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Reverse Translational Research:

Asthma Increases Sickle CellDisease Related Morbidity

and Mortality

Michael R. DeBaun, MD, MPH

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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

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What is SCD?

SCD=SCA or SCD = SCA

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SCD

SCD

Hemoglobin SS

Hemoglobin SC

Hemoglobin SB0

Hemoglobin SB+

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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

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Step 1

Targeted Intervention Trial

Observation

Retrospective / Cross-Sectional StudyStep 2

Prospective Cohort StudyStep 3

Mechanism of DiseaseStep 4

Step 5

Reverse Translational Research

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Step 2:

Retrospective Cohort Study

Asthma Increases the Risk of Acute ChestSyndrome and Rate of Painful Episodes in

Children with Sickle Cell Disease

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

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Hypothesis

Children with sickle cell disease and

asthma hospitalized for pain are atincreased risk of ACS when compared to

children with SCD and without asthma

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Development of ACS Among Children

Hospitalized for Pain: Role of Asthma

139 children with

SCD hospitalized

for pain

Cases:

63 children (45%)

developed ACS

Controls:

76 children (55%)

did not develop

ACS

Previous

diagnosis of

asthma

(35%)

Previous

diagnosis of

asthma(12%)

P

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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 childwith asthma

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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 under-recognized and under-

treated co-morbid condition in children with

sickle cell disease

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Step 3:

Prospective Cohort Study

Asthma is Associated with Acute ChestSyndrome and Pain in Children

with Sickle Cell Anemia

Boyd J, Macklin E, Strunk R, DeBaun M

Blood 2006;108(9):2923-7

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Hypotheses

- Primary

- Children with sickle cell anemia (SCA) and

asthma will be at increased risk for pain whencompared 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

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Methods: Patient SelectionCooperative Study of Sickle Cell Disease

NIH sponsored, multi-institutional study (1977 - 1998)

Pediatric cohort: 6 to 10 months

Phase 3751 pts

enrolled

450 pts enrolled

Infants < 6 mo

17 pts enrolled

Infant Cohort: 467 pts

Infants with Hb SS

Cohort: 292 pts

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Study Definitions

Asthma Physician diagnosis of asthma or documentation

of an acute asthma event

Acute Chest Syndrome (ACS) New pulmonary infiltrate on CXR or pleuriticchest 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)

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Results

257 children met study criteria

Mean follow-up

12.3 years

PFT

202 children

Asthma 18% (46/257)

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Asthma is Associated with Pain in

Children with Sickle Cell Anemia

0

50

100

150

200

250

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

Age (yrs)

Painrate

(/100pt-yrs)

AsthmaticNot Asthmatic

(p

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0

20

40

60

80

100

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

Age (yrs)

ACS

rate(/1

00p

t-yrs)

AsthmaticNot Asthmatic

Asthma is Associated with ACS in

Children with Sickle Cell Anemia

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Time to 1st ACS Episode in

Patients with Asthma(log-rank, p=0.002)

| || ||

|| |||||

||||||||||| ||| ||

||| |||||||||||||||||| ||||| |

|| | | ||

| | | | |

0 2 4 6 8 10 12 14 16 18 20

0%

20%

40%

60%

80%

100%

Time (yrs)

Perc

entageexperiencinganACSe

Asthmatic

Not asthmatic

46 30 13 12 6 5 4 2 1 1

211 144 112 97 72 51 36 17 8 2

AsthmaticNot asthmatic

||

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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.Knight-Madden et al., Thorax 2005

In a cohort of 96 children with SCD, children

with asthma had more episodes of ACS in a

five-year period (90 episodes v. 58 episodes,

p=0.03).

Nordness et al., Clin and Mol Allergy 2005

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Step 3:

Prospective Cohort Study

Asthma is Associated with Early Death inSickle Cell Anemia

Boyd J, Macklin E, Strunk R, DeBaun MHaematologica (2007)

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Hypothesis

Individuals with SCA and asthma will have

increased mortality when compared to

individuals with SCA without asthma

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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)

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Kaplan-Meier Plot of Survival in Individuals

With SCA, With and Without AsthmaCox regression hazard ratio: 2.36; 95% CI 1.21 to 4.62,Cox regression hazard ratio: 2.36; 95% CI 1.21 to 4.62,

p=0.01p=0.01

(1963 individuals with SCA, 18,496 patient-years)

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Conclusion

Asthma is an independent risk factor for

Pain and acute chest syndrome

Premature death

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Is there a temporal relationship between

mild respiratory symptoms in children with

asthma and painful episodes ?

