Asthma in Sickle Cell Disease: Implications for Treatment
Objective. To review issues related to asthma in sickle cell disease and management strategies. Data Source. A systematic review of pertinent original research publications, reviews, and editorials was undertaken using MEDLlNE, the Cochrane Library databases, and CINAHL from 1947 to November 2010. Search terms were [asthma] and [sickle cell disease]. Additional publications considered relevant to the sickle cell disease population of patients were identified; search terms included [sickle cell disease] combined with [acetaminophen], [pain medications], [vitamin D], [beta agonists], [exhaled nitric oxide], and [corticosteroids]. Results. The reported prevalence of asthma in children with sickle cell disease varies from 2% to approximately 50%. Having asthma increases the risk for developing acute chest syndrome , death, or painful episodes compared to having sickle cell disease without asthma. Asthma and sickle cell may be linked by impaired nitric oxide regulation, excessive production of leukotrienes, insufficient levels of Vitamin D, and exposure to acetaminophen in early life. Treatment of sickle cell patients includes using commonly prescribed asthma medications; specific considerations are suggested to ensure safety in the sickle cell population. Conclusion. Prospective controlled trials of drug treatment for asthma in patients who have both sickle cell disease and asthma are urgently needed.
Hindawi Publishing Corporation
Volume 2011, Article ID 740235, 15 pages
Review A rticle
Asthma in Sickle Cell Disease: Implications for Treatment
Kathryn Blake and John Lima
Biomedical Research Department, Center for Clinical Pharmacogenomics and Translational Research, Nemours Children’s Clinic,
807 Children’s Way, Jacksonville, FL 32207, USA
Correspondence should be addressed to Kathryn Blake, email@example.com
Received 17 August 2010; Revised 9 November 2010; Accepted 13 December 2010
Academic Editor: Maurizio Longinotti
Copyright © 2011 K. Blake and J. Lima. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
Objective. To review issues related to asthma in sickle cell disease and management strategies. Data Source. A systematic review of
pertinent original research publications, reviews, and editorials was undertaken using MEDLlNE, the Cochrane Library databases,
and CINAHL from 1947 to November 2010. Search terms were [asthma] and [sickle cell disease]. Additional publications
considered relevant to the sickle cell disease population of patients were identiﬁed; search terms included [sickle cell disease]
combined with [acetaminophen], [pain medications], [vitamin D], [beta agonists], [exhaled nitric oxide], and [corticosteroids].
Results. The reported prevalence of asthma in children with sickle cell disease varies from 2% to approximately 50%. Having
asthma increases the risk for developing acute chest syndrome , death, or painful episodes compared to having sickle cell disease
without asthma. Asthma and sickle cell may be linked by impaired nitric oxide regulation, excessive production of leukotrienes,
insuﬃcient levels of Vitamin D, and exposure to acetaminophen in early life. Treatment of sickle cell patients includes using
commonly prescribed asthma medications; speciﬁc considerations are suggested to ensure safety in the sickle cell population.
Conclusion. Prospective controlled trials of drug treatment for asthma in patients who have both sickle cell disease and asthma are
Asthma and sickle cell disease are interrelated, and the
presence of asthma increases morbidity and mortality in
sickle cell patients. This paper discusses the relationships
between asthma and sickle cell disease and suspected patho-
physiological commonalities. A review of guideline appro-
priate treatment in patients with asthma without sickle cell
disease and speciﬁc recommendations for sickle cell patients
in the treatment of persistent asthma and acute asthma
exacerbation is provided. Speciﬁc cautions for use of β
agonists, leukotriene modiﬁers, and systemic corticosteroid
therapies in patients with sickle cell disease are provided.
2. Search Strategy
The PubMed search engine of the National Library of
Medicine was used to identify English-language and non-
English language articles published from 1947 to November
2010 pertinent to asthma in sickle cell disease. Keywords
and topics included: asthma, sickle cell disease, acute chest
syndrome, drug classes and speciﬁc drug names used in the
treatment of asthma, vitamin D, acetaminophen, exhaled
nitric oxide, QTc, and pharmacogenetics. The same strategy
was used for the Cochrane Library Database and CINAHL.
Reference types included randomized controlled trials,
reviews, and editorials. All publications were reviewed by the
authors and those most relevant were used to support the
topics covered in this paper.
3. Epidemiology and the Comorbidities:
Asthma and Sickle Cell Disease
Sickle cell disease is a common genetic disorder believed to
aﬀect up to 100,000 persons in the United States though
the actual prevalence is unknown [1, 2]. It occurs in
approximately 1 in 350 African Americans,1 in every 32,000
Hispanic Americans (western states), and 1 in 1,000 Hispanic
Americans (eastern states) [1, 3].
Asthma aﬀects 23 mil l ion persons in the US (8 in
every 100 persons) . The prevalence rate of people ever
told that they had asthma was 115/1000 persons in 2007
. African-American children ages 0 to 17 years old are
disproportionately aﬀected having a 62% greater prevalence
rate for asthma than European Caucasians (12.8% versus
7.9%, resp.), a 250% higher hospitalization rate, and a 500%
higher death r ate .
There is now ample evidence that asthma is a com-
monly occurring comorbidity in children with sickle cell
disease. The diagnosis of asthma often includes evidence of
airway bronchodilator response to inhaled β
bronchoconstriction in response to methacholine, cold air,
or exercise in addition to medical history. The published
reported prevalence of asthma in children with sickle cell
disease has varied from 2% to approximately 50% [6–12].
Even more children appear to have airway dysfunction as
the prevalence of airways hyperresponsiveness, measured by
bronchodilator response to inhaled β
agonists or bron-
choconstrictive response to cold air or exercise, ranges from
40% to 77% of sickle cell disease patients [7–11, 13]. While
airways hyperresponsiveness can occur in the absence of
asthma, the large disparity between the prevalence of airways
hyperresponsiveness and asthma suggests that asthma could
be underdiagnosed in the sickle cell disease population.
However, a recent study found no relationship between
asthma diagnosis and other asthma indices and airway
hyperresponsiveness measured by methacholine sensitivity
It is not yet known if asthma in sickle cell disease is a
disease resulting from sickle cell disease pathophysiology or
caused by similar genetic and env ironmental factors found
in t ypical asthma. A recent study determined that even
after controlling for a personal history of asthma in the
child with sickle cell disease, simply having a sibling with
asthma increased sickle cell disease morbidity (pain: 1.91
episodes/year, 95% conﬁdence interval (CI)
acute chest syndrome (ACS): 1.48 episodes/year, 95% CI
0.97–2.26) . While these data do not distinguish between
a genetic versus environmental eﬀect on asthma, results from
a segregation analysis study of the familial pattern of inheri-
tance of asthma found that a major gene eﬀect was present
and followed Mendelian expectations . These ﬁndings
suggest that asthma in sickle cell disease patients is likely a
comorbid condition rather than a disease due to sickle cell
disease induced airway inﬂammation/bronchoconstriction.
4. Risks of Acute Chest Syndrome and Death in
Children with Sickle Cell Disease and Asthma
The presence of asthma in sickle cell disease patients carries
signiﬁcant risks of morbidity and mortality in excess of that
found in children with sickle cell disease without asthma
[5, 17]. Acute chest syndrome is characterized by a new
pulmonary inﬁltrate with fever and/or signs and symptoms
of respiratory distress. A strong relationship is present
between having asthma and risk for developing acute chest
syndrome . Children with sickle cell disease and asthma
Number of episodes (x)
Linear probability model
Proportion having asthma, P(x)
Figure 1: Prevalence of physician-diagnosed asthma and ACS
episodes. The proportion of SCD patients having physician diag-
nosed asthma was plotted against the number of episodes of ACS
in children with SCD. SCD: sickle cell disease, ACS: acute chest
syndrome, reproduced with permission from .
have a greater than 5-fold risk of de veloping acute chest
syndrome compared to children with sickle cell disease but
without asthma (Figure 1)[8, 17–19]. The median time to an
acute chest syndrome event in children with asthma has been
observed to be shorter by nearly half compared to children
without asthma . The diagnosis of asthma tends to
precede the ﬁrst episode of acute chest syndrome by 0.5 to 7
years suggesting that the presence of asthma may predispose
children to developing acute chest syndrome . In one
study, asthma increased the risk of acute chest syndrome the
greatest in children aged 2 to 4 years, and continues to confer
a greater risk of ACS until at least 12 years of age .
It is likely that the increased rate of acute chest syndrome
in children with asthma contributes to greater mortality in
this group. Children who experience acute chest syndrome
early in life are at risk of acute chest syndrome episodes
throughout childhood  and acute chest syndrome con-
tributes to the cause of death in over 60% of patients with
sickle cell disease [23, 24]. One study reported that children
with sickle cell disease with asthma have a 2.36 (hazard ratio)
greater risk of death compared to children with sickle cell
disease w ithout asthma . Despite the st rong association
between asthma and acute chest syndrome, it is not clear
if asthma triggers more frequent episodes of acute chest
syndrome or if children with frequent episodes of acute chest
syndrome are more likely to have asthma [18, 20].
5. Acute Chest Syndrome, Asthma, and
the Nitric Oxide Pa thway
Perturbations of the nitric oxide pathway contribute to the
pathophysiology of both asthma and sickle cell disease.
Under homeostatic conditions, arginine is a substrate for the
arginase I and II, and nitric oxide synthase (NOS; isoforms
1, 2, and 3) enzymes and these enzymes coregulate the
function of each other . In asthma, arg inine metabo-
lized by arginase forms ornithine and subsequently forms
polyamines and proline leading to smooth muscle contrac-
tion, collagen formation, and cell proliferation ; whereas
arginine metabolized by NOS produces nitric oxide (NO)
which also produces epithelial damage and airway hyperre-
activity . Upregulation of NOS2, and contributions from
NOS1 and NOS3, results in greater production of NO which
can be measured in expired air. Exhaled NO is increasingly
used as clinical biomarker of airway inﬂammation and
response to anti-inﬂammatory treatment [27–30]. In sickle
cell disease, erythrocyte hemolysis increases availability of
plasma arginase, which increases production of ornithine,
polyamines, and proline from arginine [31, 32]. Less arginine
is available as a substrate for NOS and production of NO
is decreased in this population [ 31 –33]. However, there are
currently no data directly linking disruptions in NO pathway
homeostasis in the vasculature to that occurr ing in the lung.
