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Elevated Serum Levels of Interleukin-5 in Patients With the Syndrome of
Episodic Angioedema and Eosinophilia
By J.H. Butterfield, K.M. Leiferman, J. Abrams, J.E. Silver, J. Bower, N. Gonchoroff, and G.J. Gleich
The syndrome of episodic angioedema and eosinophilia is
characterized by cyclic edema, marked peripheral blood
eosinophilia, and eosinophil degranulation in the dermis.
Using a sensitive immunoenrymetricmethod, we measured
serum interleukin (IL)-5 levels in four patients with this
syndrome. We also determinedthe percentage of activated T
cells in the peripheral blood of a new patient before and
during an attack. In the patient presented, IL-5 levels peaked
several days before maximal eosinophilia and then declined.
This patient’s lymphocytes showed an increased percentage,
28% (normal 2% to 3%). of activated T cells staining for both
CD3 and HLA-DR 10 days before maximal eosinophilia, but
no increase at the time of peak eosinophilia. In serum from
three previously reported cases, elevated serum IL-5 levels
were found during attacks. After glucocorticoid administration, IL-5 levels became undetectable in three of the four
patients. Production of IL-5 is likely an important determinant of the pathophysiology of this syndrome.
o 1992by The American Society of Hematology.
I
benefit from therapy with indomethacin or cimetidine. Although
injections of glucocorticoids initially afforded relief of her symptoms, prednisone (20 to 40 mg/d) administration in the weeks
before her referral was not clinically helpful. The patient had not
used aspirin and no allergies to medications were known. She
denied any relation of attacks to her menstrual cycle and had
discontinued the use of oral contraceptives 3 weeks before evaluation. She rarely drank alcoholic beverages, did not smoke or use
illicit drugs, and had traveled only to Canada. There was no history
of connective tissue disorders, parasitic disease, chronic urticaria,
or other diseases commonly associated with eosinophilia. The
family history did not reveal relatives with similar symptoms.
On physical examination, vital signs were normal. A congenital
palsy of the proximal right ann was present. Nonpitting edema of
both legs, feet, the dorsa of the hands, and the right periorbital skin
was evident. Excoriated papular, erythematous skin lesions were
present on the dorsa of the hands and feet. Cardiovascular and
neurologic systems were normal, as was the remainder of the
physical examination.
Initial laboratory values showed a total leukocyte count of
10,500Imm’ with 53% eosinophils, 26% neutrophils, 18% lymphocytes, and 2% monocytes (Fig 1); hemoglobin and platelet counts
were normal. IgM was 484 mg/dL (normal range, 60 to 300
mg/dL). Negative or normal values included the following: chest
roentgenogram, mammogram, electrocardiogram, echocardiogram, serum chemistry values, serum B,, and folate, AM and PM
cortisol levels, total hemolytic complement, C3, C4, and C1
esterase inhibitor (both quantitative and functional assays), serum
protein electrophoresis, antinuclear antibody, rapid plasma reagin,
serologies for toxoplasmosis and echinococcosis, urinalysis, and
stools for ova and parasites. Lymphocyte studies showed normal
numbers of T cells, normal percentages of T-helper and T-suppressor cells, and a normal T-helper to T-suppressor ratio. Bone
marrow aspiration and biopsy showed 30% eosinophils and
megakaryocytic hyperplasia, without evidence of malignancy. The
kalyotype was 46XX.
Clinical course. The patient was admitted to the Clinical
Research Center where her course was monitored (Fig 1). Clinical
and laboratory studies performed were approved by the Institutional Review Board of the Mayo Clinic. Informed consent was
obtained before all studies. During days 1 to 7, the patient
remained asymptomatic; her weight increased by 2.5 kg. During
days 8 to 14, she developed pronounced facial swelling, painful leg
edema, and occasional nausea and vomiting. Her weight increased
by 4 kg. Twenty-four-hour urinary volumes were 402 mL, 247 mL,
and 274 mL on days 12, 13, and 14, respectively. Eosinophils were
62% of 50,900 leukocyteslmm’ on day 15. During days 15 to 18, her
weight increased by another 4.6 kg. Leukocytes and eosinophils
increased to maxima of 57,900Imm’ and 48,350/mm3 on day 16.