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Step 3:

Retrospective Cohort Study

Painful Episodes in Children with Sickle Cell

Disease and Asthma are Temporally Associatedwith Respiratory Symptoms

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

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Hypothesis

Mild respiratory symptoms either immediately

precede or occur concomitantly with painfulepisodes more frequently in children with SCD

and asthma when compared with children

with SCD without asthma

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Presented toHematology/Pulmonaryclinic with pain episode

(n=94)

(no ACS or acuteasthma)

Noasthma

(46%)

Asthma

(54%)

Association Between Pain Episodes and

Respiratory Symptoms Within 96 hrs of

Presentation to Clinic with Pain

Respiratorysymptoms

(35%)

Respiratorysymptoms

(12%)

P = 0.016

Among children with pain and asthma, OR of having antecedent

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

Chart audit

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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

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What about a mechanism for the

association between asthma and sicklecell disease morbidity and mortality?

1. Human studiesA. Genetic studies

B. Measures of inflammation

2. Transgenic mouse model

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Sibling History of Asthma is a Risk

Factor for Pain in Children withSickle Cell Anemia

Joshua J. Field Eric A. Macklin

Yan Yan, MD

Robert C. Strunk

Michael R. DeBaunAccepted American Journal of Hematology

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Methods: Patient SelectionCooperative Study of Sickle Cell Disease

NIH sponsored, multi-institutional study (1977 - 1998)

211 children with Hgb SS

classifiable with a family

history of asthma

No family history ofAsthma (n=169)

Family history ofAsthma (n=42)

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Family History of Asthma Associated

with an Increased Rate of Pain

0.120.92 to 2.621.51Parental history of

asthma

< 0.0011.6 - 4.02.48Sibling history of

asthma

P value95%

Confidence

Interval

mean

rate ratio

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0.6820.65-1.911.12Parental asthma

0.0081.18-3.091.91Sibling asthma

With adjustment for personalasthma (age at end of follow-up, gender, andHCT and Fetal hemoglobin)

0.1200.92-2.621.51Parental asthma

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Conclusion

A familial component of asthma contributes

to an increased rate of pain

Genetic

Environment

Both genetic and environment

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Transgenic Sickle Cell Disease

Mouse Model-C57Bl/6

Blood 2006

Blood smear: sickled RBCs

Hb: Low (5-7 gm/dL) Retic: High (30-40%)

Pathology similar to humans

Clinical complications:

Poor perinatal survival (20%) Poor growth, hyposthenuria

Stroke, priapism

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Proof of Principle:

A SCD mouse with experimental asthmaBlood 2008;June 25. Epub ahead of print.

SUBCUTANEOUS

OVALBUMIN

IMPLANTATION

DAY 1

2WEEKS

DAY 21DAY 19DAY 17DAY15 DAY 23

6% OVALBUMIN AEROSOLIZATION

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Transgenic SCD Model

with Asthma

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Figure 3 C

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Step 5:

Targeted Intervention

?

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Leukotriene Pathway

Adapted from NEJM 1999, Jan 21 340 (3:197-206)

Urinary Leukotriene E4 levels Are

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Urinary Leukotriene E4 levels Are

Associated with Hospitalization for

Pain or Acute Chest Syndrome inChildren 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


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

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ControlsSCD

125

100

75

50

25

0

Median

LeukotrieneE4level(pg/mgofCreatinine)

Error bars: 95% CI

N = 71 N = 22

Hypothesis urinary leukotriene E4 levels in children

with SCD compared to children without SCD

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(31,138)66*(46, 77)61Highest Tertile (N = 25)

(17, 85)38(29, 54)42Middle Tertile (N = 24)

(20, 41)30(20, 41)30Lowest Tertile (N = 22)

95% CIADJUSTED95% CICRUDE

Pain (events per 100 patient-years)

Hypothesis: Leukotriene E4 Levels (tertiles)

are associated with an increase rate of pain

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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,


C i f d l i h i kl ll di d

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0.43018

27Current cigarette

smoking, %

0.52263Montelukast, %

1.0001210Inhaled corticosteroids , %

0.8842931Asthma diagnosis, %

0.6185952Gender, % female

0.05340 1134 12Age, y, mean SD

P value

Controls

(n=20)

Sickle cell

disease

(n=71)

Comparison of adults with sickle cell disease and

age, ethnic-matched controls

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Mean leukotriene E4 level in age, gender and ethnic-matched

controls compared to adults with sickle cell disease

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0.410

27

Has the participant ever had an attack of

heezing that has caused him/her to be short ofbreath?

0.03942

Has the participant ever had attacks of

wheezing after playing hard or exercising?

