GINA 16 – Management &
Treatment of Asthma
Raphael Northoff - PTA (pharmaceutical &technical assistant),
Observer Clínica Universidad de La Sabana
Structure
Short explanations
What is GINA?
What is asthma ?
How is asthma evaluated?
Symptoms
Exacerbation
Treating Asthma
General management
Drugs
About GINA
Asthma specialist from over 50 different nations
Launched in 1993
Semiannual meetings
Publish guidelines
With the participation of WHO and NIH
Non profit organization
How GINA defines asthma
“Asthma is a heterogeneous disease, usually
characterized by chronic airway inflammation. It is
defined by the history of respiratory symptoms
such as wheeze, shortness of breath, chest
tightness and cough that vary over time and in
intensity, together with variable expiratory airflow
limitation.”
GINA objectives
• Increase awareness of asthma and its public health consequences.
• Promote identification of reasons for the increased prevalence of
asthma.
• Promote study of the association between asthma and the
environment.
• Reduce asthma morbidity and mortality.
• Improve management of asthma.
• Improve availability and accessibility of effective asthma therapy.
GINA 16 Key changes in
Stepwise treatment (details later)
Low-resource settings
still up to 50% asthma undiagnosed, up to 34% over-
diagnosed
Prevention of asthma
Other changes
remediate dampness or mold in homes reduces asthma
symptoms and medication use in adults (Evidence A)
Vitamin D not associated with improvement in asthma
symptom control or reduction in exacerbations
Levels of symptom controlLevel of asthma symptoms control
In the last 4 weeks, has
the patient had
Well controlled Partly controlled Uncontrolled
Daytime asthma symptoms
more than twice a week?
Yes/No
None of these 1-2 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
* Includes reliever taken before exercise (many people do this routinely)
FIGURE 1: GINA 2016 teaching-slide-set
Evaluating asthma severity
Is assessed retrospectively from the level of treatment which is required to control
symptoms and exacerbations
Assess asthma severity after several month controller treatment
Severity is not statistic – it may change over month or years or as different
treatments become available
• Well-controlled with Steps 1or 2
• As-needed SABA or low-dose ICSMild asthma
• Well-controlled with Step 3
• Low-dose ICS/LABAModerate asthma
• Requires Step 4/5
• Moderate or high ICS/ LABA + add onSevere asthma
Treating asthma to control symptoms and
minimize risk
Symptom RiskC
ON
TR
OL
RE
DU
CT
ION
three categories of long-term treatment
Reliever
Taken as necessary
in case of exacerbation/
prevention of exercise
Induced bronchoconstriction
Controller
Taken regularly - reduces inflammation and exacerbation risk and controls symptoms
Add-on
Severe asthma,
persistent symptoms
Some abbreviations in common use
ICS inhaled corticosteroids
OCS oral corticosteroids
LTRA leukotriene receptor antagonists (oral)
SABA short-acting−𝛽2-agonists (inhaled)
LABA long-acting-𝛽2-agonists (inhaled)
FEV1 forced expiratory volume in one second (value for diagnosis and control of asthma, should be > 0.7)
Process of managing asthma
FIGURE 2: GINA 2016 teaching-slide-set
Don’t forget
• *Not for children <12 years
• **For children 6-11 years, the preferred Step 3 treatment is medium
dose ICS
• # For patients prescribed BDP/formoterol or BUD/ formoterol
maintenance and reliever therapy
• Tiotropium by mist inhaler is an add-on treatment for patients ≥12
years with a history of exacerbations
FIGURE 3: GINA 2016 teaching-slide-set
update
When stepping down and when stepping
up?
Considering stepping up asthma treatment
When asthma poor controlled for at least 2-3 month
Important: first check for common causes (incorrect inhaler technique, poor adherence,
symptoms not due to asthma)
Short-term step up (increase doses)
For 1-2 weeks, e.g. viral infection
Considering stepping down asthma treatment
After well-controlled asthma symptoms maintained for 3 month
Find each patient´s minimum effective dose, that control both symptoms and
exacerbations
What´s new in the stepwise treatment?
