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1996 87: 2573-2578
Phospholipase A2 levels in acute chest syndrome of sickle cell
disease
LA Styles, CG Schalkwijk, AJ Aarsman, EP Vichinsky, BH Lubin and FA Kuypers
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Phospholipase A2 Levels in Acute Chest Syndrome of Sickle Cell Disease
By Lori A. Styles, Casper G. Schalkwijk, Anton J. Aarsman, Elliott P. Vichinsky, Bertram H. Lubin,
and Frans A. Kuypers
Acute chest syndrome (ACS) is associated with significant
morbidity and is the
leading cause of death in patients with
sickle cell disease (SCD). Recent reports suggest that bone
marrow fatembolism can be detected in many cases of severe ACS. Secretoryphospholipase AZ (sPLAz) is an important inflammatorymediator and liberatesfree fatty
acids,
which are felt to be
responsible for the acute lung injury of
the fat embolism syndrome. We measured sPLAz levels in
35 SCD patients during 20 admissions for ACS, 10 admissions for vaso-occlusive crisis, and during 12 clinic visits
when patients were at the steady state. Eleven non-SCD
patients with pneumonia were also evaluated. To determine
if there was a relationship between sPLAz and the severity
of ACS we correlated sPLA, levels with the clinical course
of the patient. In comparison with normal controls(mean =
3.1
1.1 ng/mL), the non-SCD patients with pneumonia
SCD patient groups
(mean = 68.6 ? 82.9 ng/mL) and all three
*
had an elevation of sPLAz (steady state mean = 10.0 & 8.4
ng/mL; vaso-occlusive crisis mean= 23.1 ? 40.5 ng/mL; ACS
mean = 336 ? 209 ng/mL). In patients with ACS sPLAzlevels
were 1W-fold greater than normal controlvalues, 35 times
greater than values in SCD patients at baseline, and five
times greater than non-SCD patients with pneumonia. The
degree of sPLA, elevation in ACS correlated with three different measures of clinical severity and, in patients followed
sequentially, the rise in sPLAz coincided with the onset of
ACS. The dramatic elevation of sPLA, in patients with ACS
but not in patients with vaso-occlusive crisis or non-SCD
patients with pneumonia and thecorrelation between levels
of sPLAz and clinical severity suggesta role forsPLA, in the
diagnosis and, perhaps, in the pathophysiology of patients
with ACS.
0 1996 by The American Societyof Hematology.
A
patients had a diagnosis confirmed by standard electrophoresis and
isoelectric focusing methods. There were 30 patients with hemoglobin SS, two with hemoglobin SC, and three with hemoglobin S-8
thalassemia. Serum sPLAz levels were measured during 20 admissions for ACS and 10 admissions for VOC. Four patients were tested
during more than one hospitalization. Eleven SCD patients had PLAz
levels drawn during a comprehensive health care visit in the sickle
cell clinic when there was no evidence of illness. There was no
overlap in patients between the steady state and ACS groups. Secrebolism is a cause of many cases of severe ACS.’o’2In patients
tory PLAz levels were also drawn in 19 normal controls andin
who do not have SCD, pulmonary fat embolism classically pre- 11 children without SCD who were admitted to the hospital with
sents as a syndrome with pulmonarydisease with hypoxia, men- pneumonia.
tal statuschanges,andafallinplatelets
or hem~globin.’~”~ Hospitalizations. Acute chest syndrome wasdefined as the development of a new infiltrate on chest radiography in combination
Prospectivestudies in traumapatientshaverevealedthatalwith fever, respiratory symptoms, or chest pain. Patients admitted
though fat embolism occurs in the majority of trauma victims,
with ACS were treated following a standard protocol that included
theaboveconstellationofsymptomsoccurs
in about 10% of
hydration at one and one-quarter times maintenance, parenteral cefthesesame patiet~ts.’~.’~
This suggeststhatthe“fatembolism
uroxime and oral erythromycin, arterial blood gas monitoring, and
syndrome” represents only the most severe form of fat embolism
daily complete blood counts. Transfusion was used at the attending
and that pulmonary fat embolism is clinically unrecognized in
physician’s discretion based on the patient’s clinical course. Intravemost cases. The pathophysiology of pulmonary complications
nous narcotics and nonsteroidal antiinflammatory medications were
associatedwithfatembolismisincompletelyunderstood,but
used to treat accompanying pain events.