The signaling mechanisms regulating enzyme activity and
metabolism of L-arginine are exceedingly complex and the
eﬀect of polymorphisms in the arginase and NOS genes on
nitric oxide and ornithine production are only beginning to
Despite the known alterations in the arginine pathway
in sickle cell disease resulting in reduced NO formation, the
association between fraction of expired NO (FE
and frequency of ACS events is not consistent [33–36]. It
is possible that polymorphisms in the nit ric oxide pathway
may modify this relationship as the greater the number
of nitric oxide synthase gene 1 (NOS1) AAT repeats, the
lower the FE
levels in children with sickle cell disease
. Furthermore, in sickle cell patients without asthma
but not in those with asthma, the number of AAT repeats
associates with the risk of acute chest syndrome (r
(Figure 2). If future studies conﬁrm that this NOS1
polymor phism could be used to identify those children
whose acute chest syndrome episodes are unrelated to
asthma versus those whose acute chest syndrome episodes
are related to asthma, one could speculate that treatment
strategies may diﬀer for the management of acute chest
syndrome events (see Section 16). Currently however, there
are no data describing the relationship between exhaled
nitric oxide levels and acute chest syndrome in children with
sickle cell disease and asthma.
6. Painful Episodes and Respiratory Symptoms
Painful episodes, deﬁned as body pain complaints (excluding
head pain) which require administration of opioids, are the
most common cause of morbidity in sickle cell disease and
are associated with an increased risk of early death .
Children with >3 episodes of pain per year have higher
reports of breathing diﬃculty and chest pain . Pain
occurs at least 2 times more frequently in children with
asthma and sickle cell disease compared to those without
asthma . Monthly episodes of mild-to-moderate pain
<12 12 13 14 15 16
AAT repeat number in intron 13 of NOS1
Risk acute chest syndrome
Sickle cell patients with asthma
Sickle cell patients without asthma P
Quadratic regression line for SCDNA
^y = 0.82 − 0.22x +0.03x
Mean ± SD = 0.87 ± 0.09
= 0.49 ± 0.12Mean ± SD
Figure 2: Risk of ACS and NOS1 AAT repeats in intron 13. The
risk of ACS (1-[controls/(cases+controls)]) is plotted against the
number of NOS1 AAT repeats in patients with SCD with physician-
diagnosed asthma (closed circles) and without physician- diagnosed
asthma (SCDNA). ACS: acute chest syndrome, NOS1: nitric oxide
synthase 1 gene, SCDNA: sickle cell disease physician diagnosed
asthma, reproduced with permission from .
managed at home occur in up to 40% of children with
sickle cell disease and pain can occur on 30% of days [39,
40]. In children with asthma, respiratory symptoms are 3
concurrently with, painful episodes than in patients without
7. Leukotrienes and Asthma and Pain in
Sickle Cell Disease
Inﬂammatory mediators are increased in both asthma and
sickle cell disease. Leukotrienes, interleukins, soluble vas-
cular adhesion molecules, tumor necrosis factor, and C-
reactive protein are elevated in, and are believed to contribute
to the chronicity of, both asthma and sickle cell disease
[42, 43]. Cysteinyl leukotrienes (LT) are potent mediators
of inﬂammation and are synthesized from arachidonic acid
located in membrane-phospholipids by cytosolic phospho-
lipase A2 in response to stimulation [44, 45]. Arachidonic
acid is converted to 5-hydroperoxyeicosatetraenoic acid and
LTA4 by membrane-bound 5-lipoxygenase (ALOX5) and 5-
lipoxygenase activating protein (FLAP) . In human mast
cells, basophils, eosinophils, and macrophages, LTA4 is con-
verted to LTB4 by LTA4 hydrolase (LTA4H), or is conjugated
with reduced glutathione by LTC4 synthase to form LTC4
. LTC4 is transported to the extracellular space mainly
by the multidrug resistance protein 1 (MRP1) . LTC4 is
converted to LTD4 and LTE4 by γ-glutamyltransferase and
dipeptidase; LTE4 is excreted in the urine and is a measure
of whole body leukotriene production [48–50]. Leukotrienes
can also be produced by transcellular biosynthesis .
Experimentally induced asthma in a transgenic murine
model of sickle cell disease caused greater mortality due
to increased allergic lung inﬂammation (elevations in
eosinophils, eosinophil peroxidase, and IgE le vels) compared
with control sickle cell disease mice without induced asthma
. Eosinophils are a major source of leukotrienes in
asthma and elevations of LTB4 and LTC4 in blood and
LTE4 in urine occur of patients with sickle cell disease
A recent study found that urinary LTE4 levels were
elevated at baseline in children with sickle cell disease
and that hig her levels were associated with a greater than
2-fold increased rate of hospitalization for pain episodes
compared with lower levels in children without sickle cell
disease . Other data show that urinary LTE4 levels
are directly associated with increased rate of pain and
acute chest syndrome episodes in sickle cell disease patients
8. Leukotriene Pathway Genes in Asthma and
Sickle Cell Disease
Typical symptoms of asthma caused by cysteinyl leukotrienes
(LTC4, LTD4, and LTE4) are mediated by the cysteinyl
leukotriene-1 and cysteinyl l eukotriene-2 receptors [44, 58,
59]. The ALOX5 gene located on 10q11.21 encodes ALOX5,
a key enzyme in the synthesis of cysteinyl leukotrienes
. Early studies identiﬁed addition and deletion variants
= 5; variant n
= 5) in the core promoter of the
ALOX5 gene that were associated with diminished promoter-
reporter activity in tissue culture  which has been con-
ﬁrmed in both healthy African Amer icans and patients with
asthma [61, 62]. Recently, expression of 5-lipoxygenase and
5-lipoxygenase activating protein were shown to be elevated
in peripheral blood mononuclear cells from patients with
sickle cell disease . Increased expression was mediated
by placenta growth factor, an angiogenic growth factor, and
increased levels correlated with sickle cell disease severity
[63, 64]. Thus, the leukotriene pathway, and in particular the
ALOX5 gene, are implicated in both asthma and sickle cell
disease severity and morbidity.
9. Potential Relevance of Vitamin D
and Childhood Use of Acetaminophen
on Asthma in Sickle Cell Disease
Several epidemiological and association studies suppor t a
link between hypovitaminosis D (either insuﬃciency or
deﬁciency) and asthma. The prevalence of hypovitaminosis
D among African American youths has been found to
be greater in individuals with asthma (86%) compared
to controls without asthma (19%) . Epidemiological
studies also report an inverse association between maternal
intake of vitamin D and the risk of childhood wheezing and
asthma in oﬀspring [66, 67].
Among individuals with asthma, hypovitaminosis D
has been associated with asthma, asthma severity and
reduced steroid response. Brehm et al reported vitamin D
insuﬃciency in 28% of children with asthma living in Costa
Rica , which is near the equator. Additionally, vitamin
D levels were inversely associated with airway responsiveness
(methacholine challenge), total IgE and eosinophils count.
Increasing vitamin D levels were also associated with reduced
odds of hospitalization and w ith reduced odds of inhaled
corticosteroid use. In a recent study of adults with asthma,
higher vitamin D levels were associated with greater lung
function, while hypovitaminosis D was associated with
increased airway hyperresponsiveness a nd reduced glucocor-
ticoid response . These studies, though small in number,
suggest an important link between hypovitaminosis D and
Vitamin D deﬁciency in sickle cell disease patients has
become well recognized in the past decade. Between 33%
and 76% of children and adults are classiﬁed as Vitamin D
deﬁcient (<10 to12 ng/mL) and 65% to 98% are Vitamin D
insuﬃcient (<20 to 30 ng/mL) [70–75]. There are no reports
of Vitamin D levels in patients with both sickle cell disease
and asthma. It is possible that the low Vitamin D levels
observed in patients with sickle cell disease and patients
with asthma contributes to the signiﬁcantly increased mor-
bidity and mortality that is observed in patients with both
sickle cell disease and asthma compared to those without
Painful vaso-occlusive crises may occur as early as 6 to 12
months of age and monthly episodes of mild-to-moderate
pain managed at home occur in up to 40% of children with
sickle cell disease and pain can occur on 30% of days [39, 40,
76]. Acetaminophen is the most commonly used analgesic
for the management of mild-to-moderate pain  and is
a component of up to 47% of pain medications in children
with sickle cell disease . Thus, patients with sickle cell
disease have signiﬁcant exposure to acetaminophen during
Over the past decade, several publications have reported
an association with acetaminophen use prenatally and
during childhood and an increased risk of developing asthma
. In a worldwide assessment of asthma, acetaminophen
use was associated with an increased r isk of asthma in
young children and adolescents (odds ratio 1.43–3.23)
[79, 80]. Several putative mechanisms have been sug-
gested. The formation of N-acetyle-ρI-benzoquinoneimine,
a highly reactive metabolite of acetaminophen, may result in
decreased glutathione. Glutathione serves as an antioxidant
and oxygen radicals are known to produce tissue injury,
bronchoconstriction and hyperreactivity, and stimulation
of inﬂammatory mediators [78, 81]. Glutathione levels
in alveolar ﬂuid in patients with asthma are associated
with levels of bronchial hyperresponsiveness . Reduced
glutathione may also shift cytokine production from Th1
to Th2 responses. A functional genetic polymorphism in
the glutathione S-transferase P1 gene (GSTP1)ismost
common in Hispanics and African Americans and has been
associated with susceptibility to asthma development and
most recently in the relationship between acetaminophen
use and the subsequent development of asthma [78, 82].
Research is needed to determine if there is an association
between acetaminophen use in early life for the management
of pain in children with sickle cell disease and the increased
prevalence of asthma or airway hyperreactivity.
10. Management of Chronic Asthma in
Patients with Sickle Cell Disease
Medications for the treatment of asthma are classiﬁed as
long-term control or quick-relief medications . Quick-
relief medications include bronchochodilators such as short-
agonists, short-acting anticholinergics, and sys-
temic corticosteroids; long-term control medications include
inhaled corticosteroids with or without long-acting β
agonists, leukotriene modiﬁers, omalizumab, and less com-
monly these days, theophylline and cromolyn. The National
Heart, Lung, and Blood Institute revised the Guidelines
for the Diagnosis and Management of Asthma in 2007 for
diﬀerent age groups (Figures 3 and 4).
