Symposium: Overview of the 2007 NHLBI Asthma Guidelines

Pharmacotherapy of asthma: What do the 2007 NAEPP

guidelines say?
Michael Schatz, M.D., M.S.

ABSTRACT
The purpose of this article is to review the recommendations for pharmacotherapy in the new National Asthma Education
and Prevention Program (NAEPP) guidelines. There are four main changes regarding pharmacotherapy in the updated
guidelines. First, the recommendations for three age groups (0 – 4 years, 5–11 years, and ⱖ12 years) are presented separately.
Second, the steps of therapy have been expanded from 4 steps to 6 steps to simplify the action within each step. Third, medium
dose inhaled corticosteroids (ICS) or low-dose ICS plus add-on therapy are recommended for patients 5 years of age and older
who are not controlled on low dose ICS. Finally, consideration of omalizumab is recommended for allergic patients 12 years of
age and older who are not controlled on medium dose ICS plus long-acting beta agonists. For all age groups, the first step of
therapy is inhaled short-acting beta agonists as needed and the second step is low dose ICS. Oral corticosteroids are part of step
6 therapy for all age groups. In patients not already on long-term control medications, the step of initiation of therapy is based
on the assessment of severity. In patients on long-term control medications, therapy is adjusted based on the level of asthma
control. If the patient is not well controlled, therapy is usually advanced one step. If the patient is very poorly controlled,
consider stepping up two steps, a course of oral corticosteroids, or both. It is hoped that the updated NAEPP guidelines will
lead to improved quality of life for patients with asthma.
(Allergy Asthma Proc 28:628 –633, 2007; doi: 10.2500/aap.2007.28.3061)
Key words: Asthma, guidelines, inhaled corticosteroids, long-acting beta-agonists, leukotriene-receptor agonists,
pharmacotherapy, short-acting beta-agonists

A sthma is a common chronic illness that causes

substantial morbidity. In an effort to improve the
care and outcomes of patients with asthma, the Na-
therapy recommendations can be found in the com-
plete guidelines.1

tional Asthma Education and Prevention Program has
developed and disseminated Guidelines for the Diag-
nosis and Management of Asthma. The first such
guidelines were published in 1991, and the most recent
guidelines were released in August, 2007.1 The pur-
pose of this article is to review the recommendations
for pharmacotherapy in the new guidelines. Although
this article will focus on pharmacotherapy, this is but
one aspect of optimal long-term clinical management
of patients with asthma discussed in the guidelines
(Table 1). The detailed rationale for these pharmaco-
From the Department of Allergy, Kaiser-Permanente Medical Center, San Diego,
California
Presented at the Post-Conference Symposium of the Eastern Allergy Conference, Palm
Beach, Florida, May 13, 2007
Supported by an unrestricted educational grant from Genentech, Inc.
Address correspondence and reprint requests to Michael Schatz, M.D., M.S., Kaiser-
Permanente Medical Center, 7060 Clairemont Mesa Boulevard, San Diego, CA 92111
Email-address: michael.x.schatz@kp.org
Copyright © 2007, OceanSide Publications, Inc., U.S.A.
MAJOR PHARMACOTHERAPY CHANGES IN
NEW GUIDELINES
Regarding pharmacotherapy, there are four main
changes in the EPR3 guidelines from prior versions.
First, the recommendations for three age groups are
presented separately: 0 – 4 years, 5–11 years, and ⱖ12
years. Second, the steps of therapy have been ex-
panded from 4 steps to 6 steps to simplify the action
Table 1 Long-term management of asthma
Confirm diagnosis
Identify and address relevant environmental factors
and comorbid conditions
Assess severity or control (impairment and risk) and
use step therapy to achieve control
Provide self-management education and action plan
(daily actions and actions to adjust treatment for
increased symptoms)
Follow patient to be sure control is maintained at
lowest effective dose of medications

628 November–December 2007, Vol. 28, No. 6

 Persistent Asthma: Daily Medication
Intermittent
Consult with asthma specialist if step 3 care or higher is required.
Asthma
Consider consultation at step 2.

Step 6
Step up if
Step 5 Preferred: needed
Preferred:
Step 4 High-dose ICS + (first, check
High-dose ICS + either adherence,
Preferred: LABA or inhaler
Step 3 either
Montelukast
Medium-dose
LABA or technique, and
Preferred: Montelukast environmental
Step 2 ICS + either Oral systemic
Medium-dose LABA or corticosteroids control)
Preferred: ICS Montelukast
Step 1 Low-dose ICS Assess
Preferred: control
Alternative:
SABA PRN Cromolyn or Step down if
Montelukast possible
(and asthma is
well controlled
Patient Education and Environmental Control at Each Step at least
3 months)
Quick-Relief Medication for All Patients
• SABA as needed for symptoms. Intensity of treatment depends on severity of symptoms.
• With viral respiratory infection: SABA q 4–6 hours up to 24 hours (longer with physician consult). Consider short course of oral
systemic corticosteroids if exacerbation is severe or patient has history of previous severe exacerbations.
• Caution: Frequent use of SABA may indicate the need to step up treatment. See text for recommendations on initiating daily
long-term-control therapy.

