www.turner-white.com Pulmonary Disease Volume 14, Part 5 3
moglobin S. Homozygous SCD and sickle cell/β0
thalassemia are generally considered the more severe forms of the disease, with sickle hemoglobin
C disease and sickle cell/β+ thalassemia tending to
be less severe.
The incidence of ACS differs among the forms of
SCD as demonstrated by the Cooperative Study of
Sickle Cell Disease (CSSCD), a prospective study
that followed 3751 patients for 19,867 patient-years.
8 In the CSSCD, the incidence of ACS was
highest among patients with homozygous SCD
at 12. 8 cases per 100 patient-years, followed by
sickle cell/β0 thalassemia ( 9. 4 cases/100 patient-yr), sickle hemoglobin C disease ( 5. 2 cases/100
patient-yr), and sickle cell/β+ thalassemia (3.9
cases/100 patient-yr). This study also noted that
the incidence of sickle cell complications is inversely related to age, with the incidence of vaso-occlusive pain crisis or ACS decreasing steadily
from childhood to adulthood. Insight into other
clinical aspects of ACS episodes was provided by
the National Acute Chest Syndrome Study Group
(NACSSG), which evaluated 671 episodes of ACS
in 538 adult and pediatric patients over a 4-year period among 30 centers.
10 Nearly half of the patients
were admitted for reasons other than ACS, most
commonly pain, and went on to develop the syndrome later in their hospital course. Approximately
18% of patients had frequent admissions due to
recurrent episodes of this syndrome, which may
result in long-term sequelae. The CSSCD found
that ACS was the second most common reason
for hospitalization after vaso-occlusive pain crisis
( 12. 8 hospitalizations/100 patient-yr).
11 The mean
duration of hospitalization ranges from 6. 4 days10 to
10. 5 days.
11 The incidence of death from ACS also
has varied in different studies, ranging from 1.8%
in the NACSSG report to 3% in the CSSCD.
Patients older than 19 years of age have a higher
mortality rate, up to 4.3%, and the main cause of
death was respiratory failure.
11 Clinical features
may also have a link to survival. Patients with leukocytosis exceeding 15,000 cells/µL at baseline
may be at higher risk for mortality ( 2. 2 versus 1. 2
deaths per 100 person-yr).
Red cell sickling is the primary cellular event
leading to the clinical pathophysiology in SCD.
SCD results from a single gene defect in which valine is substituted for glutamic acid in the β-globin
subunit of hemoglobin A, resulting in the formation
of hemoglobin S. When deoxygenated, hemoglobin S polymerizes in the cell, distorting the cell’s
shape and causing it to stiffen and become less
14 The distorted shape and inflexibility of
sickled red blood cells make them prone to obstruct
arterioles and capillaries, leading to ischemia and
tissue damage. Other factors that contribute to the
pathogenesis of ACS include increased expression of adhesion molecules on sickle cells and
endothelium, reduced levels of nitric oxide (NO),
and release of inflammatory mediators.
Hypoxia enhances the ability of sickle cells to
adhere to vessel endothelium via interaction between very late activation antigen 4 (VLA4) on
red blood cells and the vascular cell adhesion
molecule- 1 (VCAM- 1) on vessel wall.
15, 16 Hypoxia
also has been shown to decrease production
of NO, which under normal conditions is produced
by the endothelium and inhibits VCAM- 1 up-regulation.
15, 16 In addition, free hemoglobin released
during acute and chronic hemolysis reacts with
NO to form methemoglobin and nitrate, inhibit-