Reverse Translational Research:

Asthma Increases Sickle Cell 
Disease Related Morbidity
 and Mortality
Michael R. DeBaun, MD, MPH

   
 Asthma and Sickle Cell Disease

• Definition of sickle cell disease
• Definition of asthma
• Step wise approach to clinical investigation 
of lung disease in SCD 
• Assessment of mechanism for the 
association between asthma and vaso­
occlusion
   
 What is SCD?

• SCD=SCA or SCD = SCA

   
 SCD

• SCD
– Hemoglobin SS
– Hemoglobin SC
– Hemoglobin SB0
– Hemoglobin SB+

   
 Epidemiology

• Asthma is the most common chronic disease 
of childhood 
– ~20%  of AA  children have asthma
– ~20 % of children with SCD have asthma
• Leading cause of hospitalization in pediatrics

   
 Reverse Translational Research
Step 1 Observation

Step 2 Retrospective / Cross-Sectional Study

Step 3 Prospective Cohort Study

Step 4 Mechanism of Disease

Step 5 Targeted Intervention Trial

   
 Step 1:
Observation

• 11 year old male presents to SCD clinic 
with complaint of diffuse pain for three 
weeks with no relief after oxycontin at 
home
– Meds: Folic Acid, Hydroxyurea and Albuterol
– PE: tender with palpation to back, chest, 
extremities, chest exam ­ no wheeze

   
   
 Step 2: 
Retrospective Cohort Study

Asthma Increases the Risk of Acute Chest 
Syndrome and Rate of Painful Episodes in 
Children with Sickle Cell Disease

Henderson J, Moinuddin A, Strunk R, and DeBaun M 
Pediatric Pulmonology 2004: 38(3):229­232

   
 Hypothesis

• Children with sickle cell disease and 
asthma hospitalized for pain are at 
increased risk of ACS when compared to 
children with SCD and without asthma

   
 Development of ACS Among Children 
Hospitalized for Pain: Role of Asthma
Cases: Previous
diagnosis of
63 children (45%)
asthma
developed ACS
139 children with (35%)
SCD hospitalized
for pain P<0.01

Controls: Previous
diagnosis of
76 children (55%)
asthma
did not develop
(12%)
ACS

Risk of developing ACS increased 4.0 (95% CI 1.7,9.5) in 
children with MD ­ diagnosed asthma
   
 Additional Findings

• Children with asthma received active 
treatment for asthma in only 42% of ACS 
episodes
• Readmission occurred in 10% (10/97) of 
ACS episodes 
– 80% (8/10) of readmissions occurred in child 
with asthma

   
 Conclusions

• Children with sickle cell disease and asthma 
are at increased risk of ACS and have 
higher rates of ACS and pain episodes
• Asthma is an under­recognized and under­
treated co­morbid condition in children with 
sickle cell disease

   
 Step 3: 
Prospective Cohort Study

Asthma is Associated with Acute Chest 
Syndrome and Pain in Children
 with Sickle Cell Anemia

Boyd J, Macklin E, Strunk R, DeBaun M 
Blood 2006;108(9):2923­7
   
 Hypotheses
­ Primary
­ Children with sickle cell anemia (SCA) and 
asthma will be at increased risk for pain when 
compared to children with SCA
­ Secondary
­ Children with sickle cell anemia and asthma 
will have
­ A higher incidence of ACS
­ Their first ACS event will occur earlier 

   
 Methods: Patient Selection
Cooperative Study of Sickle Cell Disease
NIH sponsored, multi­institutional study (1977 ­ 1998)

Phase 3751 pts

enrolled
Infants < 6 mo Pediatric cohort: 6 to 10 months

450 pts enrolled 17 pts enrolled

Infant Cohort: 467 pts

Infants with Hb SS

Cohort: 292 pts

   
 Study Definitions
• Asthma
– Physician diagnosis of asthma or documentation 
of an acute asthma event
• Acute Chest Syndrome (ACS)
– New pulmonary infiltrate on CXR or pleuritic 
chest pain with an abnormal perfusion lung scan  
(CSSCD definition)
• Painful event
– Pain for >2 hours, led to a clinic visit and for 
which no other explanation could be found, 
including ACS  (CSSCD definition)
   
