5 APAPARI 2017 asthma en

• Recurrent respiratory symptoms wheeze, cough, dyspnea, chest tightness – typically worse at night/early morning – exacerbated by exercise, viral infection, smoke, dust, pets, mold, dam

APAPARI Workshop Hanoi 2017

29th April 2017

Definition of asthma

• Asthma is a heterogeneous disease, usually characterized by chronic airway inflammation

• 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 2015

Definition of asthma

• Physiology: Episodic airway obstruction

characterised by expiratory airflow limitation

• Clinical manifestation: Recurrent wheeze,

cough or breathlessness, particularly at night

or early morning

• Often reversible

Definition of asthma

• Pathology: Airway inflammation, airway structural changes

Stephen T Holgate & Riccardo Polosa

Nature Reviews Immunology 8, 218-230 (March 2008)

Pathophysiology of asthma

Trends in Microbiology, July 2015, Vol 23, No 7

ICON Allergy 2012

Making the diagnosis

• Recurrent respiratory symptoms (wheeze, cough, dyspnea, chest tightness)

– typically worse at night/early morning

– exacerbated by exercise, viral infection, smoke, dust, pets, mold, dampness, weather changes, laughing, crying, allergens

• Personal history of atopy (eczema, food

allergy, allergic rhinitis)

• Family history of asthma or atopic

diseases

ICON 2012

Physical examination

• Chest auscultation for wheezing

• Symptoms/signs of other atopic diseases such

as rhinitis or eczema

ICON 2012

• Evaluation of lung function (spirometry with reversibility testing, preferred to PEFR, which can nevertheless be used

if resources are limited

• Evaluation of atopy (skin prick tests or serum-specific IgE)

• Studies for exclusion of alternative diagnoses (e.g chest ray)

Asthma management in children

Basic approach to asthma hasn’t changed – a holistic approach

• Control symptoms

• Lead a normal active life

• Normal lung function

• Prevent asthma exacerbations

• Asthma medication – prescription, convince and educate families about giving medicines properly

• Avoid or handle triggering factors, including

exercise

• Recognise signs that asthma is worsening

• Seek medical advice when needed

Levels of Asthma Control

Partly controlled

Daytime symptoms None (2 or less /

3 or more features of partly controlled asthma present in any week

Limitations of

Nocturnal

symptoms /

Need for rescue /

“reliever” treatment

None (2 or less / week)

More than twice / week Lung function

(PEF or

< 80% predicted or personal best (if known) on any day

week

GINA assessment of asthma control

Asthma symptom control Level of asthma symptom control

In the past 4 weeks, has the child had Well

Controlled Partly controlled Uncontrolled Daytime symptoms > 2/week

None of these 1-2 of these 3-4 of these

Any night waking due to asthma?

Reliever needed for symptoms >2/week

Any activity limitation due to asthma

Risk factors for poor asthma outcomes

Excessive use of SABA

Inadequate ICS – Inappropriate dosage, poor adherence or incorrect inhaler technique Low FEV1

Major psychological or socioeconomic problems

Exposures – smoking, allergen exposure

Co-morbidities – Obesity, rhinosinusitis

> 1 severe exacerbation in the last 12 months

ICON Allergy 2012

Pharmacotherapy

© Global Initiative for Asthma

Stepwise approach to control asthma symptoms

and reduce risk

Symptoms Exacerbations Side-effects Patient satisfaction Lung function

Other controller opt ions

RELIEVER

REMEMBER TO

Consider stepping down if … symptoms controlled for 3 months + low risk for exacerbations

Ceasing ICS is not advised.

STEP 1 STEP 2 STEP 3

STEP 5 STEP 4

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) As-needed SABA or

low dose ICS/formoterol#

Low dose ICS/LABA**

Med/high ICS/LABA

Diagnosis Symptom control & risk factors (including lung function) Inhaler technique & adherence Patient preference

Asthma medications Non-pharmacological strategies Treat modifiable risk factors

PREFERRED CONTROLLER CHOIC E



Add tiotropium* Add low dose High dose ICS OCS + LTRA

SLIT added as

an option

GINA 2017, Box 3-5

(1/8)

• Add-on tiotropium by soft-mist inhaler is a new

‘other controller option’ for Steps 4 and 5, in

patients ≥18 years with history of exacerbations

• Tiotropium - long-acting once-daily

anticholinergic

– Initially used in COPD

– Benefits shown in adult asthma

What’s new in GINA

Benefit of tiotropium in adolescent

and pediatric lung function

In studies of symptomatic 6- to 11- year-old and 12- to 17-year-old asthmatic patients receiving at least

an ICS, tiotropium improved peak and trough FEV1 and morning and

evening PEF

Vogelberg et al Respiratory Research

• Studies have not yet investigated the effect of

tiotropium on asthma exacerbations in paediatric and

© Global Initiative for Asthma

Stepwise management, SLIT as an add-on

option for some patients

GINA 2017, Box 3-5 (3/8) (lower part)

REMEMBER

TO

SLIT: sublingual immunotherapy

• Provide guided self-management education

• Treat modifiable risk factors and comorbidities

• 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 adding SLIT in adult HDM-sensitive patients with allergic rhinitis who have exacerbations despite ICS treatment, provided FEV1 is 70%

predicted

• Consider stepping down if … symptoms controlled for 3 months + low risk for exacerbations Ceasing ICS is not advised.