Updates in higher lever care or add-on therapy
Phenotype-guided treatment
Severe allergic asthma: add-on omalizumab (anti-IgE)
Severe eosinophilic asthma: add-on mepolizumab (anti-IL5)
Sputum-guided treatment to reduce exacerbations and/or steroid dose
examine sputum (bronchial secrete) for eosinophils, which are prevenient to an exacerbation
reduces exacerbations and/or corticosteroid dose
Aspirin-exacerbated respiratory disease: consider add-on LTRA
phenotypes may be overlapping in specific patients and may change over time
Preferred option is referral for specialist investigation
and consideration of add-on treatment
FIGURE 4: GINA 2016 teaching-slide-set
TO KEEP IN MIND !
Role in therapy - controllers
Inhaled corticosteroids (ICS)
Most recommend therapy
Anti-inflammatory, anti-allergic, immunosuppressive (effect local)
demonstrate best anti-inflammatory efficacy to treat prolonged (allergic) asthma (more effective when dosed twice daily)
Most benefits achieved with low-dose ICS
higher-dose ICS may realize little further benefits but increase risk of side effects
ICS are as first line most recommended and well evaluated treatment
Also in combination with LABA
new
adverse effects of ICS
Oropharyngealcandidiasis
Some contain lactose
(do flush out after use)
Inflammation of the throat &hoarseness
Coughing from upper airway irritation
Headache
Predominantly local side-effects like
Systemic side-effects are less general
Role in therapy - controllers
long-acting−𝜷𝟐-agonists (LABA)
Inhaled
Selective stimulation of adrenergic receptors bronchial musculature
Effect:
Spasmolytic in bronchial tubes
Bronchodilator effect
Should only be used in combination with ICS
LABA don’t have that important anti-inflammatory aspect
E.g.: salmeterol, formoterol (formotorol has an early effect access)
effect for 12 to 24
hours
Adverse effects of LABA
Tachycardia,
Arrhythmia,
Angina pectoris
Tremor, restlessness
Adverse effects appear particularly in use of high-doses
Also a stimulation of 𝛽1- receptor (heart/ CNS)
Role in therapy - controllers
Combination of ICS and LABA
As dry powder inhaler
“Adding LABA reduces symptoms and exacerbations and increases FEV1, while
allowing lower dose of ICS”
“In at-risk patients, maintenance and reliever regimen significantly reduces
exacerbations with similar level of symptom control and lower ICS doses
compared with other regimens”
Using same inhaler as controller and reliever increases adherence !
Only approved for:
low-dose beclomethasone/formoterol and low-dose budesonide/ formoterol
1 + 2 = 4
Role in therapy – reliever Short-acting-beta 2-agonists (SABA)
Selective stimulation of adrenergic receptors bronchial musculature
Effect:
Spasmolytic in bronchial tubes
Bronchodilator effect
onset of action 1 - 5 min relief for 3 - 6 hours
Taken as necessary in case of exacerbation, strong symptoms
prevention of exercise Induced bronchoconstriction
Should be used in lowest possible dose
Frequent use is part of uncontrolled asthma
Most important: Salbutamol, fenoterol, terbutaline
Role in therapy - controllers (sec. line/ add on)
Leukotriene receptor antagonists (LKRA)
oral administration
Leukotriene: strong inflammations mediators
they cause a constriction and swelling of airways in the lungs
increase secretion of mucus
Less effective than low dose ICS
May be used for some patients with both asthma and allergic rhinitis or if patient
will not use ICS
More common in pediatrics (no need to inhale)
e.g. : Montelukast
adverse effects of LKRA
Nausea, diarrhea, emesis
Skin rash,
Infection of the upper airways
Rarely Liver inflammation
(monitoring of liver values)
Some neuropsychological disturbances like
depression, hallucination, peevishness are reported
LKRA are generally well tolerated
Role in therapy – controllers (sec. line/ add-on)
Theophylline
Oral
Unspecific adenosine-receptor agonist, antagonizing equally
A2b (A3) responsible for release of inflammatory mediators
Unspecific Inhibition of phosphodiesterase (PDE)
Bronchodilation
Second line medication!