 Results

• 257 children met study criteria
• Mean follow­up
– 12.3 years
• PFT
– 202 children
• Asthma
– 18% (46/257)

   
 Asthma is Associated with Pain in 
Children with Sickle Cell Anemia
250
Asthmatic
Not Asthmatic
Pain rate (/100 pt-yrs)

200

150

100

50
(p<0.001)
0

0-2 2-4 4-6 6-8 8-10 10-12 12-20

Age (yrs)
   
Blood 2006;108(9):2923­7
 Asthma is Associated with ACS in 
Children with Sickle Cell Anemia
100

80
ACS rate (/100 pt-yrs)

60

40

20

Asthmatic
Not As thmatic
0

0-2 2-4 4-6 6-8 8-10 10-12 12-20

Age (yrs)
   
 Time to 1st ACS Episode in 
Patients with Asthma (log­rank, p=0.002)
Percentage experiencing an ACS event

100%

| | | | |
80% || | | ||
||
|| | ||||||||||||| |||| |
| |||
| |||||||
60% || |
| | | ||
| |
40%

20%
Asthmatic |
Not asthmatic |
0%
0 2 4 6 8 10 12 14 16 18 20
Time (yrs)

Asthmatic 46 30 13 12 6 5 4 2 1 1
 
Not asthmatic 211 144 112 97   72 51 36 17 8 2
Additional Evidence of an Association 
Between Asthma and ACS
• In a cohort of 80 children with SCD in 
Jamaica, asthma was associated with a 6 ­ fold 
increase in having recurrent ACS.
Knight­Madden et al., Thorax 2005

• In a cohort of 96 children with SCD, children 
with asthma had more episodes of ACS in a 
five­year period (90 episodes v. 58 episodes, 
p=0.03).  
  Nordness et al., Clin and Mol Allergy 2005
 
 Step 3: 
Prospective Cohort Study

Asthma is Associated with Early Death in 
Sickle Cell Anemia

Boyd J, Macklin E, Strunk R, DeBaun M 
Haematologica (2007)

   
 Hypothesis

• Individuals with SCA and asthma will have 
increased mortality when compared to 
individuals with SCA without asthma

   
 Methods
• Cooperative Study of Sickle Cell Disease 
– Study entry criteria
– Enrollment in CSSCD (n=  4,085)
– Hb SS ( n=2703)
– African American (n=2636)
– Followed beyond age 5 years (n=2557)
– Ability to ascertain asthma status (1963)
» Asthma (n =138)
» No asthma (n= 1825)

   
 Kaplan­Meier Plot of Survival in Individuals 
With SCA, With and Without Asthma
Cox regression hazard ratio: 2.36; 95% CI 1.21 to 4.62,
p=0.01

(1963 individuals with SCA, 18,496 patient­years)

   
 Conclusion

• Asthma is an independent risk factor for
– Pain and acute chest syndrome
– Premature death

   
 Is there a temporal relationship between 
mild respiratory symptoms in children with 
asthma and painful episodes ?

   
 Step 3: 
Retrospective Cohort Study

Painful Episodes in Children with Sickle Cell 
Disease and Asthma are Temporally Associated 
with Respiratory Symptoms 

Glassberg J, Spivey J, Strunk R, DeBaun M 
J Ped Hematol Oncol 2006;28(8):481­485

   
 Hypothesis
Mild respiratory symptoms either immediately 
precede or occur concomitantly with painful 
episodes more frequently in children with SCD 
and asthma when compared with children 
with SCD without asthma 

   
 Association Between Pain Episodes and 
Respiratory Symptoms Within 96 hrs of 
Presentation to Clinic with Pain
Respiratory
Asthma
symptoms
Presented to (54%)
Hematology/Pulmonary (35%)
clinic with pain episode
(n=94)
Chart audit P = 0.016

(no ACS or acute No Respiratory

asthma) asthma symptoms
(46%) (12%)

Among children with pain and asthma, OR of having antecedent

or concurrent respiratory symptoms = 4.9 (95% CI 2.2,10.7)
   
 Conclusions

• In children with both SCD and asthma, mild 
respiratory symptoms are a risk factor for 
painful episodes within 96 hours
• Children with SCD and asthma should be 
evaluated for respiratory symptoms at the 
beginning of their painful episodes

   
What about a mechanism for the 
association between asthma and sickle 
cell disease morbidity and mortality?