Key: Alphabetical order is used when more than one treatment option is listed within either preferred or
alternative therapy. ICS, inhaled corticosteroid; LABA, inhaled long-acting beta2-agonist; SABA, inhaled short-
acting beta2-agonist

Notes:
+ The stepwise approach is meant to assist, not replace, the clinical decisionmaking required to meet individual
patient needs.
+ If alternative treatment is used and response is inadequate, discontinue it and use the preferred treatment before
stepping up.
+ If clear benefit is not observed within 4–6 weeks and patient/family medication technique and adherence are
satisfactory, consider adjusting therapy or alternative diagnosis.
+ Studies on children 0–4 years of age are limited. Step 2 preferred therapy is based on Evidence A. All other
recommendations are based on expert opinion and extrapolation from studies in older children.
Figure 1. Stepwise approach for managing asthma in children 0 – 4 years of age.

within each step. Third, medium dose inhaled cortico-
steroids (ICS) OR low dose ICS plus add-on therapy
are recommended for patients 5 years of age and older
who are not controlled on low dose ICS. The choice
between these alternatives should be individualized
based on the preferences and circumstances of the
individual patient and clinician. Finally, consideration
of omalizumab is recommended for allergic patients 12
years of age and older who are not controlled on
medium dose ICS plus long-acting beta agonists
(LABA).
STEPS OF THERAPY
For all age groups, each step of therapy identifies
preferred medications, which represent the best bal-
ance of efficacy and safety in clinical trials for pa-
tients at that level of severity. However, pharmaco-
therapy must still be tailored to individual patients’
needs, circumstances, and responsiveness. For all
age groups, the first step of therapy is inhaled short-
acting beta agonists as needed and the second step of
therapy is low dose inhaled corticosteroids. Oral

Allergy and Asthma Proceedings 629

 Persistent Asthma: Daily Medication
Intermittent
Consult with asthma specialist if step 4 care or higher is required.
Asthma Consider consultation at step 3.

Step up if
Step 6 needed
Step 5
Preferred:
Preferred: (first, check
Step 4 adherence,
High-dose ICS + High-dose ICS
Preferred: + LABA + oral inhaler
Step 3 LABA
systemic technique,
Medium-dose
Preferred: Alternative: corticosteroid environmental
Step 2 ICS + LABA
EITHER: High-dose ICS + Alternative: control, and
Preferred: Alternative: either LTRA or comorbid
Low-dose ICS + High-dose ICS +
Low-dose ICS Theophylline conditions)
either LABA, Medium-dose
Step 1 LTRA, or ICS + either
either LTRA or
Alternative: Theophylline + Assess
Preferred: Theophylline LTRA or oral systemic
Cromolyn, LTRA, control
OR Theophylline corticosteroid
SABA PRN Nedocromil, or
Theophylline Medium-dose Step down if
ICS
possible
(and asthma is
Each step: Patient education, environmental control, and management of comorbidities. well controlled
Steps 2−4: Consider subcutaneous allergen immunotherapy for patients who have allergic asthma at least
(see notes). 3 months)
Quick-Relief Medication for All Patients

• SABA as needed for symptoms. Intensity of treatment depends on severity of symptoms: up to 3 treatments at 20-minute
intervals as needed. Short course of oral systemic corticosteroids may be needed.
• Caution: Increasing use of SABA or use >2 days a week for symptom relief (not prevention of EIB) generally indicates
inadequate control and the need to step up treatment.

Key: Alphabetical order is used when more than one treatment option is listed within either preferred or
alternative therapy. ICS, inhaled corticosteroid; LABA, inhaled long-acting beta2-agonist, LTRA, leukotriene
receptor antagonist; SABA, inhaled short-acting beta2-agonist
Notes:
+ The stepwise approach is meant to assist, not replace, the clinical decisionmaking required to meet individual
patient needs.
+ If alternative treatment is used and response is inadequate, discontinue it and use the preferred treatment before
stepping up.
+ Theophylline is a less desirable alternative due to the need to monitor serum concentration levels.
+ Step 1 and step 2 medications are based on Evidence A. Step 3 ICS + adjunctive therapy and ICS are based on
Evidence B for efficacy of each treatment and extrapolation from comparator trials in older children and adults—
comparator trials are not available for this age group; steps 4–6 are based on expert opinion and extrapolation
from studies in older children and adults.
+ Immunotherapy for steps 2–4 is based on Evidence B for house-dust mites, animal danders, and pollens; evidence
is weak or lacking for molds and cockroaches. Evidence is strongest for immunotherapy with single allergens.
The role of allergy in asthma is greater in children than in adults. Clinicians who administer immunotherapy should
be prepared and equipped to identify and treat anaphylaxis that may occur.
Figure 2. Stepwise approach for managing asthma in children 5–11 years of age.

