Asthma in Sickle Cell Disease: Implications for Treatment

Article (PDF Available)inAnemia 2011(9):740235 · March 2011with38 Reads
DOI: 10.1155/2011/740235 · Source: PubMed
Abstract
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
Anemia
Volume 2011, Article ID 740235, 15 pages
doi:10.1155/2011/740235
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 Childrens Clinic,
807 Children’s Way, Jacksonville, FL 32207, USA
Correspondence should be addressed to Kathryn Blake, kblake@nemours.org
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
cited.
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,
insucient 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.
1. Introduction
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
2
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
aect 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].
2 Anemia
Asthma aects 23 mil l ion persons in the US (8 in
every 100 persons) [4]. The prevalence rate of people ever
told that they had asthma was 115/1000 persons in 2007
[4]. African-American children ages 0 to 17 years old are
disproportionately aected 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 [5].
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
2
agonists or
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% [612].
Even more children appear to have airway dysfunction as
the prevalence of airways hyperresponsiveness, measured by
bronchodilator response to inhaled β
2
agonists or bron-
choconstrictive response to cold air or exercise, ranges from
40% to 77% of sickle cell disease patients [711, 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
[14].
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)
= 1.18–3.09;
acute chest syndrome (ACS): 1.48 episodes/year, 95% CI
0.97–2.26) [15]. While these data do not distinguish between
a genetic versus environmental eect on asthma, results from
a segregation analysis study of the familial pattern of inheri-
tance of asthma found that a major gene eect was present
and followed Mendelian expectations [16]. 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 [18]. Children with sickle cell disease and asthma
1.2
1
0.8
0.6
0.4
0.2
0
0246810
Number of episodes (x)
Observed P(x)
Linear probability model
95% Cl
y
= 0.178+0.097x
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 [18].
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, 1719]. 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 [20]. 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 [21]. 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 [20].
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 [22] 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 [17]. 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
Anemia 3
arginase I and II, and nitric oxide synthase (NOS; isoforms
1, 2, and 3) enzymes and these enzymes coregulate the
function of each other [25]. 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 [26]; whereas
arginine metabolized by NOS produces nitric oxide (NO)
which also produces epithelial damage and airway hyperre-
activity [25]. 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 [2730]. 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
eect of polymorphisms in the arginase and NOS genes on
nitric oxide and ornithine production are only beginning to
be evaluated.
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
NO
)levels
and frequency of ACS events is not consistent [3336]. 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
NO
levels in children with sickle cell disease
[33]. 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
2
= 0.76)
(Figure 2)[18]. 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 dier 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 [37].
Children with >3 episodes of pain per year have higher
reports of breathing diculty and chest pain [38]. Pain
occurs at least 2 times more frequently in children with
asthma and sickle cell disease compared to those without
asthma [20]. Monthly episodes of mild-to-moderate pain
1.1
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
<12 12 13 14 15 16
17
AAT repeat number in intron 13 of NOS1
Risk acute chest syndrome
Sickle cell patients with asthma
Sickle cell patients without asthma P
= .001
Quadratic regression line for SCDNA
^y = 0.82 0.22x +0.03x
2
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 [18].
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
timesmorelikelytoprecede,or5timesmoreliketooccur
concurrently with, painful episodes than in patients without
asthma [41].
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) [46]. 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
[45]. LTC4 is transported to the extracellular space mainly
by the multidrug resistance protein 1 (MRP1) [47]. 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 [4850]. Leukotrienes
can also be produced by transcellular biosynthesis [51].
4 Anemia
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
[52]. 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
[5357].
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 [57]. 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
[55, 56].
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
[45]. Early studies identified addition and deletion variants
(wildtype n
= 5; variant n
/
= 5) in the core promoter of the
ALOX5 gene that were associated with diminished promoter-
reporter activity in tissue culture [60] 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 [63]. 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 insuciency 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%) [65]. Epidemiological
studies also report an inverse association between maternal
intake of vitamin D and the risk of childhood wheezing and
asthma in ospring [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
insuciency in 28% of children with asthma living in Costa
Rica [68], 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 [69]. These studies, though small in number,
suggest an important link between hypovitaminosis D and
asthma.
