1. Global Initiative for Asthma (GINA) What’s new in GINA 2018?

2. Assessment of asthma – risk factors
Risk factors for exacerbations (flare-ups)
Having uncontrolled asthma symptoms is an important risk factor for exacerbations
GINA Box 2-2B lists other factors that, if present, increase the risk of exacerbations even if the patient has few symptoms
These ‘independent’ risk factors are identified from analyses that have adjusted the risk of exacerbations for symptom control
Additional risk factors for exacerbations in GINA 2018
In Box 2-2B, higher bronchodilator reversibility has been added as an additional independent risk factor for exacerbations in both adults and children (Ulrik Chest 1995, Pongracic JACI 2016)
Additional risk factors for developing persistent airflow limitation
Pre-term birth, low birth weight and greater infant weight gain have been added to the list of risk factors (den Dekker 2016)
1. Ulrik CS, Frederiksen J. Mortality and markers of risk of asthma death among 1,075 outpatients with asthma. Chest 1995;108:10-5.
2. Pongracic JA, Krouse RZ, Babineau DC, Zoratti EM, Cohen RT, Wood RA, Khurana Hershey GK, et al. Distinguishing characteristics of difficult-to-control asthma in inner-city children and adolescents. J Allergy Clin Immunol 2016;138:
3. den Dekker HT, Sonnenschein-van der Voort AMM, de Jongste JC, Anessi-Maesano I, Arshad SH, Barros H, Beardsmore CS, et al. Early growth characteristics and the risk of reduced lung function and asthma: A meta-analysis of 25,000 children. J Allergy Clin Immunol 2016;137:
What’s new in GINA 2018?

3. Assessment of risk factors for poor asthma outcomes
Risk factors for exacerbations include:
Uncontrolled asthma symptoms
Additional risk factors, even if the patient has few symptoms:
High SABA use (≥3 canisters/year)
Having ≥1 exacerbation in last 12 months
Low FEV1; higher bronchodilator reversibility
Incorrect inhaler technique and/or poor adherence
Smoking
Obesity, chronic rhinosinusitis, pregnancy, blood eosinophilia
Elevated FeNO in adults with allergic asthma taking ICS
Ever intubated for asthma
Risk factors for fixed airflow limitation include:
No ICS treatment, smoking, occupational exposure, mucus hypersecretion, blood eosinophilia; pre-term birth, low birth weight
Risk factors for medication side-effects include:
Frequent oral steroids, high dose/potent ICS, P450 inhibitors
GINA 2018, Box 2-2B (4/4)

4. Treatment steps – changes in 2018
It is explained that the reason ICS should be considered for patients with mild asthma (rather than prescribing SABA alone) is to reduce their risk of serious exacerbations (Pauwels, Lancet 2003; O’Byrne AJRCCM 2001; Reddel Lancet 2017)
Steps 3-4
From the large FDA LABA safety studies: adding LABA to ICS in a combination inhaler reduces risk of exacerbations and improves symptoms and lung function, compared with the same dose of ICS alone, but with only a small reduction in reliever use (Stempel NEJM 2016, Peters NEJM 2016)
Step 5 and Box 3-14: management of severe asthma
Subcutaneous benralizumab (monoclonal anti-IL5 receptor α antibody) is another add-on treatment for patients aged ≥12 years with severe eosinophilic asthma
1. Reddel HK, Busse WW, Pedersen S, Tan WC, Chen YZ, Jorup C, Lythgoe D, et al. Should recommendations about starting inhaled corticosteroid treatment for mild asthma be based on symptom frequency: a post-hoc efficacy analysis of the START study. Lancet 2017;389:
2. Peters SP, Bleecker ER, Canonica GW, Park YB, Ramirez R, Hollis S, Fjallbrant H, et al. Serious asthma events with budesonide plus formoterol vs. budesonide alone. N Engl J Med 2016;375:
3. Stempel DA, Raphiou IH, Kral KM, Yeakey AM, Emmett AH, Prazma CM, Buaron KS, et al. Serious asthma events with fluticasone plus salmeterol versus fluticasone alone. N Engl J Med 2016;374:
What’s new in GINA 2018?