Table 2 Initiation of step therapy in patients not on long-term control medications

Severity Age 0 – 4 Age 5–11 Age >12
Intermittent Step 1 Step 1 Step 1
Mild persistent Step 2 Step 2 Step 2
Moderate persistent Step 3* Step 3 (medium dose ICS option)* Step 3*
Severe persistent Step 3* Step 3 (medium dose ICS option) or Step 4* Step 4 or 5*
*Consider course of oral corticosteroids.

630 November–December 2007, Vol. 28, No. 6

 Persistent Asthma: Daily Medication
Intermittent
Consult with asthma specialist if step 4 care or higher is required.
Asthma Consider consultation at step 3.

Step 6 Step up if
Step 5 Preferred:
needed
Preferred: High-dose (first, check
Step 4 High-dose ICS + LABA + oral adherence,
ICS + LABA corticosteroid environmental
Step 3 Preferred:
Medium-dose ICS AND control, and
Preferred: AND
comorbid
+ LABA
Step 2 Low-dose Consider conditions)
ICS + LABA Consider
Preferred: OR Alternative: Omalizumab for Omalizumab for
Low-dose ICS patients who have patients who have
Step 1 Medium-dose ICS Medium-dose ICS
allergies allergies Assess
Alternative: Alternative: + either LTRA,
Preferred: Cromolyn, LTRA, Theophylline, or control
Low-dose ICS +
Nedocromil, or either LTRA, Zileuton
SABA PRN
Theophylline Theophylline, or
Zileuton Step down if
possible
(and asthma is
Each step: Patient education, environmental control, and management of comorbidities. well controlled
Steps 2−4: Consider subcutaneous allergen immunotherapy for patients who have allergic asthma (see notes). at least
3 months)
Quick-Relief Medication for All Patients

• SABA as needed for symptoms. Intensity of treatment depends on severity of symptoms: up to 3 treatments at 20-minute intervals
as needed. Short course of oral systemic corticosteroids may be needed.
• Use of SABA >2 days a week for symptom relief (not prevention of EIB) generally indicates inadequate control and the need to step
up treatment.

Key: Alphabetical order is used when more than one treatment option is listed within either preferred or
alternative therapy. EIB, exercise-induced bronchospasm; ICS, inhaled corticosteroid; LABA, long-acting inhaled
beta2-agonist; LTRA, leukotriene receptor antagonist; SABA, inhaled short-acting beta2-agonist

Notes:
+ The stepwise approach is meant to assist, not replace, the clinical decisionmaking required to meet individual
patient needs.
+ If alternative treatment is used and response is inadequate, discontinue it and use the preferred treatment before
stepping up.
+ Zileuton is a less desirable alternative due to limited studies as adjunctive therapy and the need to monitor liver
function. Theophylline requires monitoring of serum concentration levels.
+ In step 6, before oral systemic corticosteroids are introduced, a trial of high-dose ICS + LABA + either LTRA,
theophylline, or zileuton may be considered, although this approach has not been studied in clinical trials.
+ Step 1, 2, and 3 preferred therapies are based on Evidence A; step 3 alternative therapy is based on Evidence A
for LTRA, Evidence B for theophylline, and Evidence D for zileuton. Step 4 preferred therapy is based on
Evidence B, and alternative therapy is based on Evidence B for LTRA and theophylline and Evidence D for
zileuton. Step 5 preferred therapy is based on Evidence B. Step 6 preferred therapy is based on (EPR? 2 1997)
and Evidence B for omalizumab.
+ Immunotherapy for steps 2–4 is based on Evidence B for house-dust mites, animal danders, and pollens;
evidence is weak or lacking for molds and cockroaches. Evidence is strongest for immunotherapy with single
allergens. The role of allergy in asthma is greater in children than in adults.
+ Clinicians who administer immunotherapy or omalizumab should be prepared and equipped to identify and treat
anaphylaxis that may occur.
Figure 3. Stepwise approach for managing asthma in youths ⱖ12 years of age and adults.

