa'ents should have a wriVen asthma ac'on plan
–  The aim is to show the pa'ent how to recognize and respond to
worsening asthma
–  It should be individualized for the pa'ent’s medica'ons, level of
asthma control and health literacy
–  Based on symptoms and/or PEF (children: only symptoms)
•  The ac'on plan should include:
–  The pa'ent’s usual asthma medica'ons
–  When/how to increase reliever and controller or start OCS
–  How to access medical care if symptoms fail to respond
•  Why?
–  When combined with self-‐monitoring and regular medical review,
ac'on plans are highly effec've in reducing asthma mortality and
morbidity
GINA 2015
WriVen asthma ac'on plans
Effective asthma self-management education requires:
• Self-monitoring of symptoms and/or lung function If PEF or FEV1

<60% best, or not
• Written asthma action plan improving after
• Regular medical review 48 hours
All patients Continue reliever
Increase reliever Continue controller
Early increase in Add prednisolone
controller as below 40–50 mg/day
Review response Contact doctor
EARLY OR MILD LATE OR SEVERE
GINA 2015, Box 4-2 (1/2)

WriVen asthma ac'on plans –
medica'on op'ons
•  Increase inhaled reliever
–  Increase frequency as needed
–  Adding spacer for pMDI may be helpful
•  Early and rapid increase in inhaled controller
–  Up to maximum ICS of 2000mcg BDP/day or equivalent
–  Op'ons depend on usual controller medica'on and type of
LABA
–  See GINA 2015 report Box 4-‐2 for details
•  Add oral cor'costeroids if needed
–  Adults: prednisolone 1mg/kg/day up to 50mg, usually 5-‐7 days
–  Children: 1-‐2mg/kg/day up to 40mg, usually 3-‐5 days
–  Morning dosing preferred to reduce side-‐effects
–  Tapering not needed if taken for less than 2 weeks
GINA 2015, Box 4-‐2 (2/2)

Managing Asthma:
Sample Asthma Action Plan
Describes medicines
to use and actions to
take
National Heart, Blood, and Lung Institute Expert Panel Report 3 (EPR 3): Guidelines for the
Diagnosis and Management of Asthma. NIH Publication no. 08-4051, 2007.
Managing exacerba'ons in primary care
PRIMARY CARE Patient presents with acute or sub-acute asthma exacerbation
Is it asthma?
ASSESS the PATIENT Risk factors for asthma-related death?

Severity of exacerbation?
MILD or MODERATE SEVERE

Talks in phrases, prefers Talks in words, sits hunched
LIFE-THREATENING
sitting to lying, not agitated forwards, agitated Drowsy, confused
Respiratory rate increased Respiratory rate >30/min or silent chest
Accessory muscles not used Accessory muscles in use
Pulse rate 100–120 bpm Pulse rate >120 bpm
O2 saturation (on air) 90–95% O2 saturation (on air) <90%
PEF >50% predicted or best PEF ≤50% predicted or best URGENT
START TREATMENT
SABA 4–10 puffs by pMDI + spacer, TRANSFER TO ACUTE
repeat every 20 minutes for 1 hour CARE FACILITY
WORSENING
Prednisolone: adults 1 mg/kg, max.
50 mg, children 1–2 mg/kg, max. 40 mg While waiting: give inhaled SABA
and ipratropium bromide, O2,
Controlled oxygen (if available): target systemic corticosteroid
saturation 93–95% (children: 94-98%)
CONTINUE TREATMENT with SABA as needed

WORSENING
ASSESS RESPONSE AT 1 HOUR (or earlier)
IMPROVING
ASSESS FOR DISCHARGE ARRANGE at DISCHARGE

Symptoms improved, not needing SABA Reliever: continue as needed
PEF improving, and >60-80% of personal Controller: start, or step up. Check inhaler
best or predicted technique, adherence
Oxygen saturation >94% room air Prednisolone: continue, usually for 5–7 days
(3-5 days for children)
Resources at home adequate
Follow up: within 2–7 days
FOLLOW UP
Reliever: reduce to as-needed
Controller: continue higher dose for short term (1–2 weeks) or long term (3 months), depending
on background to exacerbation
Risk factors: check and correct modifiable risk factors that may have contributed to exacerbation,
including inhaler technique and adherence
Action plan: Is it understood? Was it used appropriately? Does it need modification?
GINA 2015, Box 4-3 (1/7)

Is it asthma?
LIFE-THREATENING
Drowsy, confused
or silent chest
URGENT
TRANSFER TO ACUTE
CARE FACILITY
While waiting: give inhaled SABA and
ipratropium bromide, O2, systemic
corticosteroid
GINA 2015, Box 4-3 (2/7) ©

© Global
Global Initiative
Initiative for
for Asthma
Asthma
Is it asthma?

