Idiopathic hypereosinophilic syndrome

with multiple organ infarction: improvement of the skin condition masking the
course of disease
Hypereosinophilic Syndrome (HES) was first described
by Chusid et al. as an idiopathic syndrome with a minimal duration of 6 months and proven organ damage [1].
A more recent definition of hypereosinophilia (HE) is a
persistent (measured at least twice every 4 weeks) and
marked (>1.5 G/L) eosinophilia. HE was further classified as HEUS (HE of undetermined significance), HEN
(neoplastic HE, e.g. FIP1L1-PDGFRA fusion gene) and
HER (reactive HE). Hypereosinophilic syndrome is diagnosed in cases with HE and proven end-organ damage, with
or without known pathogenesis [2]. According to Ogbogu
et al., HES mainly appears with dermatological (37%), pulmonary (25%) and gastrointestinal (14%) manifestations.
In this large retrospective study, more than 70% of HE
cases could not be classified as reactive or neoplastic [3].
The use of corticosteroids is standard in the treatment of
HES, with reported response rates of 85%. For add-on treatment, hydroxyurea and IFN- are most frequently used [3].
Mepolizumab, an anti-interleukin-5 monoclonal antibody,
can help tapering prednisone more quickly in patients without the FIP1L1-PDGFRA fusion gene [4]. An overview
of therapeutic approaches has recently been published [5].
In some cases of HES, multiple thromboembolic events
have been described [6]. We report a patient with HES who
developed multiple organ infarctions despite corticosteroid
treatment.
A 68-year old man presented with a pruritic, erythematous,
papular rash, located mainly on the trunk for one month. It
consisted of confluent, firm, non-scaly papules (gure 1A).
Histologic examination showed a regular epidermis and a
dermal perivascular and interstitial infiltrate consisting of
lymphocytes and numerous eosinophilic and neutrophilic
granulocytes (gure 1B). Blood analysis revealed marked
absolute eosinophilia (4.8 G/L) and minimal leukocytosis
(11.55 G/L). LDH was slightly raised (335 U/L normal
125-243 U/L) and the vitamin B12 serum level was normal.
Apart from losartan and tamsulosin, the patient did not take
any medication. The serum IgE level, as well as the rest
of the routine blood analysis, was within normal ranges.

There was no evidence of myeloproliferative HES (FIP1L1PDFRA negative in the bone marrow) or lymphocytic HES
in the immunophenotyping. A parasitic infection was ruled
out by serologic testing and stool examination. Paraneoplastic HE was excluded by MRI of the brain, CT scan
of the chest and abdomen, colonoscopy and gastroscopy.
Since there was no proof of secondary eosinophilia, idiopathic HES was diagnosed. Beside the skin, no other organs
were involved. Treatment with oral methylprednisolone
(0.5 mg/kg body weight) was started. After 4 weeks the skin
lesions had only slightly improved and PUVA treatment was
initiated (three times per week). After 10 sessions of PUVA
the skin lesions improved markedly. At the same time, the
patient was admitted to hospital with massive abdominal
pain due to infarctions of the spleen and left kidney, as
well as occlusion of the left inferior lobal pulmonary artery.
Echocardiography evidenced no source for cardiac thromboembolism. Thrombophilia screening was performed and
did not reveal any other causes of hypercoagulability. The
patient received anticoagulant therapy with low molecular
weight heparin and, subsequently, phenprocoumon. After
one year of clinical follow up under oral anticoagulation
and ongoing treatment with methylprednisolone, the patient
showed no further thrombosis or other complications.
There is no evidence-based recommendation concerning
the dosage and duration of corticosteroid treatment in HES.
During an experts meeting in 2005, a dose of 40 mg
prednisone equivalent was proposed [7]. Our patient even
received 50 mg prednisone equivalent (0.6 mg/kg body
weight). Although the absolute eosinophil count (AEC)
decreased from the baseline (4.8 G/L), it remained high,
varying from 1.75 to 3.18 G/L. Obviously the PUVA therapy confounded the interpretation of disease activity. While
there was an improvement of the exanthema, the AEC
remained elevated. Helbig et al. defined a partial response as
a decrease of AEC by 50% and symptomatic improvement.
These patients tended to have multiple organ involvement
[8]. Recently a case similar to ours was published by SunMi Park et al. [6]. This patient developed disseminated
intravascular coagulation with cerebral hemorrhage and
was treated with corticosteroids and interferon-alpha. At the
Mayo Clinic, lethal thromboembolism occurred in 13% of
247 HES patients [9]. In our case, organ infarction occurred
only 4 months after the diagnosis of HES, supporting the
need for an early treatment.

Disclosure. Financial support: none. Conict of interest:
none.

B
1

Department of Gastroenterology
and Hepatology,
Medical University of Vienna
Whringer Grtel 18-20
1090 Vienna, Austria
2
Department of Dermatology,
Hietzing Municipal Hospital,
1130 Vienna, Austria
Reprints
<hannes.trattner@gmail.com>

Figure 1. Multiple confluent papules on the trunk (A).

Histology: dense dermal infiltrate consisting of numerous
eosinophils, neutrophils and lymphocytes (B).