Allergy and Asthma Proceedings 631

Table 3 Criteria for initiating asthma long-term control therapy in children 0 – 4 years of age
1. Persistent asthma based on impairment
2. Two or more exacerbations requiring systemic corticosteroids within 6 months
3. Four or more wheezing episodes in past year that lasted ⬎1 day and affected sleep AND a positive asthma
risk profile:
One or more of the following
Parental history of asthma
Physician’s diagnosis of atopic dermatitis
Sensitization to aeroallergens
OR
Two of the following
Sensitization to foods
ⱖ4% peripheral blood eosinophilia
Wheezing apart from colds
corticosteroids represent step 6 therapy for all age
groups. Although there are few data on the efficacy
of the use of three long-term control medications in
patients not controlled on high dose ICS plus add-on
therapy, a therapeutic trial of three long-term con-
troller medications may be reasonable before resort-
ing to long-term oral corticosteroid therapy for pa-
tients in all age groups.
Age 0 – 4
Treatments are less well studied in this age group
than in older children and adults. Alternative step 2
therapy in children 4 years of age or less is either
montelukast or cromolyn. Preferred step 3 therapy is
medium dose ICS. Preferred step 4 therapy is medium
dose ICS plus either montelukast or a LABA. Preferred
step 5 therapy is high dose ICS plus either montelukast
or a LABA. Consultation with an asthma specialist is
recommended if step 3 care or higher is required. (See
Fig. 1).
Age 5–11
Alternative step 2 therapy in children ages 5–11 in-
clude a leukotriene receptor antagonist (LTRA), cro-
molyn, nedocromil, or theophylline. Preferred Step 3
therapy in this age group is either medium dose ICS or
low dose ICS plus LABA, LTRA, or theophylline. Pre-
ferred step 4 therapy is medium dose ICS plus LABA,
with alternative therapy being medium dose ICS plus
either LTRA or theophylline. Preferred step 5 therapy
is high dose ICS plus LABA with alternative therapy
being high dose ICS plus either LTRA or theophylline.
Consultation with an asthma specialist is recom-
mended if step 4 care or higher is required in this age
group. (See Fig. 2).
Age >12
As in children older than age 5, alternative step 2
therapy in patients 12 years of age or older includes an
632
LTRA, cromolyn, nedocromil, or theophylline. Pre-
ferred step 3 therapy in this age group is either me-
dium dose ICS or low dose ICS plus LABA. Alternative
therapy at this step is ICS plus LTRA, theophylline, or
zileuton. Preferred step 4 therapy is medium dose ICS
plus LABA, with alternative add-on therapy including
LTRA, theophylline, or zileuton. Preferred step 5 ther-
apy in patients aged 12 or older is high dose ICS plus
LABA. Consideration of omalizumab is recommended
at Steps 5 and 6 for allergic patients 12 years of age or
older, and consultation with an asthma specialist is
recommended if step 4 care or higher is required in this
age group. (Fig. 3).
INITIATION OF THERAPY
In patients not already on long-term control medica-
tions, the step of initiation of therapy is based on the
assessment of severity (Table 2). For children 0 – 4 years
of age, in whom asthma symptoms are frequently ep-
isodic, there are additional considerations for initiating
long-term controller therapy (Table 3). Although not
explicitly stated in the guidelines, long-term control
medication would presumably start at step 2 in these
children.
ADJUSTING THERAPY
In patients on long-term control medications, ther-
apy is adjusted based on the level of asthma control. If
the patient is not well controlled, therapy is usually
advanced one step. If the patient is very poorly con-
trolled, consider stepping up two steps, a course of oral
corticosteroids, or both. Before stepping up pharmaco-
logical therapy in patients with uncontrolled asthma,
consider as targets for therapy adverse environmental
exposures, poor inhaler technique or adherence, and
comorbidities.
Visits every 2– 6 weeks are recommended until con-
trol is achieved. When control is achieved, contact ev-
ery 3– 6 months is suggested. A step-down in therapy
November–December 2007, Vol. 28, No. 6
can be considered with well-controlled asthma for at
least 3 months. One may decrease inhaled corticoste-
roids by 25–50% every 3 months to the lowest effective
dose. It must be recognized, though, that patients may
relapse with total discontinuation of inhaled corticoste-
roids.
CONCLUSION
The new NAEPP guidelines have tried to translate
the most relevant clinical studies into practical recom-
Allergy and Asthma Proceedings
mendations for the pharmacotherapy of asthma. It is
hoped that these updated recommendations for
asthma pharmacotherapy, in conjunction with the
overall guidelines for the diagnosis and management
of asthma, will lead to improved quality of life and
reduced impairment and risk for patients with asthma.
REFERENCES
1. Available on-line at www.nhlbi.nih.gov/guidelines/asthma/
asthgdln.pdf e
633
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