For quick relief of symptoms in patients of all ages and
asthma severity, short-acting β
agonists are the preferred
therapy because of the rapid onset of eﬀect and overall
eﬀectiveness in relieving symptoms. They are also the
primary treatment for patients who have intermittent asthma
(Step 1) which is deﬁned as mild impair ment (symptoms less
than twice per week, no interference with n ormal activity,
no nocturnal awakenings, normal forced expiratory volume
in the ﬁrst second (FEV
), and one or fewer exacerbations
requiring oral steroids per year). For patients with mild-to-
severe persistent asthma, long-term control medications are
recommended and inhaled corticosteroids are the preferred
ﬁrst-line drugs with leukotriene modiﬁers, cromolyn, or
theophylline as alternative drugs in children over 5-year-
old and adults. In patients insuﬃciently controlled with
low or medium doses of inhaled corticosteroids, a long-
-agonist, leukotriene modiﬁer, or theophylline may
be added though controversy surrounds the use of adding
a long-acting β
-agonist (see Section 14). Patients with
severe persistent asthma with allergic disease may require
additional add-on treatment with omalizumab or oral
Initial severity classiﬁcation and treatment recommen-
dations and changes are guided by assessments of a
patient’s level of current impairment (symptoms, night-
time awakenings, short-acting β
-agonist use, pulmonary
function, and asthma control questionnaire assessments)
and future risk (exacerbations requiring oral corticosteroid
treatment loss of lung function over time, adverse eﬀects of
There are currently no published data from prospective
controlled trials of drug treatment for asthma symptoms
in patients who have both sickle cell disease and asthma
[32, 84]. At Nemours Children’s Clinic in Florida and
Delaware only 27%, 35%, and 49% of patients w ith sickle
cell disease and physician diagnosed asthma are treated with
a corticosteroid+long acting β
-agonist inhaler, leukotriene
modiﬁer, or corticosteroid inhaler, respectively, suggesting
undertreatment of asthma (personal data). One abstract of
a retrospective analysis observed a reduced rate of pain crises
and acute chest syndrome in children with sickle cell disease
and asthma treated with inhaled corticosteroids
11. Inhaled Short-Acting β
There are two potential concerns with the use of inhaled
agonists in patients with sickle cell disease:
genotype at the β
-adrenergic receptor gene (ADRB2)and
inherent cardiovascular eﬀects of β
Historically, use of inhaled β
agonists for the manage-
ment of asthma has been fraught with controversy relating
to epidemics of increased asthma mortality associated with
their initial introduction in the late1950s [86–89]and
more recently with analysis of drug prescription records
associating use with an increased r isk of death or near death
from asthma . However, a controlled trial of regularly
scheduled albuterol use in patients with asthma with mild
disease to examine potential adverse eﬀects demonstrated
no deterioration in asthma control with albuterol u se .
However, in current practice, regular scheduled use of short
acting inhaled β
agonists is discouraged and as-needed use
is promoted as a way to minimize exposure and to monitor
changes in asthma control. Whether these adverse eﬀects on
asthma control are due to genetic polymorphisms in ADRB2
or inherent pharmacological eﬀects of β
agonists has been
the recent focus of this controversy.
The ADRB2 is a small, intronless gene and two com-
mon nonsynonomous variants at amino acid positions 16
(Gly16Arg) and 27 (Gln27Glu) have functional relevance in
vitro [92, 93], and clinical studies have focused on outcomes
resulting from the Gly16Arg polymorphism. Several retro-
spective studies, though results have been inconsistent, have
found that patients who are homozygous Arg16 have worse
asthma control during regularly scheduled albuterol use
compared to homozygous Gly16 patients [94–97]. However
a carefully controlled prospective study found a better
relative response by patients homozygous for Gly16 treated
with regularly scheduled albuterol compared with patients
who were homozygous Arg16; the authors suggest that
adiﬀerent class of bronchodilator (e.g., anticholinergics)
may be appropriate for patients harboring the homozygous
Arg16 genotype . These ﬁndings are relevant to African
Americans with sickle cell disease because African Americans
are more likely to be homozygous Arg16 (23–30% of the
population) compared to Whites (14–16%) [99, 100]. In
addition, African Americans have a poorer bronchodilator
response to acute use of albuterol compared to Whites
[101, 102] which may place them at risk of overuse of their
albuterol inhaler for relief of symptoms.
Though rare, β
agonists can have adverse cardiovascular
eﬀects including increased atrial or ventricular ectopy and
prolongation of the QTc interval [103, 104]. In patients with
prolonged QTc, the use of β
agonists doubles the risk of
cardiac events (hazard ratio 2.0, 95% CI 1.26, to 3.15) with
a greater risk in the ﬁrst year of use . Because of the
increased frequency of prolonged QTc in patients with sickle
cell disease, β
-agonist use may pose a speciﬁc risk in this
population [32, 105, 106].
Stepwise approach for managing asthma in children 0–4 years of age
Persistent asthma: Daily medication
Consult with asthma specialist if step 3 care or higher is required
Consider consultation at step 2
ICS + either
High-dose ICS +
High-dose ICS +
Step up if
Step down if
(and asthma is
Patient education and environmental control at each step
Quick-relief medication for all patients
systemic corticosteroids if exacerbation is severe or patient has history of previous severe exacerbations.
Stepwise approach for managing asthma in children 5–11 years of age
Persistent asthma: Daily medication
Consult with asthma specialist if step 4 care or higher is required.
Consider consultation at step 3.
Low dose ICS
LTR A, or
ICS + LABA
ICS + either
LTR A o r
High-dose ICS +
High-dose ICS +
either LTRA or
+ LABA + oral
High-dose ICS +
either LTRA or
Eachstep: Patient education, environmental control, and management of comorbidities
Steps 2–4 : Consider subcutaneous allergen immunotherapy for patients who have allergic asthma
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.
Step up if
Step down if
(and asthma is
• 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
• Caution: Frequent use of SABA may indicate the need to step up treatment. See text for recommendations on initiating daily
Figure 3: Guideline recommended stepwise approach to managing asthma in young children. ICS: inhaled corticosteroid, EIB: exercise
induced bronchospasm, LABA: long-acting β
-agonist, LTRA: leukotriene receptor antagonist, and SABA: short-acting β
reproduced from .
Stepwise approach for managing asthma in youths 12 years of age and adult
Persistent asthma: Daily medication
Consult with asthma specialist if step 4 care or higher is required
Consider consultation at step 3
ICS + LABA
low-dose ICS +
ICS + LABA
ICS + either
LTR A o r
High-dose ICS +
patients who have
+ LABA + oral
patients who have
Step up if
Step down if
(and asthma is
Each step: patient education, environmental control, and management of comorbidities
Steps 2–4 :Consider subcutaneous allergen immunotherapy for patients who have allergic asthma (see notes)
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
Figure 4: Guideline recommended stepwise approach to managing asthma in adolescents and adults. ICS: inhaled corticosteroid, EIB:
exercise induced bronchospasm, LABA: long-acting β
-agonist, LTRA: leukotriene receptor antagonist, and SABA: short-acting β
reproduced from .
Despite these issues, inhaled short-acting β
should remain as ﬁrst-line ther apy for prevention and
treatment of acute bronchospasm. Inhaled short-acting
anticholinergic drugs (see Section 16) are an alternative and
can be used if there are concerns for a speciﬁc patient and the
use of short-acting β
12. Inhaled Corticosteroids
Inhaled corticosteroids are the preferred treatment for long-
term control of persistent asthma symptoms . There
are no concerns unique to patients with sickle cell disease
and asthma which would preclude use in this population.
Issues related to systemic corticosteroid use are discussed in
13. Leukotriene Modiﬁers
Leukotrienes are a known component of airway inﬂamma-
tion in asthma and in sickle cell disease thoug h the added
contribution of asthma on leukotriene level production in
patients with sickle cell disease has not been speciﬁcally
studied. However, it is reasonable to suspect that blockade of
leukotriene receptor activity by a leukotriene modiﬁer could
be eﬀective in patients who have both sickle cell disease and
Leukotriene modiﬁers include a 5-lipoxygenase inhibitor
(zileuton) and three leukotriene receptor antagonists (mon-
telukast, zaﬁrlukast, and pranlukast, the latter is available
only in Japan). Leukotriene receptor antagonists exert their
beneﬁcial eﬀects in asthma by binding to the cys-leukotriene
1 receptor and antagonizing the detrimental eﬀects of the
cysteinyl leukotrienes in airways. Despite leukotriene synthe-
sis blockade through inhibition of 5-lipoxygenase, there is
no evidence for clinical diﬀerences between 5-lipoxygenase
inhibitors and leukotriene receptor antagonists in asthma
. Several in vitro trials have documented zileuton, a
hydroxyurea derivative, may have potential beneﬁcial eﬀects
in sickle cell disease pathology including eﬀects on nitric
oxide, sickle red blood cell retention and adhesion in
the pulmonary c irculation, and decreased interleukin-13
Montelukast, however, would be the preferred leuko-
triene modiﬁer in patients with sickle cell disease and asthma
because it has well-established eﬀects on the improvements
of asthma symptoms and it can be given once daily [107,
113, 114]. The safety proﬁle of montelukast is similar to
placebo and its safety record extends over 10 years of use in
millions of patients. The other available LTD4 inhibitor at the
CysLT1 receptor, zaﬁrlukast, must be given twice daily and
may require liver function testing.
Zileuton, a leukotriene synthesis inhibitor, must be given
twice daily and treatment has been associated with increased
hepatic enzymes most often appear ing in the ﬁrst three
months of treatment with the extended release product.
These abnormalities can progress, remain unchanged, or
may resolve with continued treatment. Use of the imme-
diate release product has been associated with severe liver
injury including symptomatic jaundice, hyperbilirubinemia,
aspartate aminotransferase elevations greater than 8 times
the upper limit of nor m al, life-threatening liver injury, and
death. Liver function monitoring should be performed prior
to the start of therapy, then monthly for three months, then
every two-to-three months for the remainder of the ﬁrst
year, and then periodically. If liver dysfunction develops or
transaminase elevations are more than 5 times the upper
limits of normal, then the drug should be discontinued (from
Zileuton prescribing information).
