10. Yellow Zone Therapy Options

Yellow zone therapies are hotly debated in regard to treatment.

In the EPR 4, the expert panel reviewed the use of intermittent ICS and looking at three critical outcomes (exacerbations, asthma control and quality of life) and one important outcome (rescue medication use for this question) for asthma. There were no differences in asthma control, quality of life, in rescue therapy using the two types of intermittent ICS therapy (ICS paired with albuterol in two studies and yellow zone ICS in one study) compared to daily ICS in three studies in youth ages 12 years and older and adults with a high certainty evidence. There were also no differences in exacerbations between groups in any of the three studies but the strength of the evidence for exacerbations was low.

Highlights are below:

In children 0-4 years, with intermittent symptoms (no symptoms between illnesses), conditional recommendation of ICS + SABA concomitantly on an as needed basis at onset of respiratory infection.
In individuals ages 4 years and older with mild to moderate persistent asthma who are likely to be adherent to daily ICS treatment, the Expert Panel conditionally recommends against a short-term increase in the ICS dose for increased symptoms or decreased peak flow. This is due to lack of improvement but also concerns regarding growth. Recommendation against doubling, quadrupling or quintupling.
For those over age 16, who are possibly non-adherent, consideration can be given to increasing ICS dosing in Yellow zone.
For those individuals 4 years of age or older with moderate or severe persistent asthma, ICS/Formoterol as maintenance and reliever therapy is recommended if uncontrolled on present therapies.

A summary of the yellow zone research is below.

YELLOW ZONE THERAPY	PARTICIPANT AGE	FINDINGS	REFERENCE
Intermittent ICS	Children <6 years of age	High dose ICS reduced viral induced exacerbations by 35%	Kaiser, Sunitha V., et al. "Preventing exacerbations in preschoolers with recurrent wheeze: a meta-analysis." Pediatrics 137.6 (2016).
Intermittent ICS	School age children and adults	Reduction in oral corticosteroids but low quality evidence	Chong, Jimmy, et al. "Intermittent inhaled corticosteroid therapy versus placebo for persistent asthma in children and adults." Cochrane Database of Systematic Reviews 7 (2015).
Doubling Maintenance ICS dose	6-14 years old	No difference in PEFR	Garrett, J., et al. "Treatment of acute asthmatic exacerbations with an increased dose of inhaled steroid." Archives of disease in childhood 79.1 (1998): 12-17.
	16 years of age and above	No difference in OCS use, unscheduled doctor’s visits, symptom recovery time, PEFR recovery time	Harrison, T. W., et al. "Doubling the dose of inhaled corticosteroid to prevent asthma exacerbations: randomised controlled trial." The Lancet 363.9405 (2004): 271-275.
	Children and adults	No difference in OCS use or doctor’s visits	Quon, Bradley S., et al. "Increased versus stable doses of inhaled corticosteroids for exacerbations of chronic asthma in adults and children." Cochrane Database of Systematic Reviews 10 (2010).
Quadrupling maintenance ICS dose	16 years of age and above	Reduction in exacerbations, OCS use, unscheduled provider visits NEJM 2018 demonstrated a benefit where compliance with baseline ICS was in question. *Quadrupling ICS in patients 16 years of age and above may be most useful in those that are likely nonadherent.	Oborne, Janet, et al. "Quadrupling the dose of inhaled corticosteroid to prevent asthma exacerbations: a randomized, double-blind, placebo-controlled, parallel-group clinical trial." American journal of respiratory and critical care medicine 180.7 (2009): 598-602. McKeever, Tricia, et al. "Quadrupling inhaled glucocorticoid dose to abort asthma exacerbations." New England Journal of Medicine 378.10 (2018): 902-910.
Quintupling maintenance ICS dose	5-11 years old	No difference in OCS use, time to first exacerbation, symptom scores, albuterol use while in yellow zone	Jackson, Daniel J., et al. "Quintupling inhaled glucocorticoids to prevent childhood asthma exacerbations." New England Journal of Medicine 378.10 (2018): 891-901.
Single Maintenance and Reliever Therapy (SMART)	4-11 years old (Bisgaard et al) 11-79 years old (Rabe et al)	Compared with fixed dose ICS, SMART therapy resulted in prolonged time to first exacerbation and reduction in medically treated exacerbations by 70-79%	Bisgaard, Hans, et al. "Budesonide/formoterol maintenance plus reliever therapy: a new strategy in pediatric asthma." Chest 130.6 (2006): 1733-1743. Rabe, Klaus F., et al. "Effect of budesonide in combination with formoterol for reliever therapy in asthma exacerbations: a randomised controlled, double-blind study." The Lancet 368.9537 (2006): 744-753.
	12 years of age and older	SMART therapy resulted in reduction of medically treated exacerbations compared with inhaled corticosteroids alone	Slawson, David C. "Single Maintenance and Reliever Therapy More Effective Than Inhaled Corticosteroids and Beta Agonists for Asthma." American family physician 98.6 (2018): 383-384.
	12 years of age and older	SMART therapy inferior to daily inhaled corticosteroids in reduction of annualized exacerbation rates	O’Byrne, Paul M., et al. "Inhaled combined budesonide–formoterol as needed in mild asthma." New England Journal of Medicine 378.20 (2018): 1865-1876.

10. Yellow Zone Therapy Options

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