1. Human studies
A. Genetic studies
B. Measures of inflammation
2. Transgenic mouse model 

   
Sibling History of Asthma is a Risk 
Factor for Pain in Children with 
Sickle Cell Anemia

Joshua J. Field Eric A. Macklin 
Yan Yan, MD
Robert C. Strunk 
Michael R. DeBaun
Accepted American Journal of Hematology

   
 Methods: Patient Selection
Cooperative Study of Sickle Cell Disease
NIH sponsored, multi­institutional study (1977 ­ 1998)

211 children with Hgb SS
classifiable with a family 
history of asthma

Family history of  No family history of 
Asthma (n=42) Asthma (n=169)

   
 Family History of Asthma Associated 
with an Increased Rate of Pain
mean  95%  P value
rate ratio Confidence 
Interval

Sibling history of  2.48 1.6 ­ 4.0  < 0.001 

asthma

Parental history of  1.51 0.92 to 2.62  0.12

asthma 

   
Family History of Asthma Associated  with an Increased 
Rate of Pain
Characteristic
Mean rate
ratio for pain
episodes 95% CI P value
Without adjustment for
personal asthma (age at end of follow­
up, gender, and HCT and Fetal hemoglobin)

Sibling asthma 2.48 1.60-4.00 <0.001

Parental asthma 1.51 0.92-2.62 0.120

With adjustment for personal

asthma (age at end of follow­up, gender, and 
HCT and Fetal hemoglobin)

Sibling asthma 1.91 1.18-3.09 0.008

  Parental asthma  1.12 0.65-1.91 0.682

 Conclusion
• A familial component of asthma contributes 
to an increased rate of pain
– Genetic
– Environment
– Both genetic and environment

   
 Transgenic Sickle Cell Disease
 Mouse Model­C57Bl/6 
Blood 2006

• Blood smear: sickled RBCs
• Hb: Low (5­7 gm/dL)    Retic: High (30­40%)
• Pathology similar to humans
• Clinical complications:
• Poor perinatal survival (20%)
• Poor growth, hyposthenuria
• Stroke, priapism
   
 Proof of Principle: 
A SCD mouse with experimental asthma
Sensitization Protocol
Blood 2008;June 25. Epub ahead of print.

SUBCUTANEOUS
OVALBUMIN 6% OVALBUMIN AEROSOLIZATION
IMPLANTATION

2WEEKS

DAY 1 DAY15 DAY 17 DAY 19 DAY 21 DAY 23

   
Transgenic SCD Model
with Asthma
   
 Figure 3 C

   
 Step 5: 
Targeted Intervention

   
 Leukotriene Pathway

   
Adapted from NEJM 1999, Jan 21 340 (3:197-206)
Urinary Leukotriene E4 levels Are
Associated with Hospitalization for
Pain or Acute Chest Syndrome in
Children with Sickle Cell Disease

Jeanine E. Jennings, BS
Thiruvamoor Ramkumar, PhD
Jingnan Mao,
Jessica Boyd, MD, MPH
Mario Castro, MD, MPH
Robert C. Strunk, MD
Michael R. DeBaun, MD, MPH

America Journal of Hematology , 2008, Mar 26; 83(8):640-643.