Response to montelukast is highly variable and limits its
usefulness in asthma [115–117]; heterogeneity in response
is due in large part to genetic variability [115, 118–120]. The
pharmacogenetics of leukotriene pathway and transporter
genes may be relevant to patients with asthma and sickle
cell disease. In a six-month clinical trial of montelukast
therapy in patients with asthma, in which 80% of European
Caucasians and 47% of African Americans, carried ﬁve
tandem repeats of the ALOX5 promoter sp1 tandem repeat
polymorphism, European Caucasian participants carry ing
ALOX5 promoter on one allele had a 73% reduction in the
risk of having one or more asthma exacerbations compared
with homozygotes for the ﬁve repeat alleles [115 ]. In
contrast, there were no diﬀerences in exacerbation risk by
genotype in placebo treated patients. African Americans
were not studied for the association analysis due to too
few numbers of African American participants. However,
African Americans were nearly 3 times more likely than
Whites to carry a variant number of repeats (53% versus
20%) suggesting that Afr ican Americans with asthma and
sickle cell disease may have signiﬁcant improvements in
asthma control with montelukast therapy .
Montelukast is an orally administered drug in which
response is directly related to blood concentration and w ide
ranges of response to the same doses has been observed [ 115 ,
ber of the SLCO family of organic anion membrane transport
proteins encoded by SLCO2B1 . A nonsynonomous
polymor phism, rs1242149 (c935G > A), in SLCO2B1 has
been found to associate with signiﬁcantly reduced plasma
concentrations of montelukast and Asthma Symptom Utility
Index (ASUI) in patients with asthma treated with mon-
telukast for 6 months [119, 122].TheASUIisavalidatedtool
that assesses patient preferences for combinations of asthma-
related sy mptoms and drug eﬀects and correlates w ith
patient perception of asthma control . If these ﬁndings
are conﬁrmed, future studies would be needed to examine
dose-response relationships by genot ype to determine if
speciﬁc genotype-driven doses are required for eﬀectiveness.
Montelukast use has been associated with behavior
changes which recently prompted labeling changes to include
information that agitation, aggressive behavior or hostility,
anxiousness, depression, dream abnor m alities, hallucina-
tions, insomnia, irritability, restlessness, somnambulism,
suicidal thinking and behavior (including suicide), and
tremor may occur with montelukast use. Analyses from two
recent publications (authored by employees of Merck a nd
Co, Inc.) involving over 20,000 patients treated with mon-
telukast found no evidence of “possibly suicidality related
adverse events” nor “behavior-related adverse events” [124,
125]. In addition, analysis of three recent large asthma trials
in 569 patients treated with montelukast conducted by the
American Lung Association Asthma Clinical Research Cen-
ters network have uncovered no behavioral problems .
However, these adverse events could be of concern in
patients with sickle cell disease who are already at risk
for suicide ideation and attempted suicide and depression
[127, 128]. The Duke University Psychiatry Department
recently published data that 29% of patients with sickle cell
disease reported suicide ideation and 8% had attempted
suicide during their lifetime . Therefore, monitoring
for these adverse eﬀects in patients with sickle cell disease
would be reasonable.
14. Inhaled Long-Acting β
agonists (salmeterol and formoterol) may
be associated with particular risks in African Americans.
Several clinical studies and meta-analyses have documented
an increased risk of asthma exacerbations or death due to
asthma in patients using long-acting β
agonists with and
without inhaled corticosteroid therapy [129–132]. These
risks were identiﬁed in clinical trials prior to the marketing
of salmeterol, the ﬁrst long-acting β
-agonist available in this
country . A large postmarketing study, demonstrated
a 2-fold increase in respiratory-related deaths and over
4-fold increase in asthma-related deaths in patients treated
with salmeterol versus placebo over 6 months and these
increases were driven largely by the increases in African
American subpopulation (4- and 7-fold increases, resp.)
. Similar eﬀects on exacerbation rates have been found
for formoterol . Long-acting β
agonists are not to
be used as monotherapy and are to only be used with an
anti-inﬂammatory drug (preferably inhaled corticosteroids).
These risks appear to be even greater in children and
adolescents compared to adults based upon results presented
at an FDA Advisory Committee meeting in 2008 .
Guidelines for the Diagnosis and Management of Asthma
state that long-acting β
agonists are to be used only i n
patients who are not controlled on low- to medium-doses of
inhaled corticosteroids or whose disease is considered severe
enough to warrant initial treatment with two maintenance
therapies [83, 83].
Results from retrospective pharmacogenetic association
studies of long-acting β
agonists (salmeterol and for-
moterol) on asthma control in patients with and without
concomitant inhaled corticosteroid treatment have largely
failed to ﬁnd any association b etween the Gly16Arg genotype
and asthma control even in studies speciﬁcally evaluating
eﬀects in African Americans [100, 135–138]. Two prospective
genotype driven, randomized, double-blind trials examining
the eﬀects of salmeterol plus inhaled corticosteroid therapy
have failed to ﬁnd any signiﬁcant eﬀects on adverse asthma
outcomes by the Gly16Arg genotype [139, 140].
However , given the adverse consequences found for
African Americans in the large post marketing study with
salmeterol and FDA analysis [130, 134] it would be prudent
to carefully evaluate the risk to beneﬁt of adding either
salmeterol or formoterol to treatment in patients with sickle
cell disease and asthma.
15. Other Treatments for Long-Term Control in
Theophylline, cromolyn, and omalizumab are additional
treatment options for the patient with asthma and sickle cell
disease. Theophylline is not a particularly attractive choice
because of its cardiostimulatory eﬀects and adverse gastroin-
testinal eﬀects (nausea, dyspepsia) . Inhaled cromolyn
is exceedingly safe but is rarely used because it requires four
times daily dosing and use has been supplanted by mon-
telukast in the pediatric asthma population. Omalizumab
is an add-on option for a select set of patients 12 years
and older with moderate to severe persistent asthma who
have a positive skin test or in vitro reactivity to a perennial
aeroallergen and s ymptoms that are inadequately controlled
with inhaled corticosteroids plus a long-acting β
. Omalizumab is an anti-IgE monoclonal antibody which
binds to the Cε3 domain of free IgE in the serum and not
to IgE already bound to mast cells. The omalizumab-IgE
complex prevents IgE from binding to the Fcε-R1 on mast
cells and basophils; cross-linking IgE bound to mast cells and
basophils causes mast cell and basophil degranulation with
release of histamine, tryptase, bradykinin, prostaglandin
E2, prostaglandin F2, and leukotrienes. Omalizumab must
be given by subcutaneous injection (1 to 3 injections)
every 2 or 4 weeks and patients must be observed for
a period of time after dosing for the development of an
anaphylactic reaction. Thus, omalizumab treatment requires
considerable motivation on behalf of the patient in order to
16. Management of Acute Asthma in Patients
with Sickle Cell Disease
Risks of pharmacologic treatment during acute exacerba-
tions of asthma in patients with sickle cell disease may
require speciﬁc considerations to ensure eﬀectiveness with
minimization of adverse eﬀects. Emergency department and
hospital-based pharmacologic care of asthma in the absence
of sickle cell disease includes the use of frequent inhaled
-agonist treatment with oral (or intravenous,
if hospitalized) corticosteroids . Inhaled ipratropium
(an anticholinergic drug) can be added to short-acting β
agonist treatment in severe exacerbations. Corticosteroid
treatment should be continued until lung function is at least
70% of predicted normal function or the patient’s personal
best value, and symptoms have resolved . Corticosteroid
treatment may require up to 10 days of therapy or longer but
dose tapering is not needed for treatments less than 14 days
The p otential risks associated with high doses of inhaled
agonists in the acute management of patients
with asthma and sickle cell disease are no diﬀerent than those
previously described for as-needed use in persistent asthma.
However, because African Americans may be less responsive
to acute use of short-acting β
agonists, higher doses may be
required compared to White patients [101, 102]. The risks of
therapy associated with prolongation of the QTc should be
considered when administering multiple inhaled treatments
or continuous nebulization of short-acting β
There are no reasons to expect anticholinergic eﬃcacy or
toxicity would be any diﬀerent for patients with asthma
and sickle cell disease compared to those without sickle cell
Systemic corticosteroid use in the management of acute
chest syndrome in sickle cell patients has been associated
with rebound pain and increased early (within 2 weeks)
readmission rates in many but not all studies [142–146].
Readmission rates after treatment with corticosteroids for
acute chest syndrome in patients with asthma is no diﬀerent
than rates for all patients (including those without asthma).
While the time to readmission is longer after corticosteroid
with a taper versus without a taper, patients with a taper
are more likely to be readmitted than those without .
It is not clear however if the increased risk of readmission
in patients with a corticosteroid taper is actually due
to underdosing of corticosteroid during the taper period
resulting in inadequate resolution of symptoms prior to
discontinuation of corticosteroid treatment. This same study
showed that in patients with asthma, readmission rates
are greater in those who are treated with corticosteroids
alone compared with corticosteroids plus transfusions or
no therapy . In a large study examining over 5,000
admissions for acute chest syndrome in over 3,000 individ-
uals, 48% of patients with asthma received corticosteroid
treatment . The relative risk of readmission of patients
with asthma (compared to those without asthma) was 3.2
which was slightly reduced (relative risk 2.9) in those who
also received bronchodilators . It is not clear if the
increase in relative risk is due to the undertreatment with
corticosteroid therapy (only 48% of patients with asthma
receiving corticosteroid treatment) or a reﬂection of more
severe acute chest syndrome events in patients with asthma.
