Pulmonary Complications of
Sickle Cell Disease
Kenneth I. Ataga, MD
Comprehensive Sickle Cell Program
University of North Carolina Chapel Hill
Introduction
•
•
•
Sickle hemoglobin (Hb S) occurs when the
normal 6 glutamic acid residue is replaced
by valine
The polymerization of deoxygenated Hb S is
the primary event in the molecular
pathogenesis of SCD
SCD is also characterized by increased
adhesion of RBC and other cellular elements
to endothelium
Sickle Cell Disease
Introduction
•
SCD may be complicated by several
pulmonary complications:






Acute chest syndrome
Airway hyperreactivity/Asthma
Pulmonary embolism
Nocturnal oxyhemoglobin desaturation
Pulmonary hypertension
Pulmonary fibrosis
Acute Chest Syndrome
Case Presentation
HPI: 30 year old black female presented with a
3 day history of fever & chest pain
PMH: Homozygous SS. Multiple admits for
painful VOCs. Occasional pRBCs. S/P Lap
Cholecystectomy. G2P2
Proteinuria - S/P Renal biopsy. Path - SS
Nephropathy.
Current Meds: Folic acid (1 mg/d)
Acute Chest Syndrome
PE: BP = 124/62. P = 128. RR = 30. T = 38.5
Sclerae - icteric. Neck: few nodes. JVD at 30
Chest - rales bilaterally, dullness to percussion,
especially in R mid lung field.
CVS - Loud P2. 3/6 SEM. No edema.
Abd - Distended, non-tender. No masses or
visceromegaly. Nl BS.
Neurol - non-focal, lethargic but easily arousable.
Oriented x 3.
Acute Chest Syndrome
Adm Labs: H/H 6.4/20, WBC 23,100. Plat 270K
LFTs - WNL. LDH - 2200. TBili - 13.4
CXR: Cardiomegaly. Pulm. venous congestion.
Subsegmental atelectasis - RUL. Patchy density
in the L costophrenic angle.
EKG: Sinus tachycardia. RVH & LVH. RAD
with evidence of right heart strain.
Acute Chest Syndrome
Admission Orders:






Sputum/urine/blood cultures
Cefotaxime 1 gram IV Q8H
Azithromycin
IV fluids
O2 - 2 Liters per minute via nasal cannula
IV narcotic analgesics
Acute Chest Syndrome
6 hours later

Decreased responsiveness, somnolent,
difficult to arouse, and confused.

BP=100/52, P=156, RR=44, T38.8 C

Extremities - cool with thready pulses
Acute Chest Syndrome
Repeat Laboratory Studies

Hematocrit = 14%

WBC = 31,300

Platelets = 284K

PT = 20.6, PTT = 59.4, TCT = 11.1

ABG (2L O2): pH 7.11, PO2 89, PCO2 19

Repeat CXR - extensive infiltrates/fluid with
white out of right lung
Acute Chest Syndrome
Patient intubated
emergently and then
transferred to the Intensive
Care Unit
Acute Chest Syndrome
Multiorgan Failure
Hematologic Status
Renal Status
pRBC (8 units)
FFP
Cryoprecipitate
Coags normalized
At D/C: PT 12.0, Hct 29%
Became oliguric in
ICU
• Peak BUN/Cr = 110/4.6
• Hemodialysis x 1
• Urine output
increased
Renal function improved
At D/C: BUN 17, Cr 1.5
•
•
•
•
Acute Chest Syndrome
Respiratory System
•
•
•
•
•
•
Extubated on day #5
Slow resolution of CXR
All cultures negative
ABG on day of D/C (RA)
pH 7.53 PO2 67 PCO2 30
ABG (6 weeks later)
pH 7.43 PO2 79 PCO2 38
PFTs (6 weeks later)
FVC - 2.19 (63%)
FEV1 1.99 (68%)
DLCOc - 28%
Cardiovascular System
•
•
•
•
Pressor support on vent
Echo (day #2)- severe TR
Dilated RA & RV
Mean PA pressure = 80
Repeat echo (day of D/C)
mild TR with minimal
pulmonary hypertension
Acute Chest Syndrome Objectives
• Incidence
• Risk Factors
• Clinical Presentation
• Etiology
• Mortality
• Pathophysiology
• Treatment
Acute Chest Syndrome
Definition?
• Charache suggested this name in 1979 for
what he felt was a poorly understood
process
• A new pulmonary infiltrate in a clinically ill
patient with sickle cell disease
• Fever, cough, chest pain, tachypnea,
wheezing, rales on exam
Acute Chest Syndrome
- Sources of Data
• The Cooperative Study of
Sickle Cell Disease (CSSCD)
• The National Acute Chest
Syndrome Study Group
(NACSSG)
Acute Chest Syndrome
- CSSCD & NACSSG
ACS: Incidence and Risk Factors; Clinical
Presentation and Course
(Castro et al., Blood, 1994 & Vichinsky et al., Blood, 1997)