Hypothesis urinary leukotriene E4 levels in children
with SCD compared to children without SCD
Median Leukotriene E4 level (pg/mg of Creatinine)

125

100

75

50

25

SCD Controls
N = 71 N = 22
Error bars: 95% CI
 Hypothesis: Leukotriene E4 Levels (tertiles)
are associated with an increase rate of pain

Pain (events per 100 patient-years)

CRUDE 95% CI ADJUSTED 95% CI

Lowest Tertile (N = 22)

30 (20, 41) 30 (20, 41)

Middle Tertile (N = 24)

42 (29, 54) 38 (17, 85)

Highest Tertile (N = 25)

61 (46, 77) 66* (31,138)
Baseline Urinary Cysteinyl Leukotriene E4 is Associated
with Increased Risk for Pain and ACS in Adults with SCD

Joshua J. Field, MD,

Jim Krings,
Nicole White,
Morey Blinder, MD,
Robert C. Strunk, MD,
Michael R. DeBaun, MD, MPH
 Comparison of adults with sickle cell disease and 
age, ethnic­matched controls 
Sickle cell
disease Controls
(n=71) (n=20) P value
Age, y, mean ± SD 34 ± 12 40 ± 11 0.053

Gender, % female 52 59 0.618

Asthma diagnosis, % 31 29 0.884

Inhaled corticosteroids , % 10 12 1.000

Montelukast, % 3 6 0.522

Current cigarette 18
27 0.430
smoking, %
Mean leukotriene E4 level in age, gender and ethnic­matched 
controls compared to adults with sickle cell disease
\Relationship of ATS/DLD questions to LTE4 in adults with SCD

Symptom % with event Significance

Does the participant’s chest every sound 0.010
wheezy or whistling when he/she has a cold? 72

Does the participant’s chest ever sound wheezy 0.034

or whistling occasionally even without having a 27
cold?
Has the participant ever had attacks of 0.039
wheezing after playing hard or exercising? 42

Has the participant ever had an attack of 0.410

wheezing that has caused him/her to be short of 27
breath?
Boxplot of the unadjusted rate of pain among adults with sickle cell disease 
in lowest, middle and highest LTE4 tertile 
 Conclusions
• Leukotriene levels are elevated among
children and adults with sickle cell disease
when compared to children without sickle
cell disesae
• Baseline leukotriene levels are associated
with
– asthma symptoms
– an increase rate of painful episodes
Hypothesis: Cysteinyl leukotriene receptor
antagonist (Montelukast) improves survival in
SCD mouse model after inflammatory stimuli
(chronic airway inflammation, hypoxemia)
 Summary

• Asthma is common in children with sickle cell 
disease
• Children with asthma have an increased rate of: 
– Pain
– ACS
– Death
• The mechanism of the increased morbidity and 
mortality has not been elucidated

   
 Progression of Reverse 
Translational  Research
Step 1 Observation

Step 2 Retrospective / Cross-Sectional Study

Step 3 Prospective Cohort Study

Step 4 Mechanism of Disease

Step 5 Targeted Intervention Trial

   
 The SLCH Sickle Cell Team

   
 Thank You!

• Ping An, Michael Province, Anne Bowcock, Mario Castro, Ramu Thiruvamoor 
• Cheryl Hillery, Kirk Pritchard (Medical College of Wisconsin)
• Janet Stocks, Fenella Kirkham  (Great Ormond Street)
   
Who Should See an Asthma Specialist?

• Children with frequent 
– Pain 
• > 3 hospitalizations in a year
• History of ACS
• Children with poorly controlled asthma
• Children with severe persistent asthma
• Children with eczema or other risk factors for 
asthma
   
Proposed Relationship Between Atopy, Bronchial 
Hyper­Responsiveness, Asthma Phenotype and 
SCD Morbidity 
Atopy

Asthma Phenotype
Bronchial 
Hyper­Responsiveness

SCD
Morbidity

   
 Asthma Hypoventilation
hypoxia & acidosis [from pain and/or opioid administration]

Regional
Ventilation-perfusion hypoxia
mismatch

Normal Sickled
Acute Chest Syndrome erythrocyte erythrocyte
and/or
Vaso-occlusive episode

Increased adhesion to
microvasculature

Local vascular injury & inflammation

[Recruitment of platelets, WBC, and
RBC with increased adhesion]
Adapted from Setty et al. Blood.1999 Sep 1;94(5):1555-60
 Is Airway Hyperresponsiveness a 
Fundamental Characteristic of SCD?