5. Stepwise management - pharmacotherapy
Diagnosis
Symptom control & risk factors (including lung function)
Inhaler technique & adherence
Patient preference
REVIEW RESPONSE
ASSESS
Symptoms
Exacerbations
Side-effects
Patient satisfaction
Lung function
ADJUST TREATMENT
Asthma medications
Non-pharmacological strategies
Treat modifiable risk factors
STEP 5
STEP 4
STEP 3
Refer for add-on treatment
e.g.
tiotropium,* anti-IgE, anti-IL5*
*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
STEP 1
STEP 2
PREFERRED CONTROLLER CHOICE
Med/high ICS/LABA
Low dose ICS/LABA**
Low dose ICS
Other controller options
Consider low dose ICS
Leukotriene receptor antagonists (LTRA)
Low dose theophylline*
Med/high dose ICS
Low dose ICS + LTRA
(or + theoph*)
Add tiotropium*
Med/high dose ICS + LTRA (or + theoph*)
Add low dose OCS
As-needed short-acting beta2-agonist (SABA)
As-needed SABA or low dose ICS/formoterol#
RELIEVER
GINA 2018, Box 3-5 (2/8) (upper part)

6. Perimenstrual asthma, and asthma in pregnancy
Perimenstrual (catamenial) asthma – new section added
Asthma worse premenstrually in ~20% women
More common in older women, higher BMI, longer duration and more severe asthma; often have dysmenorrhea, shorter cycles, longer bleeding; aspirin-exacerbated respiratory disease more common (Sanchez-Ramos Exp Rev Respir Med 2017)
Add-on treatment: oral contraceptives and/or LTRA may be helpful
The recommendation against stopping ICS during pregnancy has been reinforced
ICS reduce the risk of exacerbations in pregnancy (Evidence A) (Schatz AAAI 2005; Murphy Clin Chest Med 2011)
Stopping ICS increases the risk of exacerbations in pregnancy (Evidence A) (Murphy Thorax 2006)
Sanchez-Ramos JL, Pereira-Vega AR, Alvarado-Gomez F, Maldonado-Perez JA, Svanes C, Gomez-Real F. Risk factors for premenstrual asthma: a systematic review and meta-analysis. Expert Rev Respir Med 2017;11:57-72.
Schatz M, Leibman C. Inhaled corticosteroid use and outcomes in pregnancy. Annals of Allergy, Asthma & Immunology 2005;95:234-8.
Murphy VE, Gibson PG. Asthma in pregnancy. Clin Chest Med 2011;32:93-110
Murphy VE, Clifton VL, Gibson PG. Asthma exacerbations during pregnancy: incidence and association with adverse pregnancy outcomes. Thorax 2006;61:
What’s new in GINA 2018?

7. Exhaled nitric oxide (FeNO)
FeNO is becoming more widely available in some countries
All sections on FeNO have been reviewed and updated
Decisions about initial asthma treatment
GINA recommends at least low dose ICS in almost all patients with asthma, to reduce risk of asthma exacerbations and death
SABA-only treatment considered only if symptoms < twice/month, no night waking, and no risk factors for exacerbations
In non-smoking patients, FeNO >50 ppb is associated with a good short-term response to ICS in symptoms and lung function
There are no studies examining the long-term safety (i.e. for risk of exacerbations) of withholding ICS if initial FeNO is low
In patients with a diagnosis or suspected diagnosis of asthma, FeNO can support the decision to start ICS, but cannot safely be recommended for deciding against treatment with ICS
What’s new in GINA 2018?

8. Exhaled nitric oxide (FeNO)
FeNO-guided treatment
Updated to reflect new meta-analyses (Petsky Cochrane 2016; Petsky Cochrane 2016) that separately analyzed studies in which the control algorithm was reasonably close to current clinical recommendations, and therefore provided a clinically relevant comparator
Children/adolescents: FENO-guided treatment was associated with significantly fewer exacerbations and lower exacerbation rate than treatment based on current guidelines
Adults: no significant difference in exacerbations with FENO-guided treatment compared with treatment based on current guidelines
FeNO-guided treatment is not recommended for the general asthma population at present
Further studies are needed to identify the populations most likely to benefit, and the optimal frequency of monitoring
1. Petsky HL, Kew KM, Chang AB. Exhaled nitric oxide levels to guide treatment for children with asthma. Cochrane Database Syst Rev 2016;11:Cd
2. Petsky HL, Kew KM, Turner C, Chang AB. Exhaled nitric oxide levels to guide treatment for adults with asthma. Cochrane Database Syst Rev 2016;9:Cd
What’s new in GINA 2018?