Vaso-occlusive crisis was defined as anadmission for pain, which
experimental evidence suggests that thefree fatty acids released
required parenteral narcotics and indicated no cause for pain other
by the hydrolysis of phospholipids in the embolized fat directly
than SCD. Patients admitted withVOCweretreated
following a
cause acute lung inj~ry.’’.’~.’~
PhospholipaseA2 @M,)is an
CUTE CHEST SYNDROME (ACS) is the second most
common cause of hospitalization and the leading cause
ofdeath in sicklecelldisease (SCD).”3 A majorityofSCD
patients will experience at least one episode of ACS4.5 and repeated episodes can lead to chronic lung disease.4b Despite its
substantialmorbidityandmortality,littleis
known aboutthe
etiology of ACS. Although generally attributed to infection and
infmtion,’”.7-9 recent evidence suggests that pulmonary fat em-
enzyme that cleaves phospholipids at the sn-2 position generating
free fatty acids and lysophospholipids. When arachidonic acid
From the Department of Hematology/Oncology, Children’s Hosis the fatty acid product, a variety
of inflammatory mediators
pital Oakland, and the Children’s Hospital Oakland Research Instiincludingthromboxanes,leukotrienes,andprostaglandins
are
tute, Oakland, CA; Centre
for Biomembranes and Lipid Enzymology,
generated. In addition to free fatty acids these mediators have
Department of Lipid Biochemistry, Universily of Utrecht, Utrecht,
been implicated in acute lung
injury.Ig-” Secretory PM, (sPLA,)
The Netherlands.
is found in low concentration in normal plasma,23; however, its
Submitted April 25, 1995; accepted November 2, 1995.
Supported in part by National Institutes of Health Grants No. HL
levels are increased
response
in to
In acute
the
20985, HL 27059, DK32094
respiratory distress syndrome (ARDS) SPM, levelsarevery
of HemaAddress reprint requests to Lori Styles, MD, Department
high.=-”WepostulatedthatsPLAzmay
be important in the
tology/Oncology,
Children’s
Hospital
Oakland,
747
52nd
St, OakpathophysiologyofACSandhavemeasured
this enzyme in
land, CA 94609.
serum or plasma from SCD patients in steady state, during vasoThe publication costsof this article were defrayedin part by page
occlusive crisis ( V O C ) , and during ACS.
chargepayment. This article must therefore be hereby marked
MATERIALS AND METHODS
Patients. The sPLAz level was determined in 35 SCD patients.
Patients ranged in age from 1 to 20 years (mean = 11 years). All
Blood, Vol 87, No 6 (March 15), 1996 pp 2573-2578
“advertisement” in accordance with 18 U.S.C. section I734 solely to
indicate this fact.
0 1996 by The American Society of Hematology.
0006-4971/96/8706-0023$3.00/0
2573
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STYLES
2574
L
:E
5
0
800
800
1
N
3
n
In
400
200
0
0
100
200
sPLA,
300
400
protein(ng/mL)
500
800
700
Fig 1. Correlation
of sPLA, activity
and protein
concentration.
Correlation
between
sPLAz activity
as measured
by hydrolysis
of radiolabeled
phosphotidylethanolamine,
and sPLA,
protein
concentration
as measured
by ELISA
in 26 plasma
samples
of SCD patients
fr2 =
0.9531. AU, arbitrary
units.
protocol that included intravenous
hydration,
not to exceed one and
one-half times maintenance,
intravenous
narcotics, and nonsteroidal
antiinflammatory
drugs. If fever developed,
patients were evaluated
with chest radiography,
blood and urine cultures, and intravenous
cefuroxime
was started.