• Leong et al. J Peds 1997
• Methods:
– 40 children, 30 with HbSS, 18 with Hx RAD
– 10 controls, siblings without RAD
– Airway hyperreactivity defined with cold air 
challenge

   
 Case Report
• Infant with hemoglobin SS
• 1st allergy/pulmonary evaluation at 8 months
• Persistent cough and wheeze initially noted with 
cold symptoms, but numerous precipitating factors 
apparent
• Persistent rhinorrhea, snoring
• Eczema 
• Family history of eczema in both parents and 
asthma in a sibling
   
 Case Report (continued)
• 1st ED visit at 3 months
• 1st Hosp at 8 months
• Subsequent hosp at 10 and 14 months
• After 1st evaluation, treatment with regular ICS 
started 
• Oral steroid use at home with exacerbations 
started after hosp at 10 months
• Now 24 months old with no further ED or hosp, 
normal growth and development
   
 Lung Function and Airway 
Hyperresponsiveness in Adult 
Patients with SCD

Vendramini EC, Vianna EO, Angulo IDeL, DeCastro 
FB, Martinez JAB, Terra­Filho J
Am J Med 2006;332:68­72

Methacholine challenge used to determine airway 
hyperresponsiveness in 26 adults, 9 HbSS
AHR present in 42%, not related to presence of airway 
obstruction
   
 Relationship Between Clinical Course and 
Pulmonary Function Abnormalities

Chronic Lung
Clinical Pain, Disease,
Normal Pulmonary
ACS
Course: Hypertension,
Increased rate
of death

Obstruction
Pulmonary
Normal and/or Restriction
Function: Airway Hyper-
responsiveness

   
 Asthma risk factors
• Parental history of asthma*
• Physician­diagnosed atopic dermatitis*
• Allergic sensitization to an aeroallergen*
• Wheezing unrelated to colds*
• Blood eosinophils >4%*
• Serum IgE level >95th percentile for age**

* Guilbert et al. JACI 2004;114:1282

**Burrows et al. NEJM 1989;320:271-277
   
**Sears et al. New Engl J Med 1991;325:1067-1071
 Asthma Phenotypes
Asthma Phenotype Definition

Methacholine PC20 (the methacholine concentration

challenge causing a 20% fall in forced expiratory
volume in one second) ≤12.5 mg/ml
Bronchodilator An improvement in FEV1 ≥12% (absolute
Response difference) after treatment with albuterol

Airway Obstruction FEV1/FVC ratio < 95% predicted based on

age, sex, height, and race

Physician Diagnosis Ascertained through patient and guardian

interview and medical chart review
   
 Methods
• Baseline evaluation: • Interim visits (q6 mo): 
– History and Physical – History and Physical 
– Spirometry with bronchodilator  – Spirometry with 
response bronchodilator response
– Lung volumes
– IOS
– IOS
– eNO
– eNO
– IgE, Eosinphil Count – Eosinophil Count
– Allergy Skin Test • Quarterly Telephone 
– Methacholine Challenge      (to be  Contact:
done at visit 2)              – Interim History 
– DNA collection (for Project 3)
  – Nasal brushing for STAT1     (visit 
3)
 Is Airway Hyperresponsiveness a 
Fundamental Characteristic of SCD?

   
 Background

• Leong et al. J Peds 1997
• Methods:
– 40 children, 30 with HbSS, 18 with Hx RAD
– 10 controls, siblings without RAD
– Airway hyperreactivity defined with cold air 
challenge

   
Airway Hyperresponsiveness Defined
with Cold Air Challenge

SCD and RAD, 13 (squares)

SCD without RAD, 19 (circles)
Controls, 10 (diamonds)

   
 Other Articles on Asthma 
and SCD Morbidity
• Gorin and Paraire. Postmortem revelation of SCD 
following fatal episode of acute bronchial asthma. 
Forensic Science International 2002;126:48­52