A smaller study of 53 children found no adverse eﬀect of a
short course of prednisone on readmission rate after acute
chest syndrome, though a Type II error may have precluded
observing an eﬀect . Another study found a shorter
length of stay in patients with asthma treated for acute
chest syndrome compared to those without asthma (6.4 days
versus 8.6 days, resp.) which may have been due to the
use of bronchodilators and corticosteroids for acute chest
syndrome (not currently standard treatment for acute chest
syndrome) and favored a response in those with asthma;
readmission rate was not evaluated . Thus, available
evidence suggests that even in patients with asthma, sys-
temic cor ticosteroid treatment is not without risk. Whether
management of asthma exacerbations occurring in the
absence of acute chest syndrome would identify a satisfactory
risk to beneﬁt ratio is unknown but deserves study in a
controlled tr ial. Also unclear is whether a su ﬃciently long
corticosteroid taper would lessen the risk of readmission
in patients with asthma. However, unraveling these issues
is complicated due to the overlap between the diagnosis
of acute chest syndrome events and asthma exacerbations
in patients with asthma. With the presently available data,
patients with asthma should receive standard guideline
appropriate care  which would include aggressive use
of bronchodilators with systemic corticosteroid treatment
with consideration for a suﬃciently long taper after discharge
until symptoms are completely resolved as recommended in
the current asthma guidelines . In addition, all patients
with asthma should be discharged with prescribed inhaled
corticosteroid treatment for the long-term management of
Patients with sickle cell disease and asthma have unique
characteristics that suggest they are a subpopulation of
patients with asthma that require special considerations
for management of persistent and acute asthma symptoms.
Until further evidence is available from controlled clinical
trials, the management of asthma in the patient with
sickle cell disease should be consistent with the published
Guidelines for the Diagnosis and Management of Asthma.
The pharmacogenomics of asthma therapy is of interest
but there is little ﬁrm evidence that research ﬁndings can
be translated to the clinic setting at present. Given the
overall preference for, and better adherence with, oral versus
inhaled medications, even in low-income African Americans
with asthma [147–149], and the evidence indicating a
predominate contribution of leukotrienes in both diseases,
montelukast may be an attractive choice for the treatment
of persistent asthma. Systemic corticosteroid use in acute
asthma exacerbations presents a conundrum that is not
resolved. In the typical patient with asthma without sickle
cell disease, systemic corticosteroids are standard of care
but in those with sickle cell disease may worsen sickle
cell disease outcomes after discontinuation of treatment.
At present, guideline appropriate care may be warranted.
Clearly, this population of patients with asthma requires
large controlled trials to clearly deﬁne the most appropriate
Conﬂicts of Interests
The authors have no conﬂicts of interests to report.
 K. L. Hassell, “Population estimates of sickle cell disease in
the U.S.,” American Journal of Preventive Medicine, vol. 38,
no. 4, pp. S512–S521, 2010.
hemoglobin (Hb S) allele and sickle cell disease: a HuGE
review,” American Journal of Epidemiology, vol. 151, no. 9, pp.
 R. S. Olney, “Newborn screening for sickle cell dis-
ease: public health impact and evaluation,” in Part IV.
Developing, Implementing, and Evaluating Population Inter-
ventions, chapter 22, Oxford University Press, Oxford,
UK, 2000, http://www.cdc.gov/genomics/resources/books/
 “Trends in Asthma morbidity and mortality-January 2009,”
American Lung Association Epidemiology & Statistics Unit
Research Epidemiology & Statistics Unit, January 2009.
 L. Akinbami, “The state of childhood asthma, United States,
1980–2005,” Advance data, no. 381, pp. 1–24, 2006.
 E. P. Vichinsky, L. D. Neumayr, A. N. Earles et al., “Causes and
outcomes of the acute chest syndrome in sickle cell disease,”
New England Journal of Medicine, vol. 342, no. 25, pp. 1855–
 M. A. Leong, C. Dampier, L. Varlotta, and J. L. Allen, “Airway
hyperreactivity in children with sickle cell disease,” Journal of
Pediatrics, vol. 131, no. 2, pp. 278–285, 1997.
 J. M. Knight-Madden, T. S. Forrester, N. A. Lew is, and A.
Greenough, “Asthma in children with sickle cell disease and
its association with acute chest syndrome,” Thorax, vol. 60,
no. 3, pp. 206–210, 2005.
R. Goldberg, “Prevalence and reversibility of lower airway
obstruction in children with sickle cell disease,” Journal of
Pediatrics, vol. 138, no. 2, pp. 188–192, 2001.
 K. P. Sylvester, R. A. Patey, G. F. Raﬀerty, D. Rees, S. L. Thein,
and A. Greenough, “Airway hyperresponsiveness and acute
chest syndrome in children with sickle cell anemia,” Pediatric
Pulmonology, vol. 42, no. 3, pp. 272–276, 2007.
 O. Y. Ozbek, B. Malbora, N. Sen, A. C. Yazici, E. Ozyurek, and
N. Ozbek, “Airway hyperreactivity detected by methacholine
challenge in children with sickle cell disease,” Pediatric
Pulmonology, vol. 42, no. 12, pp. 1187–1192, 2007.
 R. Bryant, “Asthma in the pediatric sickle cell patient with
acute chest syndrome,” Journal of Pediatric Health Care, vol.
19, no. 3, pp. 157–162, 2005.
and M. R. DeBaun, “Methacholine challenge in children with
sickle cell disease: a case series,” Pediatric Pulmonology, vol.
43, no. 9, pp. 924–929, 2008.
 J. J. Field, J. Stocks, F. J. Kirkham et al., “Airway hyper-
responsiveness in children with sickle cell anemia,” Chest.In
 J. J. Field, E. A. Macklin, Y. Yan, R. C. St runk, and M. R.
DeBaun, “Sibling history of asthma is a risk factor for pain
in children with sickle cell anemia,” American Journal of
Hematology, vol. 83, no. 11, pp. 855–857, 2008.
 K. L. Phillips, P. An, J. H. Boyd et al., “Major gene eﬀect and
additive familial pattern of inheritance of asthma exist among
families of probands with sickle cell anemia and asthma,”
American Journal of Human Biology, vol. 20, no. 2, pp. 149–
 J. H. Boyd, E. A. Macklin, R. C. Strunk, and M. R. DeBaun,
“Asthma is associated with increased mort ality in individuals
with sickle cell anemia,” Haematologica , vol. 92, no. 8, pp.
 L. Duckworth, L. Hsu, H. Feng et al., “Physician-diagnosed
asthma and acute chest syndrome: associations with NOS
polymorphisms,” Pediatric Pulmonology, vol. 42, no. 4, pp.
 F. Bernaudin, R. C. Strunk, A. Kamdem et al., “Asthma
is associated with acute chest syndrome, but not with an
increased rate of hospitalization for pain among children in
France with sickle cell anemia: a retrospective cohort study,”
Haematologica, vol. 93, no. 12, pp. 1917–1918, 2008.
 J. H. Boyd, E. A. Macklin, R. C. Strunk, and M. R. DeBaun,
“Asthma is associated with acute chest syndrome and pain in
children with sickle cell anemia,” Blood, vol. 108, no. 9, pp.
 K. P. Sylvester, R. A. Patey, S. Broughton et al., “Temporal
relationship of asthma to acute chest syndrome in sickle cell
disease,” Pediatric Pulmonology, vol. 42, no. 2, pp. 103–106,
 C. T. Quinn, E. P. Shull, N. Ahmad, N. J. Lee, Z. R. Rogers,
and G. R. Buchanan, “Prognostic signiﬁcance of early vaso-
occlusive complications in children with sickle cell anemia,”
Blood, vol. 109, no. 1, pp. 40–45, 2007.
 D. S. Darbari, P. Kple-Faget, J. Kwagyan, S. Rana, V. R.
Gordeuk, and O. Castro, “Circumstances of death in adult
sickle cell disease patients,” American Journal of Hematolog y,
vol. 81, no. 11, pp. 858–863, 2006.
 C. D. Fitzhugh, N. Lauder, J. C. Jonassaint et al., “Car-
diopulmonary complications leading to premature deaths in
adult patients with sickle cell disease,” American Journal of
Hematology, vol. 85, no. 1, pp. 36–40, 2010.
 N. Zimmermann and M. E. Rothenberg, “The arginine-
arginase balance in asthma and lung inﬂammation,” Euro-
pean Journal of Pharmacology, vol. 533, no. 1–3, pp. 253–262,
 D.Vercelli,“Arginase:marker,eﬀector, or candidate gene for
asthma?” Journal of Clinical Investigation, vol. 111, no. 12, pp.
 “ATS/ERS recommendations for standardized procedures for
the online and oﬄine measurement of exhaled lower respi-
ratory nitric oxide and nasal nitric oxide, 2005,” American
Journal of Respiratory and Critical Care Medicine, vol. 171, no.
8, pp. 912–930, 2005.
 A. D. Smith, J. O. Cowan, K. P. Brassett, G. P. Herbison, and
D. R. Taylor, “Use of exhaled nitric oxide measurements to
guide treatment in chronic asthma,” New England Journal of
Medicine, vol. 352, no. 21, pp. 2163–2173, 2005.
 S. A. Kharitonov, D. Yates, R. A. Robbins, R. Logan-Sinclair,
E. A. Shinebourne, and P. J. Barnes, “Increased nitric oxide in
exhaled air of asthmatic patients,” Lancet, vol. 343, no. 8890,
pp. 133–135, 1994.
 S. A. Kharitonov, D. H. Yates, and P. J. Barnes, “Inhaled glu-
cocorticoids decrease nitric oxide in exhaled air of asthmatic
patients,” American Journal of Respiratory and Critical Care
Medicine, vol. 153, no. 1, pp. 454–457, 1996.
 C. R. Morris, M. T. Gladwin, and G. J. Kato, “Nitric oxide
and arginine dysregulation: a novel pathway to pulmonary
hypertension in hemolytic disorders,” Current Molecular
Medicine, vol. 8, no. 7, pp. 620–632, 2008.
 C. R. Morris, “Asthma management: reinventing the wheel in
sickle cell disease,” American Journal of Hematology, vol. 84,
no. 4, pp. 234–241, 2009.
exhaled nitric oxide and a polymorphism in the NOS I gene
is associated with acute chest syndrome,” American Journal of
Respiratory and Critical Care Medicine, vol. 164, no. 12, pp.