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
insucient (<20 to 30 ng/mL) [7075]. 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
asthma.
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 [76] and is
a component of up to 47% of pain medications in children
with sickle cell disease [77]. Thus, patients with sickle cell
disease have significant exposure to acetaminophen during
their lifetime.
Over the past decade, several publications have reported
an association with acetaminophen use prenatally and
during childhood and an increased risk of developing asthma
[78]. 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 [78]. 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
Anemia 5
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 [83]. Quick-
relief medications include bronchochodilators such as short-
acting β
2
agonists, short-acting anticholinergics, and sys-
temic corticosteroids; long-term control medications include
inhaled corticosteroids with or without long-acting β
2
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
dierent age groups (Figures 3 and 4)[83].
For quick relief of symptoms in patients of all ages and
asthma severity, short-acting β
2
agonists are the preferred
therapy because of the rapid onset of eect and overall
eectiveness 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
1
), 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 insuciently controlled with
low or medium doses of inhaled corticosteroids, a long-
acting β
2
-agonist, leukotriene modifier, or theophylline may
be added though controversy surrounds the use of adding
a long-acting β
2
-agonist (see Section 14). Patients with
severe persistent asthma with allergic disease may require
additional add-on treatment with omalizumab or oral
corticosteroid.
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
2
-agonist use, pulmonary
function, and asthma control questionnaire assessments)
and future risk (exacerbations requiring oral corticosteroid
treatment loss of lung function over time, adverse eects of
treatment).
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 Childrens 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
2
-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
± along-
acting β
2
-agonist [85].
11. Inhaled Short-Acting β
2
-Agonists
There are two potential concerns with the use of inhaled
short-acting β
2
agonists in patients with sickle cell disease:
genotype at the β
2
-adrenergic receptor gene (ADRB2)and
inherent cardiovascular eects of β
2
-adrenergic stimulation.
Historically, use of inhaled β
2
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 [8689]and
more recently with analysis of drug prescription records
associating use with an increased r isk of death or near death
from asthma [90]. However, a controlled trial of regularly
scheduled albuterol use in patients with asthma with mild
disease to examine potential adverse eects demonstrated
no deterioration in asthma control with albuterol u se [91].
However, in current practice, regular scheduled use of short
acting inhaled β
2
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 eects on
asthma control are due to genetic polymorphisms in ADRB2
or inherent pharmacological eects of β
2
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 [9497]. 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
adierent class of bronchodilator (e.g., anticholinergics)
may be appropriate for patients harboring the homozygous
Arg16 genotype [98]. 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
2
agonists can have adverse cardiovascular
eects including increased atrial or ventricular ectopy and
prolongation of the QTc interval [103, 104]. In patients with
prolonged QTc, the use of β
2
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 [103]. Because of the
increased frequency of prolonged QTc in patients with sickle
cell disease, β
2
-agonist use may pose a specific risk in this
population [32, 105, 106].
6 Anemia
Stepwise approach for managing asthma in children 0–4 years of age
Intermittent
asthma
Persistent asthma: Daily medication
Consult with asthma specialist if step 3 care or higher is required
Consider consultation at step 2
Step 1
Step 2
Step 3
Step 4
Step 5
Step 6
Preferred:
SABA PRN
Low-dose ICS
Alternative:
Cromolyn or
montelukast
Preferred:
Medium-dose
ICS
Preferred:
Medium-dose
ICS + either
LABA or
montelukast
either
LABA or
montelukast
High-dose ICS +
Preferred:
High-dose ICS +
either
LABA or
montelukast
Oral systemic
corticosteriods
Step up if
needed
(first, check
adherence,
inhaler
technique, and
environmental
control)
Assess
control
Step down if
possible
(and asthma is
well controlled
at least
3 months)
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.
long-term-control therapy.
Stepwise approach for managing asthma in children 5–11 years of age
Intermittent
asthma
Persistent asthma: Daily medication
Consult with asthma specialist if step 4 care or higher is required.
Consider consultation at step 3.