• Knight­Madden et al. Asthma in children with SCD 
and its association with ACS. 
Thorax 2005;60:206­210
– Atopic asthma appears to be associated with recurrent 
ACS.   Early and effective anti­asthma therapy might 
reduce pulmonary morbidity associated with ACS

   
 Lung Function and Airway 
Hyperresponsiveness in Adult 
Patients with SCD

Vendramini EC, Vianna EO, Angulo IDeL, DeCastro 
FB, Martinez JAB, Terra­Filho J
Am J Med 2006;332:68­72

Methacholine challenge used to determine airway 
hyperresponsiveness in 26 adults, 9 HbSS
AHR present in 42%, not related to presence of 
obstruction
   
 What is the evidence that children 
witih sickle cell disease have asthma 
as opposed to a lung disease that 
mimics asthma?

   
  Major gene effect and additive familial 
pattern of inheritance of asthma exist among 
families of probands with sickle cell anemia 
and asthma
Am J Hum Biol. 2007.

   
 Case Report­2
• Male with SS
• 1st allergy/pulmonary evaluation at 8 month
• Persistent cough and wheeze initially noted with 
cold symptoms, but numerous precipitating factors 
apparent
• Persistent rhinorrhea, snoring
• Eczema 
• Family history of eczema in both parents and 
asthma in a sibling
   
 Case Report­2, Cont’d
• Allergy skin testing negative
• Infant pulmonary function tests
– FEV0.5 57% predicted
– Bronchodilator response = 34%
– Significant air trapping present
• Peripheral blood eosinophilia 4­6% 
when well
   
 Case Report­2, Cont’d
• 1st ED visit at 3 months
• 1st Hosp at 8 months
• Subsequent hosp at 10 and 14 months
• After 1st evaluation, treatment with regular ICS 
started 
• Oral steroid use at home with exacerbations 
started after hosp at 10 months, need infrequent
• Now 6 years old with no further ED or hosp, 
normal growth and development

   
 Rationale for study of 
lung disease
• Chronic lung disease is a major cause of morbidity and 
mortality in adult SCD patients
– Physiology is primarly restrictive
• Lung disease in children with SCD
– Children with SCD may have normal, obstructive, or mixed obstructive 
and restrictive abnormalities, but studies on limited number of children 
and no good correlations established between results and clinical course 
– Airway lability has been demonstrated in a large percentage of SCD 
children, with bronchodilator reactivity and hyper responsiveness to cold 
air  
– Spirometry values decline with increasing age in patients with SCA, 
suggesting an evolution of physiologic abnormalities from normal to 
obstruction to restriction
• Diagnosis of asthma as co­morbid condition increases 
frequency of pain and acute chest episodes, and shortens 
life
   
 Pulmonary and Allergy 
Evaluation
• Spirometry
• Impulse oscillometry
• Lung volumes
• Exhaled nitric oxide (off line)
• Airway lability – bronchodilator reactivity and 
methacholine responsiveness
• Allergy characteristics
– Aeroallergen sensitivity
– Total serum IgE
– Personal history of eczema and allergic rhinitis
– Family history of asthma and allergy (parental and siblings)
   
 Asthma Phenotype Definition
• Positive methacholine challenge, PC20 ≤12.5 
mg/ml
• Bronchodilator Response – improvement in 
FEV1 ≥12% (absolute difference) after treatment 
with albuterol
• Airway Obstruction – FEV1/FVC ratio < 95% 
predicted based on age, sex, height, and race 
(Wang and Dockery)*
• Physician Diagnosis ascertained through patient 
and parent interviews and medical chart review

  *No upper limit  of FEV1 will be set, as children

with asthma are known to have well maintained FEV1
 Case Report
• 5 year old with sickle cell/beta thalassemia anemia
• 9 prior hospitalizations
• Typical course of an exacerbation:
– Initial symptoms typical of URI, followed by tiredness 
and shortness of breath, and then cough and wheeze
– Pain followed in various locations and then diffusely
– Never heard to wheeze upon arrival at hospital