Talks in phrases, prefers Talks in words, sits hunched LIFE-THREATENING
TRANSFER TO ACUTE
CARE FACILITY
ipratropium bromide, O2, systemic
corticosteroid
GINA 2015, Box 4-3 (3/7) ©

© Global
Global Initiative
Initiative for
for Asthma
Asthma
Is it asthma?

Talks in phrases, prefers Talks in words, sits hunched LIFE-THREATENING
START TREATMENT
SABA 4–10 puffs by pMDI + spacer,
TRANSFER TO ACUTE
WORSENING While waiting: give inhaled SABA and
Prednisolone: adults 1 mg/kg, max.
50 mg, children 1–2 mg/kg, max. 40 mg ipratropium bromide, O2, systemic
Controlled oxygen (if available): target corticosteroid
GINA 2015, Box 4-3 (4/7) ©

© Global
Global Initiative
Initiative for
for Asthma
Asthma
START TREATMENT
Prednisolone: adults 1 mg/kg, max. WORSENING

WORSENING
IMPROVING
ASSESS FOR DISCHARGE

Symptoms improved, not needing SABA
PEF improving, and >60-80% of personal
best or predicted
Oxygen saturation >94% room air
Resources at home adequate

START TREATMENT

WORSENING
IMPROVING

PEF improving, and >60-80% of personal Controller: start, or step up. Check inhaler technique,
best or predicted adherence
Resources at home adequate (3-5 days for children)

START TREATMENT
While waiting: give inhaled SABA
50 mg, children 1–2 mg/kg, max. 40 mg and ipratropium bromide, O2,
Controlled oxygen (if available): target systemic corticosteroid

WORSENING
IMPROVING

PEF improving, and >60-80% of personal Controller: start, or step up. Check inhaler technique,
best or predicted adherence
Resources at home adequate (3-5 days for children)
FOLLOW UP
Reliever: reduce to as-needed
Controller: continue higher dose for short term (1–2 weeks) or long term (3 months), depending
on background to exacerbation
Risk factors: check and correct modifiable risk factors that may have contributed to exacerbation,
including inhaler technique and adherence
Action plan: Is it understood? Was it used appropriately? Does it need modification?

Managing exacerba'ons in acute care seongs
INITIAL ASSESSMENT Are any of the following present?

A: airway B: breathing C: circulation Drowsiness, Confusion, Silent chest
NO
YES
Further TRIAGE BY CLINICAL STATUS Consult ICU, start SABA and O2,
according to worst feature and prepare patient for intubation

Talks in phrases Talks in words
Prefers sitting to lying Sits hunched forwards
Not agitated Agitated
Respiratory rate increased Respiratory rate >30/min
Accessory muscles not used Accessory muscles being used
O2 saturation (on air) 90–95% O2 saturation (on air) < 90%
PEF >50% predicted or best PEF ≤50% predicted or best
Short-acting beta2-agonists Short-acting beta2-agonists

Consider ipratropium bromide Ipratropium bromide
Controlled O2 to maintain Controlled O2 to maintain
saturation 93–95% (children 94-98%) saturation 93–95% (children 94-98%)
Oral corticosteroids Oral or IV corticosteroids
Consider IV magnesium
Consider high dose ICS
If continuing deterioration, treat as

severe and re-aassess for ICU
ASSESS CLINICAL PROGRESS FREQUENTLY

MEASURE LUNG FUNCTION
in all patients one hour after initial treatment
FEV1 or PEF 60-80% of predicted or FEV1 or PEF <60% of predicted or

personal best and symptoms improved personal best,or lack of clinical response
SEVERE
MODERATE
Continue treatment as above
Consider for discharge planning and reassess frequently
GINA 2015, Box 4-4 (1/4)

INITIAL ASSESSMENT Are any of the following present?
A: airway B: breathing C: circulation Drowsiness, Confusion, Silent chest
NO
YES
Further TRIAGE BY CLINICAL STATUS Consult ICU, start SABA and O2,
according to worst feature and prepare patient for intubation



GINA 2015, Box 4-4 (3/4)

If continuing deterioration, treat as

severe and re-assess for ICU
ASSESS CLINICAL PROGRESS FREQUENTLY

MEASURE LUNG FUNCTION
in all patients one hour after initial treatment
FEV1 or PEF <60% of predicted or

FEV1 or PEF 60-80% of predicted or
personal best,or lack of clinical response
personal best and symptoms improved
SEVERE
MODERATE
Continue treatment as above
Consider for discharge planning
and reassess frequently