Step 1
Preferred:
SABA PRN
Step 2
Preferred:
Low-dose ICS
Alternative:
Cromolyn, LTRA,
nedocromil, or
theophylline
Step 3
Preferred:
medium-dose
ICS
Either:
Low dose ICS
either LABA,
LTR A, or
theophylline
or
Step 4
Preferred:
Medium-dose
ICS + LABA
Alternative:
Medium-dose
ICS + either
theophylline
LTR A o r
Step 5
Preferred:
High-dose ICS +
LABA
Alternative:
High-dose ICS +
theophylline
either LTRA or
Step 6
Preferred:
High-dose ICS
+ LABA + oral
systemic
corticosteriod
Alternative:
High-dose ICS +
theophylline +
either LTRA or
oral systemic
corticosteriod
Eachstep: 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.
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
needed
(first, check
adherence,
inhaler
technique,
environmental
control, and
comorbid
conditions)
Assess
control
Step down if
possible
(and asthma is
well controlled
at least
3 months)
Preferred:
Preferred:
SABA as needed for symptoms. Intensity of treatment depends on severity of symptoms.
With viral respiratory infection: SABA q 46 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
2
-agonist, LTRA: leukotriene receptor antagonist, and SABA: short-acting β
2
-agonist,
reproduced from [83].
Anemia 7
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
Intermittent
asthma
Step 1
Preferred:
SABA PRN
Step 2
Preferred:
Low-dose ICS
Alternative:
Cromolyn, LTRA,
nedocromil, or
theophylline
Preferred:
Low-dose
ICS + LABA
Alternative:
either LTRA,
theophylline, or
Step 3
or
medium-dose
low-dose ICS +
zileuton
Step 4
Preferred:
Medium-dose
ICS + LABA
Alternative:
Medium-dose
ICS + either
theophylline, or
LTR A o r
Step 5
Preferred:
High-dose ICS +
LABA
AND
Consider
omalizumab for
patients who have
allergies
Step 6
Preferred:
High-dose ICS
+ LABA + oral
corticosteriod
AND
Consider
omalizumab for
patients who have
allergies
Step up if
needed
(first, check
adherence,
environmental
control, and
comorbid
conditions)
Assess
control
Step down if
possible
(and asthma is
well controlled
at least
3 months)
Each step: patient education, environmental control, and management of comorbidities
Steps 24 :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
up treatment
zileuton
Figure 4: Guideline recommended stepwise approach to managing asthma in adolescents and adults. ICS: inhaled corticosteroid, EIB:
exercise induced bronchospasm, LABA: long-acting β
2
-agonist, LTRA: leukotriene receptor antagonist, and SABA: short-acting β
2
-agonist,
reproduced from [83].
Despite these issues, inhaled short-acting β
2
agonists
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
2
agonists.
12. Inhaled Corticosteroids
Inhaled corticosteroids are the preferred treatment for long-
term control of persistent asthma symptoms [83]. 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
Section 16.
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 eective in patients who have both sickle cell disease and
asthma.
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 eects in asthma by binding to the cys-leukotriene
1 receptor and antagonizing the detrimental eects of the
cysteinyl leukotrienes in airways. Despite leukotriene synthe-
sis blockade through inhibition of 5-lipoxygenase, there is
no evidence for clinical dierences between 5-lipoxygenase
inhibitors and leukotriene receptor antagonists in asthma
[107]. Several in vitro trials have documented zileuton, a
hydroxyurea derivative, may have potential beneficial eects
in sickle cell disease pathology including eects on nitric
oxide, sickle red blood cell retention and adhesion in
the pulmonary c irculation, and decreased interleukin-13
secretion [108112].
Montelukast, however, would be the preferred leuko-
triene modifier in patients with sickle cell disease and asthma
8 Anemia
because it has well-established eects 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 [115117]; heterogeneity in response
is due in large part to genetic variability [115, 118120]. 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
avariantnumber(either2,3,4,6,or7)repeatsofthe
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 dierences 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 [115].
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 ,
117, 121].MontelukastisasubstrateforOATP2B1,amem-
ber of the SLCO family of organic anion membrane transport
proteins encoded by SLCO2B1 [119]. 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 eects and correlates w ith
patient perception of asthma control [123]. 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 eectiveness.
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 [126].
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 [127]. Therefore, monitoring
for these adverse eects in patients with sickle cell disease
would be reasonable.