   
 Case Report, Cont’d
• Evaluation at 5 years (5/03) included:
– No evidence for atopy:
• Negative skin tests to aeroallergens
• Total serum IgE normal
• Elevated eosinophil count
• Family history negative for asthma
– Pulmonary function testing with restriction and air trapping:
• Spirometry – moderate reduction in FEV1 and FVC with restrictive 
pattern (FEV1 /FVC = 90%), no response to BD
• Lung volumes with air trapping (RV/TLC = 35%, normal up to 30%)
– Methacholine challenge wtih severe responsiveness (PC20 = 0.8 
mg/ml)
– Minimal snoring history, 02 saturation = 100%
   
 Case Report, Cont’d
• Initial impression was infection­induced 
asthma
• Plan to treat with ICS at first sign of a cold 
and add systemic steroid if not effective
• Continued with hospitalizations: 11/03, 
4/04, 3/05, and 2 in 2 weeks of 8/05

   
 Case Report, Cont’d

• 1st of 2 hospitalizations in 8/05
– Pain was first Sx.  Albuterol and ICS started.  
Pneumonia diagnosed.  Chest xray showed new RML 
infiltrate.  Treated with antibiotics and oral steroids (no 
cough or wheeze).  Sx resolved within 24 hr.
– 2 days after discharge respiratory Sx reoccurred 
(increased work of breathing) with pain.
• 2nd hospitalization with ICU admission
– Oral steroids started again with resolution of Sx within 
24 hours.

   
 What does this case represent?
• Case more complex than typical asthma
– Symptom progression may represent response to a viral 
infection, but wheeze heard early on at home never heard 
at time of hospitalization
– No atopy
– Severe airway responsiveness present, but not clear 
whether it is cause or effect of clinical symptoms
– Pulmonary physiology restrictive, but air trapping present
– Treatment with ICS at time of symptoms clearly not 
adequate, but oral steroids seem to be effective

   
 Questions raised by 
this case
• What is the meaning of increased airway 
responsiveness in the absence of typical 
asthma?  How does this finding alter our 
approach to treatment?
• What is the meaning of air trapping in the 
presence of restrictive lung disease?

   
 Analyses
• Evaluation for presence of lung disease: 
– Increased resistance on IOS,
– Small airway disease apparent by lung volume testing
– Obstruction apparent on spirometry
– Restrictive pattern on spirometry and by decreased total lung 
capacity 
• Categories of lung disease will be correlated 
with results of testing for patterns of morbidity 
and presence asthma risk factors

   
 Analyses
• Exhaled NO 
– measurements at regular biannual visits and at times of 
exacerbation of sickle cell disease requiring hospitalization  
• Hypotheses – elevated levels:
– will identify children at risk for exacerbation of sickle cell crises 
of either pain or ACS overall  
– will identify increased risk for exacerbation in the next 3 months 
– eNO will be elevated in SCA, especially in those with allergy 
and asthma, and that variability in levels will be associated 
morbidity

   
 Analyses
• Pulmonary function pattern will evolve during the 3­year 
follow­up interval to increased respiratory resistance 
measured by IOS, airway obstruction (obstruction 
pattern on spirometry and air trapping on lung volumes), 
and then restriction.
• Children with atopy but no diagnosis of asthma are more 
likely to acquire a diagnosis of asthma and small airway 
disease (air trapping on lung volumes and 
inhomogeneity on analysis of flow­volume curves) than 
those with no atopy.

   
 Conclusions
• Sickle cell anemia causes lung disease
• Asthma worsens the course of sickle cell disease
• Relationship between asthma and various 
manifestations of sickle cell disease is complex
• Understanding of relationship can only thorough 
analysis of patient physiology, atopy, and other 
risk factors for lung disease wit correlation to 
clinical course

   
 Sickle Cell Anemia
Sleep and Asthma Cohort Study
 Projects in SAC
Project 1: Project 2:
Asthma risk factors Sleep Disordered
& phenotypes in breathing in SCA
SCA

Project 3
Asthma­related  
Project 4:
Transgenic sickle
cell disease mouse genes in SCA