For the non-SCD
patients admitted
with pneumonia,
diagnosis
was established
with a chest radiograph
demonstrating
an infiltrate
in combination
with symptoms of respiratory
distress and hypoxia.
Clinical and Zuboratoty
assessmenf.
Clinical and laboratory
data
were collected on all hospitalized
SCD patients including history of
preceding
or accompanying
pain, PaOz on room air arterial blood
gas, transfusion
history, and the presence or absence of fever. Arterial blood gas measurements
were determined
using an AVL 995
(AVL Scientific Corp, Roswell, GA). Alveolar-arterial
oxygen gradient was calculated from room air arterial blood gas values according
to the following
formula:
(A - a) PO* = (713 X FiOZ) - (PaCO?
x 1.2) - PaOX. All sPLAz levels were measured using the method
described below. Fifteen SCD patients had two or more sPLAz level
determinations
during a single hospital admission.
In the patients
that were followed
with sequential
sPLA2 levels from before the
onset of ACS through convalescence,
the sample with the highest
sPLA, value was used in the calculation
of statistical significance.
Secretory
PU2 activity
and concentration.
Phospholipase
A2
activity was measured with I-acyl-?-[I
-“‘C]hnoleoyl-sn-glycero-3phosphoethanolamine,
prepared as described by Van den Bosch et
al,” as substrate. Enzymatic
activity was assayed by incubating 0.2
mmol/L
radioactive
substrate
(specific
radioactivity
3,000 dpm/
nmol) in 0.2 mol/L Tris/HCL
(pH 8.S), IO mmol/L Ca”+ and 5 PL
plasma in a final volume of 200 pL. After 30 minutes at 37°C.
reactions were stopped by extracting
the liberated ‘C-labeled
fatty
acid by a modified Dole-extraction
procedure”
and the radioactivity
was determined
by liquid scintillation
counting. Secretory phospholipase AZ antigen levels in plasma were determined
with a sandwich
enzyme-linked
immunosorbent
assay (ELISA)
modified from Smith
et al.3’ Two different
monoclonal
antibodies against human sPLA2
(kindly provided by Dr F.B. Taylor Jr, Oklahoma
Medical Research
Foundation,
Oklahoma
City) were used as coating and detecting
antibodies,
respectively.
Microtiter
plates (Nunc-lmmuno
Plate
MaxiSorbTM;
A/S Nunc, Roskilde, Denmark)
were coated with the
first antibody
(100 /IL, 2.5 bg/mL)
in phosphate-buffered
saline
(PBS) for 16 hours at 4°C. After washing, the wells were blocked
with 150 PL PBS containing
30 mg/mL
bovine serum albumin
ET AL
(BSA) for 30 minutes at room temperature.
Samples diluted in PBS,
1 mg/mL Tween 20 and 2 mg/mL gelatin (PTG) were incubated in
the wells for I hour, and after washing, the wells were incubated
for I hour with the detecting antibody,
which was biotinylated
and
diluted I:1000 in PTG. Thereafter
the wells were incubated for 30
minutes with streptavidin-horseradish
peroxidase
conjugate, diluted
1: 1000 in PTG. The plate was washed and the whole complex was
incubated with the chromogenic
substrate 3,3’,5,5’ tetramethyl
benridine (0.1 mg/mL),
30 yglmL
HLOZ in 0.1 mol/L sodium acetate
buffer pH 5.5 for 8 minutes. The reaction was stopped by adding
an equal volume of I mol/L H$O, to each well and the absorbance
was read at 490 nm in a microtiter
plate reader (EAR 400; SLTLabinstruments,
Austria).
Results were compared
with those obtained with cultured medium from Hep G2 cells stimulated
with
human interleukin-6.‘4
The amount of sPLAZ in this cultured medium
was assessed by comparison
with purified recombinant
human sPLAz
(kindly provided
by Dr H.M. Verheij, Department
of Enzymology
and Protein Engineering,
University
of Utrecht, Utrecht. the Netherlands). The lower limit of detection was approximately
I ng/mL and
the inter-measurement
variability
on a single sample was up to IO%
to IS%.