As add-on (Step 3/ 4) when patient don’t achieve relief from ICS/ LABA
but less effective then increasing the ICS/ LABA doses
Low therapeutic range and unspecific action
Xanthine derivative
Adverse effects of theophylline
Potential for significant side effects, which due to the unspecific action of
theophylline (effect also on A1 and A2a)
In low serum concentration side effect occur similar to those of caffeine
Over dose more than 20 mcg/ ml
Can be reduced by close monitoring and adequate doses
Nausea and vomit
insomnia Tachycardia, arrhythmia, tremor and convulsing
Role in therapy - controllers (sec. line/ add on)
Tiotropium
Inhaled (mist inhaler)
inhibition of muscarinic Ach-receptors (anticholinergic)
Bronchodilator effect by inhaling
Reduces significantly exacerbations (and asthma symptoms )
to prevent wheezing, shortness of breath, coughing and chest tightness
May be used as add-on therapy for patients with history of exacerbations
can improve outcomes for patients with asthma who remain symptomatic despite
the use of ICS/LABA maintenance therapy
disadvantage of non anti-inflammatory aspect
Adverse effects of tiotropium
As consequence of inhibiting the muscarine-receptors there can appear
Dry mouthand bitter
taste
Indigestion, Constipation
and stomache
pain
Muscle pain
Role in therapy – controllers (sec. line/ add-on)
Monoclonal Anti-IgE antibody omalizumab
injected once in six month (s.c.)
It binds the IgE molecule
in so doing it prevents the union from IgE with cell-surface receptors
As adjustment the inflammatory reaction is likely to be stabilized, that means
Less release of inflammation mediators, production of anti-gens and IgE-syntesis
For patients with:
severe allergic asthma uncontrolled with high-dose ICS/ LABA
exalted serum concentration of IgE (phenotype treatment)
Could be an option to prevent side-effects of instead taken OCS
IgE blood levels should measured when medicating with omalizumab
High treatment costs
FIGURE 5: N Engl J Med 2006;354:2689-95
Adverse effects of omalizumab
risks of the development of cancer
Omalizumab 0,5% and Placebo 0.2%¹
Risk of the development of
anaphylaxis
Omalizumab is intended to prevent anaphylaxis but in
clinical trials 3 persons (<0.01%) had anaphylaxis¹
Rash, nausea, diarrhea, vomit,
Epistaxis and injection side effects
¹FDA, Center for Biologics Evaluation and Research. BLA STN 103976/0, review of clinical safe-ty data: original BLS
submitted on June 2, 2000 and response to complete review let-ter submitted on December 18, 2002. Rock-ville, Md.:
Department of Health and Human Services, 2003.
Role in therapy – controllers (sec. line/add-on)
Monoklonal Anti-IL5 antibody
injected monthly (s.c.)
Anti-IL5 binds with high affinity to free IL5 – inhibition of
IL5 plays a key role in eosinophil proliferation, differentiation, maturation, migration
to tissue sites and survival
Eosinophils are noted for increasing the possibility of exacerbations
Effect:
reduces exacerbations
no improvement in symptoms, lung function or airway hyperesponsivness
Indicated for severe eosinophilic asthma (phenotype) when
persistent sputum eosinophilia
despite high doses of inhaled corticosteroids
update
Mepolizumab
binds IL5
Role in therapy – controllers (sec. line/add-on)
Monoklonal Anti-IL5 antibody
injected monthly (s.c.)
Mepolizumab is the most studied anti-IL5 in the treatment of severe asthma
For others like reslizumab or benralizumab not sufficient evidence
Adverse effects of mepolizumab
Because of the recent use of mepolizumab adverse effects are mostly documented
in studies
Headacheand dorsal
pain
Injection sideeffects like
pain, rush orswelling
Role in therapy – controllers (sec. line)
Oral corticosteroids (OCS)
Anti-inflammatory , anti-allergic, immunosupprressive (systemic effect)
Only local effects are needed
ICS should always be preferred before OCS!
high risk for adverse effects
Low dose OCS (≤7.5mg/day prednisone equivalent)
Is used for severe asthma if other options aren´t efficient enough
Short-term treatment after exacerbation
Asses and monitor for osteoporosis
Adverse effects of OCS
Short-term use of OCS (after exacerbation) is less likely for occurrence of adverse
effects
Treatment by long-term OCS increases significantly the risk of heavy adverse
effects
Osteoporosis
Obesity
Skin thinning
arterial hypertension
Glaucoma
Diabetes
Slow wound heeling
Emotional disturbances
Muscle weakness