9. Exhaled nitric oxide (FeNO)
In children ≤5 years with recurrent coughing and wheezing
Elevated FeNO recorded >4 weeks from any URTI predicts physician-diagnosed asthma at school age (Singer 2013)
Elevated FeNO at age 4 increases the odds for wheezing, physician-diagnosed asthma and ICS use by school age, independent of clinical history and presence of specific IgE (Caudri JACI 2010)
1. Caudri D, Wijga A, CM AS, Hoekstra M, Postma DS, Koppelman GH, Brunekreef B, et al. Predicting the long-term prognosis of children with symptoms suggestive of asthma at preschool age. J Allergy Clin Immunol 2009;124: e1-7.
What’s new in GINA 2018?

10. Follow-up after an asthma exacerbation
Follow up all patients regularly after an exacerbation, until symptoms and lung function return to normal
Patients are at increased risk during recovery from an exacerbation
The opportunity
Exacerbations often represent failures in chronic asthma care, and they provide opportunities to review the patient’s asthma management
At follow-up visit(s), check:
The patient’s understanding of the cause of the flare-up
Modifiable risk factors, e.g. smoking
Adherence with medications, and understanding of their purpose
SABA is being taken only as-needed, not regularly
Inhaler technique skills
Written asthma action plan
GINA 2018, Box 4-5

11. Asthma-COPD overlap
“Asthma-COPD overlap” does not mean a single disease entity
It includes patients with several different forms of airways disease (phenotypes) caused by a range of different underlying mechanisms
Persistent airflow limitation may be found in:
Some children with asthma (McGeachie NEJM 2016)
Many adults with a history of asthma (Lange NEJM 2015)
Patients with low lung function in early adulthood with normal decline over time (Lange NEJM 2015)
Patients with normal lung function in early adulthood but rapid decline over time (Lange NEJM 2015)
Treatment of patients with asthma-COPD overlap
Few studies – overlap patients are excluded from most RCTs
The interim safety recommendation for ICS to be included in treatment for patients with COPD and a history of asthma is supported by a well-designed case-control study (Gershon JAMA 2014)
McGeachie MJ, Yates KP, Zhou X, Guo F, Sternberg AL, Van Natta ML, Wise RA, et al. Patterns of growth and decline in lung function in persistent childhood asthma. N Engl J Med 2016;374:
Lange P, Celli B, Agusti A, Boje Jensen G, Divo M, Faner R, Guerra S, et al. Lung-function trajectories leading to chronic obstructive pulmonary disease. N Engl J Med 2015;373:
Gershon AS, Campitelli MA, Croxford R, et al. Combination long-acting β-agonists and inhaled corticosteroids compared with long-acting β-agonists alone in older adults with chronic obstructive pulmonary disease. JAMA 2014;312:
What’s new in GINA 2018?

12. Children aged ≤5 years – key changes
Step 2 (initial controller treatment) for children with frequent viral-induced wheezing and with interval asthma symptoms
A trial of regular low-dose ICS should be undertaken first
As-needed (prn) or episodic ICS may be considered
The reduction in exacerbations seems similar for regular and high dose episodic ICS (Kaiser Pediatr 2015)
LTRA is another controller option
Step 3 (additional controller treatment)
First check diagnosis, exposures, inhaler technique, adherence
Preferred option is medium dose ICS
Low-dose ICS + LTRA is another controller option
Blood eosinophils and atopy predict greater short-term response to moderate dose ICS than to LTRA (Fitzpatrick JACI 2016)
Relative cost of different treatment options in some countries may be relevant to controller choices
1. Kaiser SV, Huynh T, Bacharier LB, Rosenthal JL, Bakel LA, Parkin PC, Cabana MD. Preventing exacerbations in preschoolers with recurrent wheeze: A meta-analysis. Pediatrics 2016;137.
2. Fitzpatrick AM, Jackson DJ, Mauger DT, Boehmer SJ, Phipatanakul W, Sheehan WJ, Moy JN, et al. Individualized therapy for persistent asthma in young children. J Allergy Clin Immunol 2016;138: e12.
What’s new in GINA 2018?