Secretory PLAL concentration
as measured with ELISA in plasma
was shown to have an excellent linear correlation
with sPLAz activity
(r2 = 0.953), contirming
that the sPLAz found in the plasma is in
an active form (Fig I). Virtually
identical results were found when
either plasma or serum was used. Hence, sPLA2 concentration
data
was used to analyze the relationship
between the presence of active
sPLAZ and ACS. Nineteen normal (hemoglobin
AA) controls also
had PLAL determination
to confirm that assay values were in the
expected range reported in other series.
Statisticul
evaluution.
Statistical evaluation
was performed
using a nonparametric
procedure
for the four patient groups (ACS,
VOC, SCD at steady state, and non-SCD
with pneumonia)
using
the Kruskal-Wallis
One Way Analysis of Variance on Ranks. Dunn’s
Method
was used to determine
if individual
group medians were
signiticantly
different.
RESULTS
Compared
with
values
obtained
from
control
patients,
mean sPLAZ concentrations
were elevated
in all three SCD
patient groups
studied
(ACS,
VOC,
and steady state) and in
the non-SCD group with pneumonia (Table 1). Steady state
SCD patients had a mean sPLA2 level of 10.0 2 8.4 ng/mL
(median = 9 ng/mL), which was three times higher than
values in normal controls (mean = 3. I f 1.1 ng/mL, median
= 3.1 ng/mL). Sickle cell disease patients with VOC had a
similar
threefold
to fivefold
The sPLA2 concentration
Table
1. Secretory
elevation
above
PLAz Levels
in Sickle
Patient
Groups
Mean (median)
(ng/mL)
Steady
voc
state SCD (n = 11)
(n = 10)
ACS (n = 20)
Pneumonia (n = 11)
(non-SCD)
normal
controls.
of patients with VOC (mean = 23.7
8.4 (9)
Cell
Disease
Range
hg/mL)
P
V.3llEF
1.1-28.5
<.05
1.8-134.6
c.05
10.0
i
23.7
2 40.5
(8.7)
336
+ 209
(289)
12-725
68.6
2 82.9
(38)
6-267
1.05
* P values are for differences
between ACS and the other patient
groups using analysis of variance techniques
(see the Materials and
Methods section). All other comparisons
are not significant.
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2575
PHOSPHOLIPASE A, IN ACUTECHESTSYNDROME
600
500
400
SPLA,
(nglml)
300
VOC
!
,
ACS
A
i
300
200
100
200
0
-8
100
-6
-4
-2
0
2
6
4
8
Hospital Day
0
ACS
VOC
STEADY
STATE
PNEUMONIA
(NON-SCD)
Fig 2. sPLA, levels in different SCD patient groups. Comparison
of mean sPLA2 levels
in three different groups ofSCD patients and in
non-SCD patients with pneumonia. ACS, n = 20; VOC, vaso-occlusive
crisis, n = 10; steady state SCD patients at the time of routine comprehensive health care visit, n = 11; non-SCD pneumonia patients, n
= 11.
40.5 ng/mL, median = 8.7 ng/mL) was not significantly
different from the value found in SCD patients in the steady
state. Four of the ten patients with VOC had fever during
hospitalization. Comparison of the febrile and afebrile
groups showed no difference in sPLA2 concentration ( P =
.45).
Acute chest syndrome patients had a mean sPLA, level
of 336 ? 209 ng/mL (median = 289 ng/mL), which was
100 times greater than normal controls and 35 times greater
than in samples from SCD patients in the steady state (Fig
2). In 18 of the 20 ACS episodes there was a history of
vaso-occlusive pain preceding or accompanying ACS. Both
patients without a history of pain were under 3 years of age
and one of these was the only ACS patient without a significant elevation of sPLA2 above baseline (12 ng/mL). Phospholipase A2 levels in ACS patients were also significantly
elevated above non-SCD pneumonia patients (mean = 68.6
? 82.9 ng/mL, median = 38 ng/mL).