14. Inhaled Long-Acting β
2
-Agonists
Long-acting β
2
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
2
agonists with and
without inhaled corticosteroid therapy [129132]. These
risks were identified in clinical trials prior to the marketing
of salmeterol, the first long-acting β
2
-agonist available in this
country [129]. 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.)
[130]. Similar eects on exacerbation rates have been found
for formoterol [133]. Long-acting β
2
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 [134].
Guidelines for the Diagnosis and Management of Asthma
state that long-acting β
2
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].
Anemia 9
Results from retrospective pharmacogenetic association
studies of long-acting β
2
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
eects in African Americans [100, 135138]. Two prospective
genotype driven, randomized, double-blind trials examining
the eects of salmeterol plus inhaled corticosteroid therapy
have failed to find any significant eects 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
Persistent Asthma
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 eects and adverse gastroin-
testinal eects (nausea, dyspepsia) [141]. 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
2
-agonist
[83]. 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
be eective.
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 eectiveness with
minimization of adverse eects. Emergency department and
hospital-based pharmacologic care of asthma in the absence
of sickle cell disease includes the use of frequent inhaled
short-acting β
2
-agonist treatment with oral (or intravenous,
if hospitalized) corticosteroids [83]. Inhaled ipratropium
(an anticholinergic drug) can be added to short-acting β
2
-
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 [83]. Corticosteroid
treatment may require up to 10 days of therapy or longer but
dose tapering is not needed for treatments less than 14 days
[83].
The p otential risks associated with high doses of inhaled
short-acting β
2
agonists in the acute management of patients
with asthma and sickle cell disease are no dierent 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
2
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
2
agonists [32].
There are no reasons to expect anticholinergic ecacy or
toxicity would be any dierent for patients with asthma
and sickle cell disease compared to those without sickle cell
disease.
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 [142146].
Readmission rates after treatment with corticosteroids for
acute chest syndrome in patients with asthma is no dierent
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 [145].
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 [145]. 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 [143]. 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 [143]. 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 eect of a
short course of prednisone on readmission rate after acute
chest syndrome, though a Type II error may have precluded
observing an eect [142]. 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
10 Anemia
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 [12]. 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 ciently 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 [83] which would include aggressive use
of bronchodilators with systemic corticosteroid treatment
with consideration for a suciently long taper after discharge
until symptoms are completely resolved as recommended in
the current asthma guidelines [83]. In addition, all patients
with asthma should be discharged with prescribed inhaled
corticosteroid treatment for the long-term management of
asthma.
17. Conclusions
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 [147149], 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
care.
Conflicts of Interests
The authors have no conflicts of interests to report.
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    • "en. In addition to the production of antibodies, the macrophages of the spleen are involved in the removal of bacteria from the circulation by phagocytosis. Thus, asplenia in SCD subjects decreases the phagocytic potential of SCD subjects, permitting overwhelming bacteremia, septicemia, or meningitis before adequate antibody production could occur. [7] Extant literature review has shown the relationship between allergic condition (asthma) and SCD. However, it is not yet known if asthma in SCD is a disease resulting from SCD pathophysiology or caused by similar genetic and environmental factors found in typical asthma. The reported prevalence of asthma in children with SCD varies from "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Susceptibility of sickle cell disease subjects to various infectious agents is on the increase, but information relating SCD to allergic condition is scarce. Hence, assessment of immunoglobulin status in SCD children may provide useful information to improve management of SCD children. Objectives: To determine the levels of immunoglobulin classes (IgG, IgA, IgM, and IgE) in Nigerian HbSS children below 5 years of age compared with sex- and age-matched HbAA children. Materials and Methods: Blood samples were collected from a total of 45 children less than 5 years of age who were recruited into the study as follows: 26 HbSS and 19 HbAA subjects for the estimation of serum immunoglobulin levels using enzyme-linked immunosorbent assay (ELISA) techniques and determination of genotype using electrophoresis technique. Results: IgG concentration was nonsignificantly higher (P = 0.997) in HbSS children (1022.56 ± 148.97 ng/ml) compared to HbAA children (933.68 ± 106.10 ng/ml). IgA (P = 0.906) and IgM (P = 0.986) concentrations were nonsignificantly lower in HbSS children (255.07 ± 133.71 ng/ml) compared to HbAA children. IgE was significantly higher (P = 0.000***) in HbSS (108.67 ± 69.22 IU/ml) compared to HbAA (24.51 ± 17.58 IU/ml) children. Conclusion: SCD children in steady state have adequate levels of Ig classes. Non-specific elevation of IgE levels may be a factor of inflammatory response in SCD children, and this may be proposed for reduced allergic reaction among SCD children.