 K. J. Sullivan, N. Kissoon, E. Sandler et al., “Eﬀ
ect of oral argi-
nine supplementation on exhaled nitric oxide concentration
in sickle cell anemia and acute chest syndrome,” Jour nal of
Pediatric Hematology/Oncology, vol. 32, no. 7, pp. e249–e258,
 R. E. Girgis, M. A. Qureshi, J. Abrams, and P. Swerdlow,
“Decreased exhaled nitric oxide in sickle cell disease: rela-
tionship with chronic lung involvement,” American Journal
of Hematology, vol. 72, no. 3, pp. 177–184, 2003.
 S. S. Pawar, J. A. Panepinto, and D. C. Brousseau, “The eﬀect
of acute pain crisis on exhaled nitric oxide levels in children
with sickle cell disease,” Pediatric Blood and Cancer, vol. 50,
no. 1, pp. 111–113, 2008.
 P. Niscola, F. Sorrentino, L. Scaramucci, P. de Fabritiis, and P.
Cianciulli, “Pain syndromes in sickle cell disease: an update,”
Pain Medicine, vol. 10, no. 3, pp. 470–480, 2009.
 E. Jacob, M. M. Sockrider, M. Dinu, M. Acosta, and B. U.
Mueller, “Respiratory symptoms and acute painful episodes
in sickle cell disease,” Journal of Pediatric Oncology Nursing,
vol. 27, no. 1, pp. 33–39, 2010.
 B. S. Shapiro, D. F. Dinges, E. C. Orne et al., “Home manage-
ment of sickle cell-related pain in children and adolescents:
natural history and impact on school attendance,” Pain, vol.
61, no. 1, pp. 139–144, 1995.
 C. Dampier, B. N. Y. Setty, B. Eggleston, D. Brodecki, P.
O’Neal, and M. Stuart, “Vaso-occlusion in children with
sickle cell disease: clinical characteristics and biologic corre-
lates,” Journal of Pediatric Hematology/Oncology, vol. 26, no.
12, pp. 785–790, 2004.
 J. Glassberg, J. F. Spivey, R. Strunk, S. Boslaugh, and M. R.
DeBaun, “Painful episodes in children with sickle cell disease
and asthma are temporally associated with respirator y symp-
toms,” Journal of Pediatric Hematology/Oncology, vol. 28, no.
8, pp. 481–485, 2006.
 S. T. Holgate, “Pathogenesis of asthma,” Clinical and E xperi-
mental Allerg y, vol. 38, no. 6, pp. 872–897, 2008.
 O. S. Platt, “Sickle cell anemia as an inﬂammatory disease,”
Journal of Clinical Investigation, vol. 106, no. 3, pp. 337–338,
 J. M. Drazen, E. Israel, and P. M. O’Byrne, “Treatment of
asthma with drugs modifying the leukotriene pathway,” New
England Journal of Medicine, vol. 340, no. 3, pp. 197–206,
 Y. Kanaoka and J. A. Boyce, “Cysteinyl leukotrienes and their
receptors: cellular distribution and function in immune and
inﬂammatory responses,” Journal of Immunology, vol. 173,
no. 3, pp. 1503–1510, 2004.
 J. W. Woods, J. F. Evans, D. Ethier et al., “5-lipoxygenase
and 5-lipoxygenase-activating protein are localized in the
nuclear envelope of activated human leukocytes,” Journal
of Experimental Medicine, vol. 178, no. 6, pp. 1935–1946,
 B. K. Lam, W. F. Owen, K. F. Austen, and R. J. Soberman,
“The identiﬁcation of a distinctexportstepfollowingthe
biosynthesis of leukotriene C by human eosinophils,” Journal
of Biological Chemistry, vol. 264, no. 22, pp. 12885–12889,
 M. E. Anderson, R. D. Allison, and A. Meister, “Inter-
conversion of leukotrienes catalyzed by puriﬁed γ-glutamyl
transpeptidase: concomitant formation of leukotriene D4
and γ-glutamyl amino acids,” Proceedings of the National
Academy of Sciences of the United States of America, vol. 79,
no. 4, pp. 1088–1091, 1982.
 C. W. Lee, R. A. Lew is, E. J. Corey, and K. F. Austen, “Con-
version of leukotriene D to leukotriene E by a dipeptidase
released from the speciﬁc granule of human polymorphonu-
clear leukocytes,” Immunology, vol. 48, no. 1, pp. 27–35, 1983.
 N. Rabinovitch, “Urinary leukotriene E,” Immunology and
Allergy Clinics of North America, vol. 27, no. 4, pp. 651–664,
 G. Folco and R. C. Murphy, “Eicosanoid transcellular biosyn-
thesis: from cell-cell interactions to in v ivo tissue responses,”
Pharmacological Rev iews, vol. 58, no. 3, pp. 375–388, 2006.
 S. D. Nandedkar, T. R. Feroah, W. Hutchins et al.,
“Histopathology of experimentally induced asthma in a
murine model of sickle cell disease,” Blood, vol. 112, no. 6,
pp. 2529–2538, 2008.
 B. N. Y. Setty and M. J. Stuart, “Eicosanoids in sickle cell
disease: potential relevance of neutrophil leukotriene B to
disease pathophysiology,” Journal of Laboratory and Clinical
Medicine, vol. 139, no. 2, pp. 80–89, 2002.
 B. O. Ibe, J. Kurantsin-Mills, J. U. Raj, and L. S. Lessin,
“Plasma and urinary leukotrienes in sickle cell disease:
possible role in the inﬂammatory process,” European Journal
of Clinical Investigation, vol. 24, no. 1, pp. 57–64, 1994.
 J. J. Field, R. C. Strunk, J. E. Knight-Perry, M. A. Blinder, R. R.
Townsend, and M. R. DeBaun, “Urinary cysteinyl leukotriene
E signiﬁcantly increases during pain in children and adults
with sickle cell disease,” American Journal of Hematology, vol.
84, no. 4, pp. 231–233, 2009.
 J. J. Field, J. Krings, N. L. White et al., “Urinary cysteinyl
leukotriene e is associated with increased risk for pain and
acute chest syndrome in adults with sickle cell disease,” Amer-
ican Journal of Hematology, vol. 84, no. 3, pp. 158–160, 2009.
 J. E. Jennings, T. Ramkumar, J. Mao et al., “Elevated urinary
leukotriene E levels are associated with hospitalization for
pain in children with sickle cell disease,” American Journal of
Hematology, vol. 83, no. 8, pp. 640–643, 2008.
 J. M. Drazen and K . F. Austen, “Leukotrienes and airway
responses,” American Review of Respiratory Disease, vol. 136,
no. 4, pp. 985–998, 1987.
 M. D. Thompson, J. Takasaki, V. Capra et al., “G-protein-
coupled receptors and asthma endophenotypes: the cysteinyl
leukotriene system in perspective,” Molecular Diag nosis and
Therapy, vol. 10, no. 6, pp. 353–366, 2006.
 K. H. In, K. Asano, D. Beier et al., “Naturally occurring
mutations in the human 5-lipoxygenase gene promoter
that modify transcription factor binding and reporter gene
transcription,” Journal of Clinical Investigation,vol.99,no.5,
pp. 1130–1137, 1997.
B. Stephensen, and H. Allayee, “Functional analysis of
5-lipoxygenase promoter repeat variants,” Human Molecular
Genetics, vol. 18, no. 23, pp. 4521–4529, 2009.
 O. Kalayci, E. Birben, C. Sackesen et al., “ALOX5 promoter
genotype, asthma severity and LTC production by
eosinophils,” Allergy, vol. 61, no. 1, pp. 97–103, 2006.
 N. Patel, C. S. Gonsalves, M. Yang, P. Malik, and V. K. Kalra,
“Placenta growth factor induces 5-lipoxygenase-activating
protein to increase leukotriene formation in sickle cell
disease,” Blood, vol. 113, no. 5, pp. 1129–1138, 2009.
 N. Perelman, S. K. Selvaraj, S. Batra et al., “Placenta growth
factor activates monocytes and correlates with sickle cell
disease severity,” Blood, vol. 102, no. 4, pp. 1506–1514, 2003.
 R. J. Freishtat, S. F. Iqbal, D. K. Pillai et al., “High prevalence
of vitamin D deﬁciency among inner-city African American
youth with asthma in Washington, DC,” Journal of Pediatrics,
vol. 156, no. 6, pp. 948–952, 2010.
 R. Beasley, “The burden of asthma with speciﬁc reference
to the United States,” Journal of Allergy and Clinical
Immunology, vol. 109, no. 5, pp. S482–S489, 2002.
 C. A. Camargo Jr., S. L. Rifas-Shiman, A. A. Litonjua et al.,
“Maternal intake of vitamin D during pregnancy and risk of
recurrent wheeze in children at 3 y of age,” American Journal
of Clinical Nutrition, vol. 85, no. 3, pp. 788–795, 2007.
 J. M. Brehm, J. C. Celed
on, M. E. Soto-Quiros et al., “Serum
vitamin D levels and markers of severity of childhood asthma
in Costa Rica,” American Journal of Respiratory and Critical
Care Medicine, vol. 179, no. 9, pp. 765–771, 2009.
D. Y. M. Leung, “Vitamin D levels, lung function, and steroid
response in adult asthma,” American Journal of Respiratory
and Critical Care Medicine, vol. 181, no. 7, pp. 699–704, 2010.
 B. M. Goodman III, N. Artz, B. Radford, and I. A. Chen,
“Prevalence of vitamin D deﬁciency in adults with sickle cell
disease,” Journal of the National Medical Association, vol. 102,
no. 4, pp. 332–335, 2010.
 E. Chapelon, M. Garabedian, V. Brousse, J. C. Souberbielle,
J. L. Bresson, and M. de Montalembert, “Osteopenia and
vitamin D deﬁciency in children with sickle cell disease,”
European Journal of Haematology, vol. 83, no. 6, pp. 572–578,
 A. J. Rovner, V. A. Stallings, D. A. Kawchak, J. I. Schall, K.
Ohene-Frempong, and B. S. Zemel, “High risk of vitamin D
deﬁciency in children with sickle cell disease,” Journal of the
American Dietetic Association, vol. 108, no. 9, pp. 1512–1516,
 A. H. Adewoye, T. C. Chen, Q. Ma et al., “Sickle cell bone
disease: response to vitamin D and calcium,” American
Journal of Hematology, vol. 83, no. 4, pp. 271–274, 2008.