Follow-‐up a[er an exacerba'on
•  Follow up all pa'ents regularly a[er an exacerba'on, un'l
symptoms and lung func'on return to normal
–  Pa'ents are at increased risk during recovery from an exacerba'on
•  The opportunity
–  Exacerba'ons o[en represent failures in chronic asthma care,
and they provide opportuni'es to review the pa'ent’s asthma
management
•  At follow-‐up visit(s), check:
–  The pa'ent’s understanding of the cause of the flare-‐up
–  Modifiable risk factors, e.g. smoking
–  Adherence with medica'ons, and understanding of their purpose
–  Inhaler technique skills
–  WriVen asthma ac'on plan
GINA 2015, Box 4-‐5

Short-‐acAng beta2 agonists[edit]
generic name (Trade Name)
salbutamol (albuterol (US name), Ventolin)
levosalbutamol (levalbuterol (US name),
Xopenex)
terbutaline (Bricanyl)
pirbuterol (Maxair)
procaterol
clenbuterol
metaproterenol (Alupent)
fenoterol
bitolterol mesylate
ritodrine
isoprenaline
Long-‐acAng beta2 agonists[edit]
salmeterol (Serevent Diskus)
formoterol (Foradil, Symbicort)
bambuterol
clenbuterol
olodaterol (Striverdi)
vilanterol

G IN A: Lobal I'a've For Sthma

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G lobal

GINA Global Strategy for Asthma

© Global Initiative for Asthma

Treat for ASTHMA

GINA 2015, Box 1-1 (1/4) ©

Treat for ASTHMA Treat for alternative diagnosis

GINA 2015, Box 1-1 (2/4) ©

Consider trial of treatment for

Treat for ASTHMA Treat for alternative diagnosis

GINA 2015, Box 1-1 (3/4) ©

Empiric treatment with YES NO YES

Treat for ASTHMA Treat for alternative diagnosis

GINA 2015, Box 1-1 (4/4) ©

GINA 2015, Box 1-­‐2

GINA 2015 © Global Initiative for Asthma

GINA Global Strategy for Asthma

© Global Initiative for Asthma

GINA 2015, Box 2-­‐1

A. Symptom control Level of asthma symptom control

Yesq Noq None of 1-2 of 3-4 of

GINA 2015, Box 2-­‐2A © Global Initiative for Asthma

B. Risk factors for poor asthma outcomes

• Assess risk factors at diagnosis and periodically

GINA 2015 Box 2-­‐2B (1/4) © Global Initiative for Asthma

GINA 2015, Box 2-2B (2/4) © Global Initiative for Asthma

GINA 2015, Box 2-2B (3/4) © Global Initiative for Asthma

GINA 2015, Box 2-2B (4/4) © Global Initiative for Asthma

GINA Global Strategy for Asthma

© Global Initiative for Asthma

GINA 2015, Box 3-2

The ‘preferred treatment’ at each step is based on:

GINA 2015, Box 3-­‐4 (1/2)

GINA 2015, Box 3-­‐4 (2/2)

PREFERRED STEP 3 Refer for

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

GINA 2015, Box 3-5 (1/8) © Global Initiative for Asthma

GINA 2015, Box 3-5 (2/8) (upper part)

• Provide guided self-management education

GINA 2015, Box 3-5 (3/8) (lower part)

STEP 3 Refer for

Other Consider low Med/high dose ICS Add tiotropium# Add

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

STEP 3 Refer for

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

STEP 3 Refer for

Other Consider low Med/high dose ICS Add tiotropium# Add

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

as-­‐needed inhaled reliever

STEP 3 Refer for

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

• Before considering step-­‐up

STEP 3 Refer for

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

GINA 2015, Box 3-5, Step 5 (8/8)

• Preferred op'on is referral for specialist inves'ga'on and

Beclometasone dipropionate (CFC) 200–500 >500–1000 >1000

GINA 2015, Box 3-­‐6 (1/2)

GINA 2015, Box 3-­‐7

This slide shows examples of interventions with high quality evidence

GINA 2015, Box 3-­‐10 (1/2)

GINA 2015, Box 3-­‐10 (2/2)

GINA 2015, Box 3-­‐14 (1/2)

GINA Global Strategy for Asthma

GINA 2015, Box 1-‐2

GINA 2015, Box 2-‐1

GINA 2015, Box 2-‐2A © Global Initiative for Asthma

•  Assess risk factors at diagnosis and periodically

GINA 2015 Box 2-‐2B (1/4) © Global Initiative for Asthma

GINA 2015, Box 3-‐4 (1/2)

GINA 2015, Box 3-‐4 (2/2)

as-‐needed inhaled reliever

•  Before considering step-‐up

•  Preferred op'on is referral for specialist inves'ga'on and

GINA 2015, Box 3-‐6 (1/2)

GINA 2015, Box 3-‐7

GINA 2015, Box 3-‐10 (1/2)

GINA 2015, Box 3-‐10 (2/2)

GINA 2015, Box 3-‐14 (1/2)

GINA 2015, Box 4-‐1

GINA 2015, Box 4-‐2 (2/2)

GINA 2015, Box 4-‐5