The patient underwent skin biopsy of an indurated lesion in an
N 1984, Gleich e t a1 reported four cases of a novel
syndrome of recurrent angioedema, urticaria, fever,
and weight gain.’ Symptomatic episodes were associated
with marked weight increase and eosinophilia; histologic
studies showed eosinophil infiltration and degranulation in
the dermis. IgM levels were increased in all four patients.
Since the initial series, additional reports have appeared in
the
the youngest patient was a 21/2-year-old
child.3 In contrast to patients with the idiopathic hypereosinophilic syndrome, patients with episodic angioedema
and eosinophilia have no increased risk of cardiovascular
~
interleukin (1L)-5 is a
morbidity or m ~ r t a l i t y .Because
specific stimulator of human eosinophil differentiation: as
well as a selective eosinophil chemoattractant’ and eosinophil activation factor,8 we assayed serum IL-5 levels from
four patients with episodic angioedema and eosinophilia:
three previously reported cases’ and o n e new case. Here,
we report that serum IL-5 levels are increased in this
syndrome and fluctuate in relationship to blood eosinophilia and clinical findings.
MATERIALS AND METHODS
Case report. A 19-year-old nonatopic woman was referred to
the Mayo Clinic for diagnosis and treatment of a 3X-year history of
episodic angioedema and eosinophilia. In the months before her
evaluation, she had experienced recurrent attacks of increasingly
severe edema of the face, hands, feet, and legs associated with
dyspnea on exertion, fever to 40T, and weight gain of up to 18 kg.
Leukocyte counts ranged from 31,000 to 51,000/mm3,with 70% to
84% eosinophils. The attacks had occurred approximately once per
month and had lasted an average of 2 weeks. She had derived no
From the Division of Allergic Diseases and Intemal Medicine, the
Departments of Dermatology, Immunology, Laboratory Medicine and
Pathololgy, Mayo Clinic and Mayo Foundation, Rochester, MN; and
the DNAX Research Institute, Palo Alto, CA, and Lykens, PA.
Submitted May 28,1991; accepted September 23,1991.
Supported by Grants No. AI 15231, RR 00585, and AR 36008, from
the National Institutes of Health, and by the Mayo Foundation.
Address reprint requests to J.H. Buttefield, MD, Division of Allergic
Diseases and Intemal Medicine, Mayo Clinic, Rochester, MN 55905.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
“advertisement” in accordance with 18 U.S.C. section 1734 solely to
indicate this fact.
0 1992 by The American Society of Hematology.
0006-49711921 7903-0019$3.00/0
688
Blood, Vol79, No 3 (February 1). 1992: pp 688-692
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IL-5 IN EPISODIC ANGIOEDEMA AND EOSINOPHILIA
689
blood mononuclear cell supernatants.'" The sera from the previously reported cases had been collected during observation of
attacks and had been stored at -20°C.
Activated T-cell analysis. Two-color flow cytometric assays of
peripheral blood lymphocytes were used to determine the percentage of activated T cells in the present patient's peripheral blood.
Assays were performed using a fluorescent activated cell sorter
(Becton Dickinson, San Jose, CA) and monoclonal antibodies
(Becton Dickinson) to the following cell surface markers: CD3
(Leu 4), HLA-DR, CD25 (IL-2 receptor), CD71 (transferrin
receptor), CD20 (Leu 16), CD4 (Leu 3A), and CD8 (Leu 2A).
Assays were performed on day 6 (immediately before onset of her
attack), on day 16 (during the peak of the eosinophilia), and during
clinical attacks following discharge.
ImmunodermatoZogV studies. Immunophenotyping of infiltrating dermal lymphocytes was performed on lesional skin obtained by punch biopsy from the right thigh." Biopsy sections were
stained for eosinophil granule major basic protein by indirect
immunofluorescence.'* A specimen from this biopsy was also
examined after routine hematoxylin and eosin staining.