Allergen specific immuno-therapy (SCIT/SLIT) in asthma with rhinitis

• Administration of increasing doses of allergen extracts to

induce persistent clinical tolerance in patients with allergen- induced symptoms

• Effective in improving rhinitis

• Adults and adolescents with allergic rhinitis known to be more likely to have increased bronchial hyper-responsiveness

• Evidence that 3-year SCIT can reduce the development of

asthma symptoms and improved bronchial responsiveness1

• May prevent development of sensitisation to additional

allergens2

1 Moller J Allergy Clin Immunol 2002

2 Pajno Clin Exp Allergy 2001

Allergen specific immuno-therapy

(SCIT/SLIT)

• Effects generally to be greatest when

standardized, single-allergen extracts of house dust mites, animal dander, grass, or tree pollen are administered

• Evidence is lacking for the use of multi-allergen extracts and for mold and cockroach allergens

• Concerns re local and systemic SE (eg

bronchoconstiction) esp in poor asthma control

• Not for severe asthmatics

Intermittent versus daily inhaled corticosteroids for

persistent asthma in children and adults

Conclusions:

• Daily ICS was superior in

 Indicators of lung function

 Airway inflammation

 Asthma control and reliever use

• Both similarly effective (low quality evidence)

 Use of of rescue oral steroids

 Rate of adverse health events

• Moderate growth suppression was associated with daily compared to intermittent inhaled steroids

Chauhan BF, Chartrand C, Ducharme FM Intermittent versus daily inhaled corticosteroids for persistent asthma in children and

adults.

Cochrane Database of Systematic Reviews 2013, Issue 2.

Compliance with therapy

Allergy Clin Immunol 2012

Compliance with therapy

25

adolescents

NUH data

New ICS / LABA

• Fluticasone furoate / vilanterol (Relvar)

• Vilanterol - LABA with 24-hour activity

developed as a once-daily treatment in

combination with a novel ICS, fluticasone

furoate,

• Once daily ICS dosing increases medication

adherence and reduces health care costs,

irrespective of whether treatment is

stepped up or down

• FDA approval for:

– Chronic obstructive pulmonary disease

(COPD) in 2013

– Asthma in patients 18 years and older in

2015

New ICS / LABA

• Exclusive pediatric studies of

Fluticasone furoate /

vilanterol are limited

• In 5- to 11-year-old patients

with well-controlled asthma,

– similar tolerability, safety

profile, pharmacodynamic

effect, and pharmacokinetic

profile as fluticasone furoate

alone

Clinical Therapeutics/Volu

me 36, Number 6,

2014

Median percentage adherence was 84%

(10th percentile 54%, 90th percentile 96%) in the intervention group,

compared with 30% (8%, 68%) in the control group (p<0·0001).

Use of an

electronic monitoring device with

an audiovisual reminder led to

SMART therapy

• Single combination budesonide-formoterol inhaler

maintenance and reliever therapy (SMART) >12y

Superior to budesonide/formoterol and budesonide alone in

• Reducing the rate of asthma exacerbations

• Prolonging the time to first exacerbation

• Reducing the risk of exacerbations requiring medical attention, mild exacerbation days, and nocturnal awakenings

• But not symptom-free

days orasthma control days

• ?Improved linear growth

Chest.130.

6.1733

N = 341

• 66% of parents concerned about inhaled

Side-effects of long term inhaled

corticosteroid use

• Effect on height:

– Long-term use >12 months of ICS is associated

with a slight reduction in growth velocity and final adult height in children.

(Meta-analysis: PLOS ONE | DOI:10.1371/journal.pone.0133428 July 20, 2015)

Ultimately, children with asthma treated with ICS

attain normal adult height (predicted from family

members) even with higher doses of ICS, although

it is reached at a later than normal age

Pedersen S Am J Respir Crit Care Med 2001;164(4):521-535

PLOS ONE | DOI:10.1371/journal.pone.0133428 July 20, 2015

N Engl J Med 2012

Side-effects of long term inhaled

corticosteroid use

• Other side-effects in children:

– Overall little evidence for other side effects in children with standard low to medium doses of ICS

– Possibly oral candidiasis

– However, with high-dose ICS, there is still a theoretical risk of increased steroidal side-effects