13. Stepwise approach – pharmacotherapy (children ≤5 years)
PREFERRED CONTROLLER CHOICE
STEP 1
STEP 2
Continue controller & refer for specialist assessment
Double ‘low dose’ ICS
Daily low dose ICS
Other controller options
Leukotriene receptor antagonist (LTRA)
Intermittent ICS
Low dose ICS + LTRA
Add LTRA
Inc. ICS frequency
Add intermitt ICS
RELIEVER
As-needed short-acting beta2-agonist (all children)
CONSIDER THIS STEP FOR CHILDREN WITH:
Infrequent viral wheezing and no or few interval symptoms
Symptom pattern consistent with asthma and asthma symptoms not well-controlled, or ≥3 exacerbations per year
Symptom pattern not consistent with asthma but wheezing episodes occur frequently, e.g. every 6–8 weeks. Give diagnostic trial for 3 months.
Asthma diagnosis, and not well-controlled on low dose ICS
Not well-controlled on double ICS
First check diagnosis, inhaler skills, adherence, exposures
GINA 2018, Box 6-5 (3/8)

14. Low daily dose, mcg (with lower limit of age-group studied)
‘Low dose’ inhaled corticosteroids (mcg/day) for children ≤5 years – updated 2018
Inhaled corticosteroid
Low daily dose, mcg (with lower limit of age-group studied)
Beclometasone dipropionate (HFA)
100 (ages ≥5 years)
Budesonide (nebulized)
500 (ages ≥1 year)
Fluticasone propionate (HFA)
100 (ages ≥4 years)
Mometasone furoate
110 (ages ≥4 years)
Budesonide (pMDI + spacer)
Not sufficiently studied in this age group
Ciclesonide
Triamcinolone acetonide
This is not a table of equivalence
A low daily dose is defined as the lowest approved dose for which safety and effectiveness have been adequately studied in this age group
GINA 2018, Box 6-6
GINA 2018, Box 6-6

15. Children aged ≤5 years – key changes
Home management of intermittent viral-triggered wheezing
Preemptive episodic high-dose episodic ICS may reduce progression to exacerbation (Kaiser Pediatr 2016)
However, this has a high potential for side-effects, especially if continued inappropriately or is given frequently
Family-administered high dose ICS should be considered only if the health care provider is confident that the medications will be used appropriately, and the child closely monitored for side-effects
Emergency department management of worsening asthma
Reduced risk of hospitalization when OCS are given in the emergency department, but no clear benefit in risk of hospitalization when given in the outpatient setting (Castro-Rodriguez Pediatr Pulm 2016)
1. Kaiser SV, Huynh T, Bacharier LB, Rosenthal JL, Bakel LA, Parkin PC, Cabana MD. Preventing exacerbations in preschoolers with recurrent wheeze: A meta-analysis. Pediatrics 2016;137.
2. Castro-Rodriguez JA, Beckhaus AA, Forno E. Efficacy of oral corticosteroids in the treatment of acute wheezing episodes in asthmatic preschoolers: Systematic review with meta-analysis. Pediatr Pulmonol 2016;51:
What’s new in GINA 2018?

16. Other changes Primary prevention of asthma
A systematic review of randomized controlled trials on maternal dietary intake of fish or long-chain polyunsaturated fatty acids during pregnancy showed no consistent effects on the risk of wheeze, asthma or atopy in the child (Best Am J Clin Nutr 2016)
One recent study demonstrated decreased wheeze/asthma in pre-school children at high risk for asthma when mothers were given a high dose fish oil supplement in the third trimester (Bisgard NEJM 2016); but ‘fish oil’ is not well defined, and the optimal dosing regimen has not been established
1. Best KP, Gold M, Kennedy D, Martin J, Makrides M. Omega-3 long-chain PUFA intake during pregnancy and allergic disease outcomes in the offspring: a systematic review and meta-analysis of observational studies and randomized controlled trials. Am J Clin Nutr 2016;103:
2. Bisgaard H, Stokholm J, Chawes BL, Vissing NH, Bjarnadottir E, Schoos AM, Wolsk HM, et al. Fish oil-derived fatty acids in pregnancy and wheeze and asthma in offspring. N Engl J Med 2016;375:
What’s new in GINA 2018?

17. New GINA resources
A practical pocket guide for assessment and management of patients with difficult to treat and severe asthma is being developed
Planned for publication in Q2 or Q3 2018
Resources for the asthma toolbox are being pilot-tested and will be added to the GINA website