IO-~IIT"
WBC,
Bk
Serum
11-5,
pglml
Prednisone,
mg
24-hr
urinary
output,
cc
RESULTS
0
'
2
4
6
8
10
12
14
16
18
20
22
Day
Fig 1. Laboratoryfindings in the patient presented here. Note the
biphasic increase in IL-5 levels. Although IL-5 levels were already
decreasing on day 16, the day of maximal blood eosinophilia, prednisone administration was associated with disappearance of IL-5
from the circulation. IL-5 was measured in duplicate samples of
patient serum diluted 1:l with assay diluent. The reported IL-5 value
represents the mean, corrected for sample dilution. The assay detection threshold was 50 to 100 pg/mL per sample.
edematous area of the thigh. On days 16 and 17, leukaphereses
were performed, yielding a total of 3 x 10" eosinophils. Prednisone, 80 mg/d, was begun on day 17 following the leukapheresis.
Between days 17 and 19, total leukocyte count and eosinophil
count rapidly decreased; urine output increased slowly, weight
remained stable, and hemoglobin decreased from 13.4 g/dL to 10.4
g/dL. On the night of days 19 to 20, while still receiving 80 mg of
prednisone daily, she experienced an acute episode of sinus
bradycardia (42 bpm) and orthopnea. Clinical examination showed
jugular venous distension, bibasilar lung dullness, and epigastric
tenderness. Chest roentgenogram showed bilateral pleural effusions and bibasilar infiltrates. A n echocardiogram showed elevated
pulmonary and systemic venous pressures and normal cardiac
output consistent with volume overload. Administration of furosemide, 80 mg intravenously, resulted in diuresis of 6,100 mL,
weight loss, and clinical improvement during the next 24 hours.
The diuresis was sustained with metolazone 5.0 mg/d. The patient
was discharged on day 22 with a tapering course of prednisone and
metolazone 5.0 mg/d. The total weight gain during observation was
10 kg; however, by the time of discharge, a diuresis-induced loss of
11.2 kg had occurred. With metolazone, she subsequently lost an
additional 10 kg over the next 2 weeks for a total loss of 21.2 kg; her
basal weight was 68 kg.
fL-5 assay. Sera from this patient, as well as from three
previously reported cases of this syndrome (Gleich et al,' cases 1,3,
and 4), were assayed for IL-5 by an immunoenzymetric assay using
two monoclonal antibodies, JES1-39D10 as coating antibody, and
JES1-SA10 derivatized with the hapten nitroiodophenyl, as the
detecting antibody in conjunction with L-cell-derived recombinant
IL-5 as the standard. This assay has been used to quantify IL-5 in
T-cell clone supernatants,' as well as mitogen-activated peripheral
Serum IL-5 levels. Serum IL-5 values for the patient
presented in the case report are shown in Fig 1. IL-5 levels
showed a biphasic increase with peaks on days 9 and 14.
Interestingly, days 13 and 14 were the days of lowest
24-hour urine output (247 mL and 274 mL, respectively). By
the day of maximal blood eosinophilia, day 16, serum IL-5
level had decreased and it became undetectable following
prednisone administration.
Serum IL-5 levels from two previously reported cases' of
the syndrome of episodic angioedema and eosinophilia
along with other clinical features are shown in Figs 2 and 3.
Both patients showed serum IL-5 levels that were elevated
or became elevated during clinical attacks with marked
eosinophilia. Another reported case showed elevated levels
of IL-5 during two attacks of angioedema (Table 1).In the
present case (Fig 1) and in patient 4 (Fig 3), IL-5 levels
were decreasing before treatment with prednisone and
-1
2
3
4
5
6
7
8
9
10
11
Day
Fig 2. Laboratoryvalues in a previously reported patient (Gleich et
al.' patient 3) with episodic angioedema during an attack of swelling.
Here the level of IL-5 decreased spontaneously (78%). Prednisone
administrationwas associated with a further reduction, but IL-5 was
still detectable.
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BUTTERFIELD ET AL
DISCUSSION
Serum
IL-5,
Pglml
Prednisone,
mg
Day
Fig 3. Laboratoryvalues in a previously reported patient (Gleich et
al,‘ patient 4) with episodic angioedema. Here, IL-5 levels decreased
spontaneously and, after prednisone administration, IL-5 was not
detectable.
thereafter became undetectable, whereas in patient 3 (Fig
2) IL-5 remained measurable after prednisone administration.