 A. Lal, E. B. Fung, Z. Pakbaz, E. Hackney-Stephens, and E.
P. Vi chinsky, “Bone mineral density in children with sickle
cell anemia,” Pediatric Blood and Cancer, vol. 47, no. 7, pp.
V. A. Stallings, and B. S. Zemel, “Low vitamin D status in
children with sickle cell disease,” Journal of Pediatrics, vol.
145, no. 5, pp. 622–627, 2004.
 J. Stinson and B. Naser, “Pain management in children with
sickle cell disease,” Pediatric Drugs, vol. 5, no. 4, pp. 229–241,
 S. L. Yoon and S. Black, “Comprehensive, integrative man-
agement of pain for patients with sickle-cell disease,” Journal
of Alternative and Complementary Medicine, vol. 12, no. 10,
pp. 995–1001, 2006.
 H. Farquhar, A. Stewart, E. Mitchell et al., “The role of
paracetamol in the pathogenesis of asthma,” Clinical and
Exper imental Allergy, vol. 40, no. 1, pp. 32–41, 2010.
 R. W. Beasley, T. O. Clayton, J. Crane et al., “Acetaminophen
use and risk of asthma, rhinoconjunctivitis and eczema
in adolescents: ISAAC phase three,” American Journal of
Respiratory and Critical Care Medicine. In press.
 R. Beasley, T. Clayton, J. Crane et al., “Association between
paracetamol use in infancy and childhood, and risk of
asthma, rhinoconjunctivitis, and eczema in children aged 6-
7 years: analysis from Phase Three of the ISAAC programme,”
The Lancet, vol. 372, no. 9643, pp. 1039–1048, 2008.
 V. W. Persky, “Acetaminophen and Asthma,” Thorax, vol. 65,
no. 2, pp. 99–100, 2010.
 M. S. Perzanowski, R. L. Miller, D. Tang et al., “Prenatal
acetaminophen exposure and risk of wheeze at age 5 years
in an urban low-income cohort,” Thorax,vol.65,no.2,pp.
 EPR 3. National Asthma Education and Prevention
Program, Expert Panel Report 3: Guidelines for the diagnosis
and management of asthma, U.S. Depar tment of Health and
Hu man Services, Public Health Service, National Institutes of
Health, National Heart, Lung, and Blood Institute, Bethesda,
Md, USA, August 2007, no. 08-4051.
 J. J. Field and M. R. DeBaun, “Asthma and sickle cell
disease: two distinct diseases or part of the same process?”
Hematology/American Society of Hematology. Education
Program, pp. 45–53, 2009.
 S. A. Schroeder and A. G. Nepo, “Treatment of asthma in
children with sickle cell disease can prevent recurrences of
acute chest syndrome,” American Journal of Respiratory and
Critical Care Medicine, vol. 177, article A262, 2008.
 C. G. Giuntini and P. L. Paggiaro, “Present state of the
controversy about regular inhaled β-agonists in asthma,”
European Respiratory Journal, vol. 8, no. 5, pp. 673–678, 1995.
 M. R. Sears, R. M. Sly, and R. O’Donnell, “Relationships
between asthma mortality and t reatment,” Annals of Allergy,
vol. 70, no. 5, pp. 425–426, 1993.
 W. H. Inman and A. M. Adelstein, “Rise and fall of asthma
mortality i n England and Wales in relation to use of pres-
surised aerosols,” Lancet, vol. 2, no. 7615, pp. 279–285, 1969.
 N. Pearce, R. Beasley, J. Crane, C. Burgess, and R. Jackson,
“End of the New Zealand asthma mortality epidemic,”
Lancet, vol. 345, no. 8941, pp. 41–44, 1995.
 W. O. Spitzer, S. Suissa, P. Ernst et al., “The use of β-agonists
and the risk of death and near death from asthma,” New Eng-
land Journal of Medicine, vol. 326, no. 8, pp. 501–506, 1992.
 J. M. Drazen, E. Israel, H. A. Boushey et al., “Comparison of
regularly scheduled with as-needed use of albuterol in mild
asthma,” New England Journal of Medicine, vol. 335, no. 12,
pp. 841–847, 1996.
 S. A. Green, J. Turki, M. Innis, and S. B. Liggett, “Amino-
terminal polymorphisms of the human β
receptor impart distinct agonist-promoted regulatory prop-
erties,” Biochemistry, vol. 33, no. 32, pp. 9414–9419, 1994.
 S. A. Green, J. Turki, P. Bejarano, I. P. Hall, and S. B. Liggett,
“Inﬂuence of beta 2-adrenergic receptor genotypes on
signal transduction in human airway smooth muscle cells,”
American Journal of Respiratory Ce ll and Molecular Biolog y,
vol. 13, no. 1, pp. 25–33, 1995.
 E. Israel, J. M. Drazen, S. B. Liggett et al., “The eﬀect
of polymorphisms of the β
-adrenergic receptor on the
response to regular use of albuterol in asthma,” American
Journal of Respiratory and Critical Care Medicine, vol. 162,
no. 1, pp. 75–80, 2000.
 D. R. Taylor, J. M . Drazen, G. P. Herbison, C. N. Yandava,
R. J. Hancox, and G. I. Town, “Asthma exacerbations during
long term β agonist use: inﬂuence of β
polymorphism,” Thorax, vol. 55, no. 9, pp. 762–767, 2000.
 D. K. C. Lee, C. E. Bates, and B. J. Lipworth, “Acute systemic
eﬀects of inhaled salbutamol in asthmatic subjects expressing
common homozygous β
-adrenoceptor haplotypes at
positions 16 and 27,” British Journal of Clinical Pharmacology,
vol. 57, no. 1, pp. 100–104, 2004.
 R. J. Hancox, M. R. Sears, and D. R. Taylor, “Polymorphism
of the β
-adrenoceptor and the response to long-term
β-agonist therapy in asthma,” European Respiratory Journal,
vol. 11, no. 3, pp. 589–593, 1998.
 E. Israel, V. M. Chinchilli, J. G. Ford et al., “Use of regularly
scheduled albuterol treatment in asthma: genotype-stratiﬁed,
randomised, placebo-controlled cross-over trial,” Lancet,
vol. 364, no. 9444, pp. 1505–1512, 2004.
 G. A. Hawkins, K. Tantisira, D. A. Meyers et al., “Sequence,
haplotype, and association analysis of ADRβ2inamulti-
ethnic asthma case-control study,” Ame rican Journal of
Respiratory and Critical Care Medicine, vol. 174, no. 10, pp.
 E. R. Bleecker, R. M. Lawrance, H. J. Ambrose, and M.
Goldman, “Beta2-adrenergic receptor gene polymorphisms:
is Arg/Arg genotype associated with serious adverse events
during treatment with budesonide and formoterol in one
pressurized metered-dose inhaler (BUD/FM pMDI) within
racial groups?” American Journal of Respiratory and Critical
Care Medicine, vol. 177, article A775, 2008.
 K. Blake, R. Madabushi, H. Derendorf, and J. Lima, “Popula-
tion pharmacodynamic model of bronchodilator response to
inhaled albuterol in children and adults with asthma,” Chest,
vol. 134, no. 5, pp. 981–989, 2008.
 G. E. Hardie, J. K. Brown, and W. M. Gold, “Adrenergic
responsiveness: FEV1 and symptom diﬀerences in Whites
and African Americans with mild asthma,” Journal of
Asthma, vol. 44, no. 8, pp. 621–628, 2007.
 P. Thottathil, J. Acharya, A. J. Moss et al., “Risk of cardiac
events in patients with asthma and long-QT syndrome
treated with beta
agonists,” American Journal of Cardiology,
vol. 102, no. 7, pp. 871–874, 2008.
 S. R. Salpeter, T. M. Ormiston, and E. E. Salpeter, “Cardiovas-
cular eﬀects of β-agonists in patients with asthma and COPD:
a meta-analysis,” Chest, vol. 125, no. 6, pp. 2309–2321,
 B. U. Mueller, K. J. Martin, W. Dreyer, L. I. Bezold, and
D. H. Mahoney, “Prolonged QT interval in pediatric sickle
cell disease,” Pediatric Blood and Cancer,vol.47,no.6,pp.
 F. Akg
ul, E. Seyfeli, I. Melek et al., “Increased QT dispersion
in sickle cell disease: eﬀect of pulmonary hypertension,” Acta
Haematologica, vol. 118, no. 1, pp. 1–6, 2007.
 H. W. Kelly, “Non-corticosteroid thera py for long-term
control of asthma,” Expert Opinion on Pharmacotherapy, vol.
8, no. 13, pp. 2077–2087, 2007.
 B. A. Rohrman and D. A. Mazziotti, “Quantum chemical
design of hydroxyurea derivatives for the treatment of sickle-
cell anemia,” Journal of Physical Chemistry B, vol. 109, no. 27,
pp. 13392–13396, 2005.
 J. Haynes Jr., B. Obiako, J. A. King, R. B. Hester, and S.
Ofori-Acquah, “Activated neutrophil-mediated sickle red
blood cell adhesion to lung vascular endothelium: role of
phosphatidylserine-exposed sickle red blood cells,” American
Journal of Physiology, vol. 291, no. 4, pp. H1679–H1685,
 S. Kuvibidila, B. S. Baliga, R. Gardner et al., “Diﬀerential
eﬀects of hydroxyurea and zileuton on interleukin-13
secretion by activated murine spleen cells: implication on
the expression of vascular cell adhesion molecule-1 and
vasoocclusion in sickle cell anemia,” Cytokine, vol. 30, no. 5,
pp. 213–218, 2005.
 J. Haynes Jr., B. S. Baliga, B. Obiako, S. Ofori-Acquah, and B.
Pace, “Zileuton induces hemoglobin F synthesis in erythroid
progenitors: role of the L-arginine-nitric oxide signaling
pathway,” Blood, vol. 103, no. 10, pp. 3945–3950, 2004.
 J. Haynes Jr. and B. Obiako, “Activated polymorphonuclear
cells increase sickle red blood cell retention in lung: role of
phospholipids,” American Journal of Physiology, vol. 282, no.
1, pp. H122–H130, 2002.
 K. V. Blake, “Montelukast: data from clinical trials in the
management of asthma,” Annals of Pharmacotherapy, vol. 33,
no. 12, pp. 1299–1314, 1999.