Data from 3751 patients with 19,867 pt-years of
follow-up
Causes & Outcomes of ACS in SCD
(Vichinsky et al., NEJM, 2000)

Data from 538 patients with 671 episodes of ACS
Acute Chest Syndrome
- Incidence
• ACS incidence is higher in SS
•
•
patients (12.8/100 pt-yrs) and S0 thal
patients (9.4/100 pt-yrs)
ACS incidence in SC patients was
5.5/100 pt-yrs and in S+ thal patients
was 3.9/100 pt-yrs
Within each Hb type, incidence of
ACS was strongly, but inversely
associated with age
Acute Chest Syndrome
- Incidence (SS)
Age Group (yrs)
<2
2-5
5-10
10-20
> 20
Episodes of ACS
(per 100 patient years)
20.8
25.3
15.6
9.3
8.8
from Castro et al. Blood, 1994
Acute Chest Syndrome
- Incidence (SC)
Age Group (yrs)
<2
2-5
5-10
10-20
> 20
Episodes of ACS
(per 100 patient years)
10.3
10.1
4.3
4.0
3.3
from Castro et al. Blood, 1994
Acute Chest Syndrome
- Risk factors
Significant in multivariable analysis

Young age

Low fetal hemoglobin level

High hemoglobin level in steady state

High WBC in steady state
from Castro et al., Blood, 1994
Acute Chest Syndrome
- Effect of Hgb F Level on Risk
Relationship
between Hb F
and ACS for the
age groups
shown
from Castro, et al., Blood, 1994.
Acute Chest Syndrome
- Effect of Steady State Hgb Level
Relationship
between total
hemoglobin and
rate of ACS in 3
age groups
from Castro, et al., Blood, 1994.
Acute Chest Syndrome
- Clinical Presentation
•
•
•
Frequency of presenting symptoms in
ACS is age-dependent
Young children (2 – 4 yrs) present
commonly with fever, cough, wheezing
and rarely have pain
Adults are often afebrile, have SOB,
and severe pain in arms and legs
Acute Chest Syndrome
Clinical Presentation
• On x-ray, upper lobe disease is
predominant in children, while
multilobe/lower lobe disease is more
common in adults
• Children require less blood transfusions
than adult patients
• Duration of hospitalization is ~ 5.4 days in
children compared to ~ 9 days in adults
Acute Chest Syndrome
Effect on Mortality



ACS during initial 2 yrs
of f/u and those who
did not.
Survival difference
esp after age of 20
Adults with ↑ ACS rate
have a higher mortality
than those with low
rates
from Castro, et al., Blood, 1994
Acute Chest Syndrome
Mortality (CSSCD)
Overall death rate: 1.8% (32 / 1741)

In patients < 20 years, death rate =
1.1% (14 of 695 pts/1,322 events)