– Need to be aware that poor-control exposes the child

to increased frequency of oral steroid treatment for exacerbations which carry a far greater SE risk profile

Use of ICS as rescue therapy in ED for

children with acute asthma

• Mixed results; not currently recommended

– Some studies have found benefits of inhaled glucocorticoids compared with oral glucocorticoids (e.g, earlier discharge from the ED, less vomiting,

decreased relapse rate, improved clinical parameters, improved pulmonary function)

– Other studies have found oral and inhaled glucocorticoids to have similar

outcomes

– One study found improved pulmonary function and a lower relapse rate with oral prednisone compared with inhaled fluticasone

– Two randomized trials found no additional benefit to adding

nebulized budesonide to standard therapy early in the course of treatment– Systematic reviews concluded that episodic high-dose inhaled

glucocorticosteroids (1,600–3,200 mcg/day- budesonide) provide some

benefit in episodic wheeze in younger children (50% reduction in requirement for oral steroids) but no effect on hospitalisation rates or duration of

symptoms

Concept of the difficult asthmatic

• Majority of children with asthma have mild / moderate disease – adequately controlled by avoidance of trigger factors and medications

• 5% have chronic symptoms and / or recurrent exacerbations despite maximum treatment with conventional medications

The difficult asthmatic

Rhinitis and asthma

• Adults and adolecents with allergic rhinitis known to be more likely to have increased bronchial hyper-

responsiveness

• More recently also shown in children with allergic

rhinitis but no asthma

• 76% of patients with asthma have rhinitis, and up to

• For individuals with allergic rhinitis and no clinical

asthma, there are histological abnormalities of

bronchial mucosa, including thickening of the lamina

1 De Groot Thorax 2012

2 Djukanovic Eur Respir J 1992

Dysfunctional breathing

• Exercise-induced bronchospasm (EIB)

• Vocal cord dysfunction (VCD)

Corbo Epidemiology 2008

Tsai Journal of Asthma 2007

Obesity

Difficult-to-treat asthma with potentially reversible factors

• Poor adherence to treatment

• Poor inhalation technique

• Allergen exposure

• Smoke exposure

• Food allergy

Smoke exposure

• Exposure can happen before or after birth

• Pre-natal smoking is associated with pre-school asthma symptoms

• Excess incidence of wheezing in smoking

households mainly in early wheezers

• Among children with established asthma,

parental smoking is associated with more

disease

• Passive smoke exposure may lead to a pauci- eosinophilic, steroid-resistant phenotype (like active adult smokers)

True “severe therapy-resistant

asthma”

• Non-responder to conventional treatment

• No exacerbating factors identified

Investigating “severe therapy-resistant

asthma”

• Skin-prick testing aeroallergens

• Exhaled NO – Relationship between FeNO and asthma severity is unclear

• Spirometry

• Induced sputum cell counts

• Saliva for cotinine concentrations

Petsky Thorax 2012

Investigating “severe therapy-resistant

asthma”

• Home visit

– Adherence to treatment

– Environmental tobacco smoke

– Ongoing allergen exposure

Any non-invasive biomarkers?

• Sputum eosinophils

Fleming Thorax 2012

Any non-invasive biomarkers?

• Biomarkers in exhaled breath condensate

Treating “severe therapy-resistant

asthma”

• Steroid resistance

– Parenteral steroids to ensure complete adherence

Treating “severe therapy-resistant

asthma”

• Eosinophilic inflammation

– High dose inhaled corticosteroids

– SMART (budesonide + formoterol)

Neutrophilic asthma

• Low-dose theophylline

– Accelerate neutrophil apoptosis

– May restore steroid responsiveness

• Macrolides – efficacy derived from benefit in other neutrophilic airway disease

Severe asthma with fungal

sensitisation

• Itraconazole

• Voriconazole

Future treatment options

• Recurrent wheezing occurs in a large proportion of children 5 years and younger

• Previous classifications do not appear to identify stable phenotypes and their clinical usefulness in uncertain

• A diagnosis of asthma in young children with a history of wheezing

is more likely if they have:

 Wheezing or coughing with exercise, laughing or crying in the absence of respiratory infection

 A history of other allergic diseases or asthma in first degree

Features suggestive of asthma in

children <5 years

Feature Characteristics suggesting asthma

Cough Recurrent or persistent non productive cough

that may be worse at night or accompanied

by wheezing Cough occurring with exercise, laughing or crying in the absence of apparent respiratory infection

Wheeze Recurrent wheezing including during sleep or

with triggers

Difficulty or heavy breathing or shortness of

breath Occurring with exercise, laughing or crying

Reduced activity Not running, playing or laughing at the same

intensity as other children Tires earlier

Past or family history Other allergic diseases (AR or AD)

Asthma in first degree relatives

Therapeutic trial with low dose ICS Clinical improvement during 2-3 months of

controller treatment and worsening after stopping it.