In the 15 SCD patients followed with serial sPLA2 measurements, sPLA2 levels seemed to parallel their clinical
course. Seven patients withVOC were followed with sequential sPLA2 levels and four of these went on to develop
ACS. In allfour of these patients, sPLA2levels rose abruptly
with the development of ACS and then decreased as the
patient clinically improved (Fig 3). In the three patients who
did not develop ACS, sPLA2 levels remained low. The remaining eight patients were admitted with a diagnosis of
ACS. Sequential evaluation of sPLA2 concentration in these
patients documented that sPLA2levels were highest with the
onset of ACS and declined as the patient recovered.
Secretory PLA2 levels were highest in patients with clinically more severe lung disease as assessed by arterial blood
gas results and the need for transfusion. Arterial blood gas
measurements in room air were performed on 15 ACS pa-
Fig 3. Sequential sPLA2 levels in four SCD patients admitted with
VOC. Four patients admitted with VOC were followed with sequenshown
tial sPLA, levels andwent on to develop ACS. Their levels are
here. Three patients admitted with VOC and monitored in time did
not develop ACS, and sPLA, levels remained low. Hospital day 0 is
the day the diagnosis of ACS was made. Hospital days before and
after the day ACS was diagnosed are designated
by negative orpositive numbers, respectively.
tients. Comparisons of ACS patients with and without significant hypoxia (Pa02 <70 and 270 mm Hg) and with and
without increased alveolar-arterial O2 gradients (>30 and
s 3 0 mm Hg) revealed an excellent correlation between elevated sPLA2 clinical severity (Fig 4).
Secretory PLA2 concentration was also compared in the
transfused versus untransfused patient groups. One patient
from the transfused group was removed from the analysis
because he was transfused secondary to aplastic crisis and
not due to pulmonary disease. Also, one severely alloimmunized patient was removed from the analysis because, despite
1
700
1
p=o.009
c70
PaO,
p0.014
>30
c30
p0.012
-
+
TXN
Fig 4. Correlation of S P W levels with measuresof severity. Comparison of sP& levels
in ACS patients with and without hypoxia
(PaO, 5 7 0 and >70 mm Hg, respectively), with and without increased
alveolar-arterialOz gradient ([A - alOz >30 and s30 mm Hg, respectively) and in those who did (+) and did not (-1 need transfusion
(TXN).Error bars indicate f l SD. N = 15 for all three comparisons.
PaOzpartial pressure of oxygen in arterial blood.
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2576
STYLES ET AL
severe hypoxia, he could notbe transfused secondary due
to a lack of compatible blood. Secretory PLA2 levels were
significantly higher in the group needing transfusion, suggesting a relationship between sPLA2concentration and clinical severity (Fig 4).
DISCUSSION
30
Elevatedlevelsof
sPLA2 havebeenreportedin
~psis,lo.fs-37multi-organdysfunction:*,38.3yand
arthriti~.~'.~
Secretory PLA2is felt to be an important mediatorof inflammationintheseconditionsas
it canhydrolyzearachidonicacid
from the sn-2 position of phospholipids providing the essential
substrate fora number of eicosanoids?' SecretoryPLAz is upregulated in response to proinflammatory cytokines such as tumor
1.26.274'43 In animal models, PLA2
necrosis factor and interleukinadministenxi intravenously or instilled intratracheally, produces
diffuse ARDS-like changes including
diffuse alveolar edema and
an inflammatory cell in flu^.^.^^ This samelung injury can be
prevented by pretreatment with inhibitors of
PLAl.46"7In humans, sPLAz is increased in patients with ARDS and has been
shown to correlate with outcome, severity of lung injury, and
alveolar-arteriaI oxygen @ent.28J9.48.49
We found dramatically elevated levels of sPLA, in SCD
patients with ACS. Similar elevations were not seen in SCD
patients with VOC alone andthe presence or absence of
fever with pain crisis did not alter this result. Despite the
fact that most of these ACS patients were not seriously ill,
their sPLAz levels were similar to that found in critically ill
patients with ARDS and
Additionally, sPLA2 levels inthe ACS group were nearlyfive times greater than
levels in non-SCD patients with pneumonia and suggest that
sPLA, elevation is not just a secondary marker for lung
damage.