0.034

27

Does the participants chest ever sound wheezy

or whistling occasionally even without having acold?

0.01072

Does the participants chest every sound

wheezy or whistling when he/she has a cold?

Significance% with eventSymptom

\Relationship of ATS/DLD questions to LTE4 in adults with SCD

Boxplot of the unadjusted rate of pain among adults with sickle cell disease

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Boxplot of the unadjusted rate of pain among adults with sickle cell disease

in lowest, middle and highest LTE4 tertile

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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

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Hypothesis: Cysteinyl leukotriene receptor

antagonist (Montelukast) improves survival in

SCD mouse model after inflammatory stimuli

(chronic airway inflammation, hypoxemia)

S

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Summary

Asthma is common in children with sickle celldisease

Children with asthma have an increased rate of:

Pain ACS

Death

The mechanism of the increased morbidity andmortality has not been elucidated

Progression of Reverse

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Step 1

Targeted Intervention Trial

Observation

Retrospective / Cross-Sectional StudyStep 2

Prospective Cohort StudyStep 3

Mechanism of DiseaseStep 4

Step 5

Progression of Reverse

Translational Research

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The SLCH Sickle Cell Team

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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)

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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

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Bronchial

Hyper-Responsiveness

Asthma Phenotype

Atopy

SCD

Morbidity

Proposed Relationship Between Atopy, Bronchial

Hyper-Responsiveness, Asthma Phenotype and

SCD Morbidity

Asthma Hypoventilation

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Adapted from Setty et al. Blood.1999 Sep 1;94(5):1555-60

Increased adhesion to

microvasculature

Regional

hypoxia

Normal

erythrocyte

Sickled

erythrocyteAcute Chest Syndrome

and/or

Vaso-occlusive episode

Local vascular injury & inflammation

[Recruitment of platelets, WBC, and

RBC with increased adhesion]

Asthma

hypoxia & acidosis

Hypoventilation

[from pain and/or opioid administration]

Ventilation-perfusion

mismatch

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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 airchallenge

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Case Report

Infant with hemoglobin SS

1st allergy/pulmonary evaluation at 8 months

Persistent cough and wheeze initially noted withcold symptoms, but numerous precipitating factorsapparent

Persistent rhinorrhea, snoring

Eczema Family history of eczema in both parents and

asthma in a sibling

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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

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Hyperresponsiveness in Adult

Patients with SCD

Vendramini EC, Vianna EO, Angulo IDeL, DeCastro

FB, Martinez JAB, Terra-Filho J

Am J Med 2006;332:68-72

Methacholine challenge used to determine airwayhyperresponsiveness in 26 adults, 9 HbSS

AHR present in 42%, not related to presence of airwayobstruction

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Relationship Between Clinical Course and

Pulmonary Function Abnormalities

Clinical

Course:Normal

Pain,

ACS

Chronic Lung

Disease,

PulmonaryHypertension,

Increased rate

of death

PulmonaryFunction:

Normal

Obstruction

and/or

Airway Hyper-

responsiveness

Restriction

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Asthma risk factors

Parental history of asthma*

Physician-diagnosed atopic dermatitis*

Allergic sensitization to an aeroallergen*

Wheezing unrelated to colds*

Blood eosinophils >4%*

Serum IgE level >95th percentile for age**

* Guilbert et al.JACI2004;114:1282

**Burrows et al. NEJM1989;320:271-277

**Sears et al.New Engl J Med1991;325:1067-1071

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Asthma Phenotypes

Ascertained through patient and guardian

interview and medical chart review

Physician Diagnosis

FEV1/FVC ratio < 95% predicted based on

age, sex, height, and race

Airway Obstruction

An improvement in FEV1 12% (absolute

difference) after treatment with albuterol

Bronchodilator

Response

PC20

(the methacholine concentration

causing a 20% fall in forced expiratory

volume in one second) 12.5 mg/ml

Methacholine

challenge

DefinitionAsthma Phenotype

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Methods

Baseline evaluation:

History and Physical

Spirometry with bronchodilatorresponse

Lung volumes

IOS

eNO

IgE, Eosinphil Count

Allergy Skin Test Methacholine Challenge (to bedone at visit 2)

DNA collection (for Project 3)

Nasal brushing for STAT1 (visit3)

Interim visits (q6 mo):

History and Physical

Spirometry with

bronchodilator response IOS

eNO

Eosinophil Count

Quarterly TelephoneContact:

Interim History

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Is Airway Hyperresponsiveness aFundamental Characteristic of SCD?