T-cellanalyses. Analyses of T cells from the new patient
showed an increased percentage, 28% (normal 2% to 3%),
of activated T cells staining both for CD3 and HLA-DR on
day 6. On day 16, at the peak of eosinophilia, no increase in
activated T-cell numbers was observed, and on neither date
were increases found in the percent of T cells bearing other
activation markers (CD71 or CD25), or labeling with
anti-CD20, -CD4, or -CD8. Subsequent T-cell analyses
performed during attacks were likewise negative for increased percentages of T cells bearing activation markers.
Immunodemzatology studies. The skin biopsy specimen
stained with hematoxylin and eosin showed perivascular
mononuclear cell infiltration throughout the dermis with
occasional eosinophils. Immunocytochemical analyses of
the skin biopsy specimen showed that the majority of
infiltrating cells were T-helper cells possessing CD2, CD3,
and CD4 markers. As in previously reported case^,'^.^
extensive extracellular eosinophil granule major basic protein deposition was observed in the dermis.
Table 1. IL-5 Levels in a Patient With Episodic Angioedema
Associated With Eosinophilia
Date
Clinical Course
8/20/81
Attack of angioedema, 7.3-kg weight gain, leukocyte
count 37.5 x 103/mm3,75% eosinophils. IL-5,345
pg/mL (normal; undetectable).
Attack of angioedema. Leukocyte count 31.4 x
103/mm3,76% eosinophils. IL-5,251 pg/mL.
Prednisone begun with a dosage schedule of 60 mg for
days 1 and 2,40 mg for days 3 and 4,20 mg for days
5 and 6, and 10 mg on day 7.
Patient well. Leukocyte count 8 x 103/mm3,13%
eosinophils. IL-5, undetectable.
2/2/82
2/3/82
2/10/82
Data from Gleich et al,’ Patient 1.
The T-lymphocyte dependency of blood eosinophilia was
recognized around 1970.”-” Subsequent studies showed
that T-cell-deficient mice (Nu/Nu) fail to develop primary
or secondary eosinophilia when infected with Ascaris suum
larvae16 or Schistosoma mansoni cercariae.” Eosinophil
colony-stimulating factors have been demonstrated in the
supernatants of sensitized T cells from patients with allergic
eosinophilia,’8 from cultured T-cell leukemia-lymphoma
cells,” and from murine T-cell hybridomas.” Sanderson et
a1 identified a murine T-cell-derived eosinophil differentiating factor that caused production of eosinophils in vitro.21~22
The cDNA for this factor coded for a protein identical to
murine IL-5.22IL-5 prolonged in vitro survivalz3of eosinophils and converted normodense human eosinophils to
hypodense cells.24 Recombinant human IL-5 has been
shown to selectively stimulate production of eosinophils in
human bone marrow cultures,25 to act as a chemotactic
and to cause a selective activation of human
eosinophil function, inducing changes in cell morphology,
polarization of granules, membrane ruffling, production of
oxygen radicals, and degranulation.26z
The IL-5 immunoenzymetric assay used in this series for
the determination of serum IL-5 has proven to be relatively
robust. It has been used to determine serum IL-5 levels
longitudinally both in cancer patients treated with IL-zz9
and in onchocerciasis patients undergoing the Mazotti
reaction in response to antihelminth treatment?’ Serum
IL-5 has been undetectable by this immunoassay in large
numbers of serum samples unassociated with eosinophilia,
indicating that normal serum levels are below the assay
threshold of detection. In a study involving serum IL-3
associated with a chromosomal translocation event in acute
lymphocytic leukemia with eosinophilia;’ the absence of
serum IL-5 was documented both by this immunoassay and
a bioassay for IL-5, rendered monospecific using specific
neutralizing anti-IL-5 monoclonal a n t i b ~ d i e sIn
. ~this
~ study,
the immunoassay precision was clearly good enough to
discriminate fluctuations of IL-5 serum levels longitudinally
within a particular patient, a finding that we believe to be
important in future investigation of this disease.