9/14 were < 3 yrs
In patients > 20 years, death rate =
4.3% (18 of 271 pts/419 events)
Etiology of Acute Chest Syndrome
(NACSSG )
(Total # of episodes = 671 in 538 pts)
• A specific cause was identified in 256
•
•
(38%)
After excluding cases with incomplete
data, a specific cause was found in 70%
of cases
Pulmonary infarction was presumed to be
the cause in 16% of episodes with
complete data but no identified etiology
Acute Chest Syndrome –
Etiology
Acute Chest Syndrome
Isolated Pathogens (NACSSG )
(Infectious pathogens were identified in 249 of 671
episodes of ACS)
•
•
•
•
•
•
•
Chlamydia
Mycoplasma
RSV
Staph Aureus
S. Pneumoniae
Parvovirus
Rhinovirus
71
61
26
12
11
10
8
•
•
•
•
•
•
•
Parainfluenza
H. flu
CMV
Influenza A
Legionella
E. Coli
EBV
6
5
4
4
4
3
3
Acute Chest Syndrome
Pathogenesis
•
•
ACS appears to be caused by hypoxiaenhanced RBC-pulmonary microvessel
adhesion
Factors that inhibit this interaction
may be potentially beneficial in the
treatment of this complication
Acute Chest Syndrome
•
•
•
Pathogenesis
Hypoxia enhances sRBC adherence to
endothelial cells
Hypoxia has been shown to decrease the
production of NO, which inhibits VCAM-1
upregulation
sRBC also inhibit NO production by 
protein levels of constitutive NO synthase
in endothelial cells
From Stuart & Setty, Blood, 1999
Pathogenesis
(Plasma levels of sVCAM-1 and NO from control and SCD patients – Stuart and
Setty, Blood, 1999)
Acute Chest Syndrome
Pathogenesis
•
•
•
In-vitro studies show that in the presence of
both hypoxia and oleic acid:

There is  expression of VCAM-1 in pulmonary
endothelial cells

There is  adherence of sRBC to endothelial cell
monolayers
Administration of NO substrates reduce
adhesion of sRBC to endothelial cells after
exposure to hypoxia
 expression of adhesion molecules by hypoxia,
cytokines and fat embolization with  NO
contributes to pathogenesis of ACS
From Stuart & Setty, Blood, 1999
Acute Chest Syndrome
•
•
•
•
Treatment
Early diagnosis is important, but also crucial
to recognize that VOC may be prodrome of
ACS
Broad spectrum antibiotics – cephalosporin +
macrolide
Bronchodilator, incentive spirometry  chest
PT
Early RBC transfusion (Simple vs Exchange)

•
Phenotypically matched RBC
Gentle hydration
Acute Chest Syndrome
Treatment
•
•
Hydroxyurea – known to decrease
the frequency of acute chest
syndrome
Experimental treatments

Steroids

Varespladib

Inhaled nitric oxide
Acute Chest Syndrome
Prevention
•
•
•
Styles et al evaluated whether RBC
transfusion before ACS eliminates or
lessens severity of ACS
Patients admitted for pain crisis were
followed with daily sPLA2 levels
Patients with  sPLA2 (> 100 ng/mL), fevers
& -ve CXR were enrolled
Styles et al, Br J Haematol, 2007
Acute Chest Syndrome
Prevention
•
•
•
•
Patients randomized to transfusion to Hb of
10 g/dL or standard care
7 patients in Tx arm (mean sPLA2 = 303  275
ng/ml) and 8 in non-Tx arms (mean sPLA2 =
434  250 ng/ml, NS)
5/8 in non-Tx arm developed ACS in 48 Hrs
0/7 in Tx arm developed ACS (p =0.026, OR
23.6, CI: 1 to 557)
Styles et al, Br J Haematol, 2007
Acute Chest Syndrome
Prevention
•
•
•
Length of hospitalization was 1 day shorter
in the transfused group
This pilot study shows that prevention of
ACS is possible with transfusion using
sPLA2 as a screening tool
With side effects of transfusion, other
interventions that reduce sPLA2 (e.g.
varespladib) are now in clinical trials
Styles et al, Br J Haematol, 2007
Acute Chest Syndrome
Summary
•
•
•
ACS is seen most commonly in the youngest
patients with SCD
The etiology of ACS is varied: even with
extensive investigation, infection is found in
only a minority of cases
Acute pain episode appears to be a prodrome
for acute chest syndrome
Acute Chest Syndrome
Next Steps
More research is needed!



Further elucidate the pathophysiology of acute
chest syndrome
Analyze the pathophysiology of lung damage
from PFE
Treatment and prevention trials
Acute Chest Syndrome
Current Studies!
•
•
Varespladib Infusion (A-001) for the
Prevention of Acute Chest Syndrome in
At-Risk Patients with SCD and Vasoocclusive crisis
Blood Transfusion for the Prevention of
Acute Chest Syndrome in At-Risk
Patients with SCD and Vaso-occlusive
crisis (PROACTIVE)