 G. P. Currie and K. McLaughlin, “The expanding role of
leukotriene receptor antagonists in chronic asthma,” Annals
of Allergy, Asthma and Immunology,vol.97,no.6,pp.
 J. J. Lima, S. Zhang, A. Grant et al., “Inﬂuence of leukotriene
pathway polymorphisms on response to montelukast in
asthma,” American Journal of Respiratory and Critical Care
Medicine, vol. 173, no. 4, pp. 379–385, 2006.
 K. Malmstrom, G. Rodriguez-Gomez, J. Guerra et al., “Oral
montelukast, inhaled beclomethasone, and placebo for
chronic asthma: a randomized, controlled trial,” Annals of
Internal Medicine, vol. 130, no. 6, pp. 487–495, 1999.
 S. J. Szeﬂer, B. R. Phillips, F. D. Martinez et al.,
“Characterization of within-subject responses to ﬂuticasone
and montelukast in childhood asthma,” Journal of Allergy
and Clinical Immunology, vol. 115, no. 2, pp. 233–242, 2005.
 M. Klotsman, T. P. York, S. G. Pillai et al., “Pharmacogenetics
of the 5-lipoxygenase biosynthetic pathway and variable
clinical response to montelukast,” Pharmacogenetics and
Genomics, vol. 17, no. 3, pp. 189–196, 2007.
 E. B. Mougey, H. Feng, M. Castro, C. G. Irvin, and J. J.
Lima, “Absorption of montelukast is transporter mediated:
a common variant of OATP2B1 is associated with reduced
plasma concentrations and poor response,” Pharmacogenetics
and Genomics, vol. 19, no. 2, pp. 129–138, 2009.
 J. J. Telleria, A. Blanco-Quiros, D. Varillas et al., “ALOX5
promoter genotype and response to montelukast in
moderate persistent asthma,” Respiratory Medicine, vol. 102,
no. 6, pp. 857–861, 2008.
 B. Knorr, S. Holland, J. D. Rogers, H. H. Nguyen, and T. F.
Reiss, “Montelulkast adult (10-mg ﬁlm-coated tablet) and
pediatric (5-mg chewable tablet) dose selections,” Journal
of Allergy and Clinical Immunology, vol. 106, no. 3, pp.
 C. G. Irv in, D. A. Kaminsky, N. R. Anthonisen et al.,
“Clinical trial of low-dose theophylline and montelukast in
patients with poorly controlled asthma,” American Journal
of Respiratory and Critical Care Medicine, vol. 175, no. 3, pp.
 D. A. Revicki, N. K. Leidy, F. Brennan-Diemer, S. Sorensen,
and A. Tog ias, “Integrating patient preferences into health
outcomes assessment: the multiattribute asthma symptom
utility index,” Chest, vol. 114, no. 4, pp. 998–1007, 1998.
 G. Philip, C. Hustad, G. Noonan et al., “Reports of suicidality
in clinical trials of montelukast,” Journal of Allergy and
Clinical Immunology, vol. 124, no. 4, pp. 691–696.e6, 2009.
 G. Philip, C. M. Hustad, M. P. Malice et al., “Analysis of
behavior-related adverse experiences in clinical trials of
montelukast,” Journal of Allergy and Clinical Immunology,
vol. 124, no. 4, pp. 699–706.e8, 2009.
 J. T. Holbrook and R. Harik-Khan, “Montelukast and emo-
tional well-being as a marker for depression: results from 3
randomized, double-masked clinical trials,”
Journal of Allergy
and Clinical Immunology, vol. 122, no. 4, pp. 828–829, 2008.
 C. L. Edwards, M. Green, C. C. Wellington et al., “Depression,
suicidal ideation, and attempts in black patients with sickle
cell disease,” Journal of the National Medical Association, vol.
101, no. 11, pp. 1090–1095, 2009.
 J. U. Ohaeri, W. A. Shokunbi, K. S. Akinlade, and L. O. Dare,
“The psychosocial problems of sickle cell disease suﬀerers
and their methods of coping,” Social Science and Medicine,
vol. 40, no. 7, pp. 955–960, 1995.
 W. Castle, R. Fuller, J. Hall, and J. Palmer, “Serevent
nationwide surveillance study: comparison of salmeterol
with salbutamol in asthmatic patients who require regular
bronchodilator treatment,” British Medical Journal, vol. 306,
no. 6884, pp. 1034–1037, 1993.
 H. S. Nelson, S. T. Weiss, E. K. Bleecker, S. W. Yancey, and P.
M. Dorinsky, “The s almeterol multicenter asthma research
trial: a comparison of usual pharmacotherapy for asthma or
usual pharmacotherapy plus salmeterol,” Chest, vol. 129, no.
1, pp. 15–26, 2006.
 S. R. Salpeter, N. S. Buckley, T. M. Or miston, and E. E.
Salpeter, “Meta-analysis: eﬀect of long-acting β-agonists on
severe asthma exacerbations and asthma-related deaths,”
Annals of Internal Medicine, vol. 144, no. 12, pp. 904–912,
 S. R. Salpeter, A. J. Wall, and N. S. Buckley, “Long-acting
beta-agonists with and without inhaled corticosteroids and
catastrophic asthma events,” American Journal of Medicine,
vol. 123, no. 4, pp. 322–328.e2, 2010.
 M. Mann, B. Chowdhury, E. Sullivan, R. Nicklas, R. An-
thracite, and R. J. Meyer, “Serious asthma exacerbations in
asthmatics treated with high-dose formoterol,” Chest, vol.
124, no. 1, pp. 70–74, 2003.
 J. M. Kramer, “Balancing the beneﬁts and risks of inhaled
long-acting beta-agonists—the inﬂuence of values,” New
England Journal of Medicine, vol. 360, no. 16, pp. 1592–1595,
 E. R. Bleecker, S. W. Yancey, L. A. Baitinger et al., “Salmeterol
response is not aﬀected by β
-adrenergic receptor genotype
in subjects with persistent asthma,” Journal of Allergy and
Clinical Immunology, vol. 118, no. 4, pp. 809–816, 2006.
 E. R. Bleecker, D. S. Postma, R. M. Lawrance, D. A. Meyers,
H. J. Ambrose, and M. Goldman, “Eﬀect of ADRB2 poly-
morphisms on response to longacting β
a pharmacogenetic analysis of two randomised studies,”
Lancet, vol. 370, no. 9605, pp. 2118–2125, 2007.
 E. R. Bleecker, R. Lawrance, H. Ambrose, and M. Goldman,
“Beta2-adrenergic receptor Gly16Arg variation: eﬀect
on response to budesonide/formoterol (BUD/FM) or
budesonide (BUD; post-formoterol) in children and
adolescents with asthma,” American Journal of Respiratory
and Critical Care Medicine, vol. 177, article A776, 2008.
 W. Anderson, S. A. Bacanu, E. R. Bleecker et al., “A prospec-
tive haplotype analysis of beta2-adrenergic receptor poly-
morphisms and clinical response to salmeterol and salme-
terol/ﬂuticasone propionate,” American Journal of Respiratory
and Critical Care Medicine, vol. 177, article A775, 2008.
 M. E. Wechsler, S. J. Kunselman, V. M. Chinchilli et al.,
“Eﬀect of β
-adrenergic receptor polymorphism on response
to longacting β
agonist in asthma (LARGE trial): a
genotype-stratiﬁed, randomised, placebo-controlled, cross-
over trial,” The Lancet, vol. 374, no. 9703, pp. 1754–1764,
 E. R. Bleecker, H. S. Nelson, M. Kraft et al., “β
morphisms in patients receiving salmeterol with or without
ﬂuticasone propionate,” American Journal of Respiratory and
Critical Care Medicine, vol. 181, no. 7, pp. 676–687, 2010.
 K. Blake, “Theophylline,” in Pediatric Asthma,S.Murphy
and H. W. Kel ly, Eds., pp. 363–431, Marcel Dekker, New
 R. Kumar, S. Qureshi, P. Mohanty, S. P. Rao, and S. T. Miller,
“A short course of prednisone in the management of acute
chest syndrome of sickle cell disease,” Journal of Pediatric
Hematology/Oncology, vol. 32, no. 3, pp. e91–e94, 2010.
 A. Sobota, D. A. Graham, M. M. Heeney, and E. J. Neufeld,
“Corticosteroids for acute chest syndrome in children
with sickle cell disease: variation in use and association
with length of stay and readmission,” American Journal of
Hematology, vol. 85, no. 1, pp. 24–28, 2010.
 D. S. Darbari, O. Castro, J. G. Taylor et al., “Severe vasoocclu-
sive episodes associated with use of systemic corticosteroids
in patients with sickle cell disease,” Journal of the National
Medical Association, vol. 100, no. 8, pp. 948–951, 2008.
 J. J. Strouse, C. M. Takemoto, J. R. Keefer, G. J. Kato, and J. F.
Casella, “Corticosteroids and increased risk of readmission
after acute chest syndrome in children with sickle cell
disease,” Pediatric Blood and Cancer,vol.50,no.5,pp.
 M. S. Isakoﬀ, J. A. Lillo, and J. N. Hagstrom, “A single-
institution experience with treatment of severe acute chest
syndrome: lack of rebound pain wi th dexametha-sone plus
transfusion therapy,” Journal of Pediatric Hematology/Oncolo-
gy, vol. 30, no. 4, pp. 322–325, 2008.
 M. P. Celano, J. F. Linzer, A. Demi et al., “Treatment
adherence a mong low-income, african american children
with persistent asthma,” Journal of Asthma,vol.47,no.3,pp.
 L. Hendeles, M. Asmus, and S. Chesrown, “What is the role
of budesonide inhalation suspension for nebulization?” The
Journal of Pediatric Pharmacology and Therapeutics, vol. 6,
pp. 162–166, 2001.
 C. Rand, A. Bilderback, K. Schiller, J. M. Edelman, C. M.
Hustad, and R. S. Zeiger, “Adherence with montelukast or
ﬂuticasone in a long-term clinical trial: results from the mild
asthma montelukast versus inhaled corticosteroid trial,”
Journal of Allergy and Clinical Immunology, vol. 119, no. 4,
pp. 916–923, 2007.