Here, we report elevated serum levels of immunoreactive
IL-5 in patients with the syndrome of episodic angioedema
and eosinophilia and show that an increase in the serum
IL-5 level was detected before peak eosinophil numbers in
the peripheral blood. In three of the four patients studied,
as shown in Figs 1, 2, and 3, IL-5 levels spontaneously
decreased during the latter stages of the attacks. The
presence of eosinophilia and leukocytosis before an increase in IL-5 values (Fig 3) could be explained by a cyclic
increase in IL-5 which antedated our period of observation.
Alternatively, the biologic activity of IL-5 in vivo may be
greater than our current ability to detect this lymphokine in
vitro. During treatment with prednisone, IL-5 levels became undetectable in three of four patients (Figs l and 3,
Table l), with associated clinical improvement, decreased
eosinophil numbers, and weight loss. Because IL-5 levels
were already decreasing before prednisone administration,
the contribution of this therapy to the final IL-5 levels must
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IL-5 IN EPISODIC ANGIOEDEMA AND EOSINOPHILIA
691
remain somewhat speculative. During each of the leukaphereses on days 16 and 17, approximately 220 mL of cells
was removed, but approximately 500 mL of a volume
expander was infused. Therefore, it is possible that in the
present case the leukaphereses may have had a dilutional
effect on serum IL-5 values. Interestingly, in the patient
reported here, an intravascular fluid-overloaded state developed following prednisone administration. This resulted
clinically in acute bradycardia, orthopnea, and the presence
of bibasilar infiltrates on chest x-ray; echocardiogram showed
no evidence of cardiac dysfunction. The fluid overload may
have occurred because of differences between the rate of
fluid mobilization from tissue and excretion by the kidneys.
Intravenous administration of furosemide resulted in rapid
diuresis and resolution of clinical symptoms. Chronologically, maximum IL-5 levels occurred on days 13 and 14;
interestingly, these 2 days were also the days with the lowest
urinary output (247 mL/24 h, 274 mL/24 h, respectively),
while maximum eosinophil levels occurred on days 16 and
17, respectively. It is interesting that the peak eosinophilia
lagged behind the peak serum IL-5 level by approximately 3
to 4 days. This may represent the time it takes for late-stage
eosinophil progenitors to fully differentiate into mature
eosinophils. It is not known whether IL-5 affects renal
function; however, one possibility for the peak values on
days 13 and 14 was decreased urinary excretion of this
lymphokine. It is also noteworthy that the increased percentage of activated T-helper cells occurred before the development of elevated IL-5 values. In a previous report of a
patient with the syndrome of episodic angioedema and
eosinophilia: normal percentages of CD4 helper cells and
CD8 suppressor cells were reported in the peripheral
circulation; importantly, however, 32% of the CD4 cells
expressed the HLA-DR activation antigen (normal value,
<2%). In the case presented here, we found a similar
percentage (28%) of CD3' T cells expressing for the DR
activation antigen 10 days before the maximal eosinophil
count. However, we have no direct evidence that the
activated T cells were responsible for the elevated IL-5
values detected and the underlying reason for increased
IL-5 production in this disorder remains to be elucidated.
One must remain cognizant of the possibility that activated
lymphocytes may not be the sole, or even predominant,
source for elevated IL-5 detected in this syndrome. Recent
studies have shown that mast cells may express mRNA for
IL-5, as well as other cytokines, in response to cross-linkage
of Fc, receptors or to calcium ionophore^.'^.^^ Because of its
multiple recognized effects on eosinophil proliferation,
chemotaxis, and survival, we believe the elevated serum
levels of IL-5 in the syndrome of episodic angioedema and
eosinophilia may be of importance in explaining many of
the pathophysiologic aspects of this disorder.
ACKNOWLEDGMENT
We thank Dr W.C. Ehmann, M.S. Hershey Medical Center,
Hershey, PA, for referring this patient to us, and Linda H. Arneson
for secretarial assistance.
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1992 79: 688-692
Elevated serum levels of interleukin-5 in patients with the syndrome of
episodic angioedema and eosinophilia
JH Butterfield, KM Leiferman, J Abrams, JE Silver, J Bower, N Gonchoroff and GJ Gleich
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