As in ARDS, sPLA2 concentration in patients with ACS
correlated with several measures of clinical severity. The
correlation between sPLA2 and arterial-alveolar gradient is
particularly relevant as Emre et a15"recently reported this to
be the strongest predictor of clinical severity in ACS. In the
ACS patients followed sequentially, the increase in sPLA2
coincided with the onset of ACS and levels declined as the
patient improved. In total, these results suggest that there is
a relationship between sPLA, and ACS.
The detection of fat embolism and elevated levels of
sPLAl in ACS suggests a causal relationship between free
fatty acids, fatty acid-derived lipid mediators, and ACS.
Since vaso-occlusive crisis can result inthe intravascular
release of bone marrow fat and lead to pulmonary fat embolism, this may trigger the upregulation of sPLA2and generate
more free fatty acids, either systemically or locally in the
lung. While the pulmonary toxicity of increased free fatty
acids in an in vitro setting, as well as in animal models, is
well established,6.'8documenting the toxic effects of free
fatty acids in vivo has been more difficult. A recent report,
however, indicates that both palmitic and oleic acid levels
as wellas total free fatty acids are elevated in ACS but
not in vaso-occlusive crisis5' and further supports the above
hypothesis. Bronchoalveolar lavage (BAL) has recently been
demonstrated tobe a safe and effective meansto detect
pulmonary fat embolism. The ACS patients in this study did
not undergo BAL but correlating sPLA, levels with the results of BAL, in the future, could also help document a
relationship between sPLA, and fat embolism. Implicating
sPLA, in the pathophysiology of ACS and fat embolism has
clinical importance in that sPLA2 may be useful as an early
marker for ACS. In the vaso-occlusive crisis patients followed sequentially, sPLAz levels seemed to increase in the
2 to 3 days before ACS. These data are preliminary, however, and sequential sPLA2 levels on a large number of SCD
patients admitted with pain will be necessary to further evaluate sPLAzs usefulness as a predictor for ACS. If sPLA,
proves accurate in predicting ACS, therapies such as transfusion or sPLA2 inhibitors could be considered earlier in disease. Because of the association of sPLA, with rheumatoid
arthritis and sepsis, there is already considerable interest in
the development of PLA2 inhibitor^.^"^'
Ourstudy also demonstrated elevated sPLA, levels in
SCD patients at baseline compared with normal controls. If
bone marrowfat embolism is a stimulus for sPLA,, increased
baseline sPLA, levels may reflect ongoing or intermittent
leakage of marrow fat intravascularly. Alternatively, higher
levels of sPLA2at baseline may reflect a disturbed balance of
inflammatory mediators. In support of this latter hypothesis,
reports in SCD patients have documented elevations ofendotoxin,'* tumor necrosis factor and interleukin- 1 ,5y all known
to upregulate sPLA2. Other studies have also reported that
SCD patients oftenhave altered levels of lipidmediators
sPLA2, including prostaglandins,
relatedtotheactionof
leukotrienes, and thromboxanes.h"~hJ
In summary, we documented dramatically elevated levels
of sPLA2 in association with ACS. The rise in sPLA2 coincided with the onset of ACS and the degree of sPLAz elevation correlated with several measures of clinical severity. In
addition to documenting high levels of sPLA2 in ACS, we
foundthat SCD patients have elevated levels at baseline
compared with normal controls. The significance of this is
unknown at present but may reflect an altered regulation of
the inflammatory system. Secretory PLA2 may be useful in
identifying patients at risk for ACS and provide justification
for the evaluation of additional therapies to treat thiscomplication.
ACKNOWLEDGMENT
We are indebted to Jolene Edwards
for editorial assistance.
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