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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 airchallenge

Airway Hyperresponsiveness Defined

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SCD and RAD, 13 (squares)SCD without RAD, 19 (circles)

Controls, 10 (diamonds)

y yp p

with Cold Air Challenge

O h A i l A h

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Other Articles on Asthma

and SCD Morbidity

Gorin and Paraire. Postmortem revelation of SCDfollowing fatal episode of acute bronchial asthma.Forensic Science International 2002;126:48-52

Knight-Madden et al. Asthma in children with SCDand its association with ACS.

Thorax 2005;60:206-210

Atopic asthma appears to be associated with recurrentACS. Early and effective anti-asthma therapy mightreduce pulmonary morbidity associated with ACS


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Hyperresponsiveness in Adult

Patients with SCD

Vendramini EC, Vianna EO, Angulo IDeL, DeCastro

FB, Martinez JAB, Terra-Filho J

Am J Med 2006;332:68-72

Methacholine challenge used to determine airwayhyperresponsiveness in 26 adults, 9 HbSS

AHR present in 42%, not related to presence ofobstruction

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What is the evidence that childrenwitih sickle cell disease have asthma

as opposed to a lung disease that

mimics asthma?

Major gene effect and additive familial

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pattern of inheritance of asthma exist among

families of probands with sickle cell anemia

and asthma

Am J Hum Biol. 2007.

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Case Report-2

Male with SS

1st allergy/pulmonary evaluation at 8 month

Persistent cough and wheeze initially noted withcold symptoms, but numerous precipitating factorsapparent

Persistent rhinorrhea, snoring

Eczema Family history of eczema in both parents and

asthma in a sibling

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Case Report-2, Contd

Allergy skin testing negative

Infant pulmonary function tests

FEV0.5 57% predicted

Bronchodilator response = 34%

Significant air trapping present

Peripheral blood eosinophilia 4-6%when well

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Case Report-2, Contd

1st ED visit at 3 months

1st Hosp at 8 months

Subsequent hosp at 10 and 14 months

After 1st evaluation, treatment with regular ICSstarted

Oral steroid use at home with exacerbationsstarted 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

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y

lung disease

Chronic lung disease is a major cause of morbidity andmortality in adult SCD patients

Physiology is primarly restrictive

Lung disease in children with SCD

Children with SCD may have normal, obstructive, or mixed obstructiveand restrictive abnormalities, but studies on limited number of childrenand no good correlations established between results and clinical course

Airway lability has been demonstrated in a large percentage of SCDchildren, with bronchodilator reactivity and hyper responsiveness to coldair

Spirometry values decline with increasing age in patients with SCA,

suggesting an evolution of physiologic abnormalities from normal toobstruction to restriction

Diagnosis of asthma as co-morbid condition increasesfrequency of pain and acute chest episodes, and shortenslife

Pulmonary and Allergy

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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

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Asthma Phenotype Definition

Positive methacholine challenge, PC20 12.5mg/ml

Bronchodilator Response improvement inFEV1 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 patientand 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

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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 tirednessand shortness of breath, and then cough and wheeze

Pain followed in various locations and then diffusely

Never heard to wheeze upon arrival at hospital

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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 = 0.8mg/ml)

Minimal snoring history, 02 saturation = 100%

Case Report, Contd

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Initial impression was infection-induced

asthma

Plan to treat with ICS at first sign of a coldand 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, Contd

Case Report Contd

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1st of 2 hospitalizations in 8/05 Pain was first Sx. Albuterol and ICS started.

Pneumonia diagnosed. Chest xray showed new RMLinfiltrate. 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.

Case Report, Contd

What does this case represent?

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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 heardat time of hospitalization

No atopy

Severe airway responsiveness present, but not clearwhether 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

Q i i d b

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Questions raised by

this case What is the meaning of increased airway

responsiveness in the absence of typical

asthma? How does this finding alter ourapproach to treatment?

What is the meaning of air trapping in the

presence of restrictive lung disease?

Analyses

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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

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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 crisesof 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 allergyand asthma, and that variability in levels will be associated

morbidity

Analyses

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Analyses

Pulmonary function pattern will evolve during the 3-yearfollow-up interval to increased respiratory resistancemeasured by IOS, airway obstruction (obstructionpattern 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 airwaydisease (air trapping on lung volumes andinhomogeneity on analysis of flow-volume curves) than

those with no atopy.

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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 otherrisk factors for lung disease wit correlation to

clinical course

Sickle Cell Anemia

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Sleep and Asthma Cohort Study

Projects in SAC

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Projects in SAC

Project 4: Asthma-related

Project 1:Asthma risk factors

& phenotypes inSCA

Project 2:Sleep Disorderedbreathing in SCA

Project 3

T i i kl

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