    Full-text · Article · Feb 2014 · The Journal of Alternative and Complementary Medicine
    • "It remains, however, unclear whether asthma/recurrent wheezing in patients with SCD is a complication of their disease or a comorbidity. Nevertheless , our results support the recommendation that any signs of asthma in SCD patients should be carefully investigated and aggressively managed [19]. Although asthma was associated with an increased risk of mortality, we did not find obstructive lung abnormalities to be more common in those who died. "
    [Show abstract] [Hide abstract] ABSTRACT: Purpose: Sickle cell disease (SCD) patients with asthma have an increased risk of death. Acute chest syndrome (ACS) is a major cause of mortality in patients with SCD, and ACS may be more common in SCD patients who smoke. The purpose of this study was to test the hypothesis that mortality in young adults with SCD would be greater than that of controls during a 10-year period and to determine whether asthma, reduced lung function, ACS episodes, and/or smoking predicted mortality during the follow-up period. Methods: The outcomes during a 10-year period were ascertained of SCD patients and race-matched controls who had taken part in a pulmonary function study when they were between age 19 and 27 years. Smoking and asthma status and whether they had had ACS episodes were determined, and lung function was measured at the initial assessment. Results: Seventy-five subjects with SCD were followed for 683 patient years. There were 11 deaths with a mortality rate of 1.6 deaths per 100 patient years, which was higher than that of the controls; one death in 47 controls was observed for 469 patient years with a mortality rate of 0.2 per 100 patient years (p = 0.03). There were no significant associations of body mass index, recurrent episodes of acute chest, steady state haemoglobin, or gender with mortality. Adjusting for baseline lung function in SCD patients, "current" asthma [hazard ratio (HR) 11.2; 95 % confidence interval (CI) 2.5-50.6; p = 0.002] and smoking [HR 2.7; (95 % CI 1.3-5.5); p = 0.006] were significantly associated with mortality during the 10-year period. Conclusions: Our results indicate that young adults with SCD should be discouraged from smoking and their asthma aggressively treated.
    Full-text · Article · Nov 2012
  • [Show abstract] [Hide abstract] ABSTRACT: The study was conducted to: (1) investigate both pharmacologic and complementary therapies used for pain management by caregivers of children with sickle cell disease (SCD), (2) investigate the prevalence and types of complementary therapies used for pain management by caregivers of children with SCD, and (3) explore caregivers' interests in using complementary therapies in the future. A cross-sectional, descriptive design was used. Sixty-three caregivers of children with SCD were asked to complete a questionnaire while they visited a SCD clinic. Chi-square tests were performed to compare demographic variables, examine use of pharmacologic therapies for pain management between age groups, and compare use of pharmacologic and complementary therapies. The most frequently used pain medications for children with SCD (mean age 9 years) were ibuprofen (37.5%), acetaminophen with codeine (32.1%), and acetaminophen with oxycodone (14.5%). More than 70% of 63 caregivers (mean age 33 years) were using some form of complementary therapies (3.67 +/- 2.95, range: 0-9) for their child. The most commonly used therapies were prayer, spiritual healing by others, massage, and relaxation. Complementary therapy use was significantly higher among caregivers of children who were taking two or more analgesics compared to children taking no analgesics or one analgesic (chi (2) = 3.954, p = 0.047). Although no difference was found in nonopioid analgesic use, there was significant difference in opioid analgesic use (chi (2) = 14.736, p = 0.002) and total medication use (chi (2) = 11.025, p = 0.012) between children < or = 12 years and > or =13 years. Caregivers of children using greater numbers of conventional pain medications were more likely to be using complementary therapies as well. If offered in the future, many caregivers were willing to try various types of complementary therapies for pain management.
    Article · Dec 2006
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