274

Hannes TRATTNER1
Friedrich BREIER2
Andreas STEINER2
Marlies WRUHS2
Robert FELDMANN2

1. Chusid MJ, Dale DC, West BC, Wolff SM. The hypereosinophilic
syndrome: analysis of fourteen cases with review of the literature.
Medicine (Baltimore) 1975; 54: 1-27.
EJD, vol. 24, n 2, March-April 2014

Bullous pemphigoid (BP) is an autoimmune subepidermal

blistering disease that commonly presents with IgG autoantibodies to the NC16a domain of BP180 and/or BP230 [1].
The detection of other types of antibodies in BP patients
has occasionally been reported [2, 3]. This report describes
a BP patient in whom only IgG antibodies to the 120-kDa
LAD-1 were detected.
A 65-year-old Japanese female presented with pruritic blisters. The patient had no particular familial history; however,
she had been treated with furosemide, telmisartan and
trichlormethiazide for chronic renal failure and hypertension for two years. A physical examination revealed tense
blisters and areas of erosion on the trunk and extremities
(gure 1A). No mucosal involvement was observed. Laboratory examinations revealed slight eosinophilia (7.8%;
white blood cells: 4,480/L), with elevated levels of serum
IgE (1,260 mg/dL), serum blood urea nitrogen (65 mg/dL)
and creatinine (3.2 mg/dL). A drug-induced lymphocyte
stimulation test was performed for furosemide, telmisartan and trichlormethiazide, with no positive reactivity.
Histopathology of a biopsy specimen obtained from a
skin lesion showed subepidermal separation (gure 1B)
and infiltration of eosinophils and neutrophils in the
upper dermis (gure 1C). Direct immunofluorescence (IF)
demonstrated linear deposits of IgG and C3 in the basement membrane zone (BMZ) (gures 1D-E); however, no
IgA deposition was observed. Indirect IF revealed IgG antiBMZ antibodies reactive to the epidermal side of a 1-M
NaCl-split skin section (gure 1F). The results of enzymelinked immunosorbent assays for the NC16a domain of
EJD, vol. 24, n 2, March-April 2014

Epidermal
1 2 3

HaCaT
1 2 3

230 kDa
210 kDa
190 kDa
180 kDa

120 kDa

160 kDa
230 kDa

Patient (IgG)
Normal control (lgA)
LAD control (IgA)

Bullous pemphigoid with IgG anti-LAD-1

antibodies

Patient (IgG)
BP control
PNP control

doi:10.1684/ejd.2014.2307

PVcontrol

2. Valent P, Klion AD, Horny HP, et al. Contemporary consensus proposal on criteria and classication of eosinophilic disorders and related
syndromes. J Allergy Clin Immunol 2012; 130: 607-12.
3. Ogbogu PU, Bochner BS, Buttereld JH, et al. Hypereosinophilic
syndrome: a multicenter, retrospective analysis of clinical characteristics and response to therapy. J Allergy Clin Immunol 2009; 124:
1319-25.
4. Rothenberg ME, Klion AD, Roufosse FE, et al. Treatment of patients
with the hypereosinophilic syndrome with mepolizumab. N Engl J Med
2008; 358: 1215-28.
5. Simon HU, Klion A. Therapeutic Approaches to Patients with Hypereosinophilic Syndromes. Semin Hematol 2012; 49: 160-70.
6. Park SM, Park JW, Kim SM, et al. A case of hypereosinophilic
syndrome presenting with multiorgan infarctions associated with disseminated intravascular coagulation. Allergy Asthma Immunol Res
2012; 4: 161-4.
7. Klion AD, Bochner BS, Gleich GJ, et al. Approaches to the treatment
of hypereosinophilic syndromes: a workshop summary report. J Allergy
Clin Immunol 2006; 117: 1292-302.
8. Helbig G, Wisniewska-Piaty K, Francuz T, Dziaczkowska-Suszek J,
Kyrcz-Krzemien S. Diversity of clinical manifestations and response to
corticosteroids for idiopathic hypereosinophilic syndrome: retrospective study in 33 patients. Leuk Lymphoma 2013; 54: 807-11.
9. Podjasek JC, Buttereld JH. Mortality in hypereosinophilic syndrome: 19 years of experience at Mayo Clinic with a review of the
literature. Leuk Res 2013; 37: 392-5.

Figure 1. A) Blisters and areas of erosion on the trunk and

extremities. B) Histopathology showing subepidermal separation. Scale bars: 500 m. (C) Infiltration of eosinophils and
neutrophils in the upper dermis. Scale bars: 100 m. D,E)
Direct IF of a perilesional skin biopsy specimen showing linear deposition of IgG (D) and C3 (E) in the BMZ. Scale bars:
100 m. F) Indirect IF of a 1-M NaCl-split skin section showing IgG binding to the epidermal side (serum dilution 1:160).
Scale bars: 100 m. G) Immunoblotting using normal human
epidermal extract showing IgG antibodies of positive control
pemphigus vulgaris (PV) serum reacting with the 160-kDa
desmoglein 1 (Dsg1) and 130-kDa Dsg3 (lane 1), IgG antibodies of positive control paraneoplastic pemphigus (PNP) serum
reacting with the 210-kDa envoplakin and 190-kDa periplakin
(lane 2), IgG antibodies of positive control BP serum reacting
with 230-kDa BP230 and 180-kDa BP180 (lane 3), and the
IgG antibodies of the present patients serum clearly reacting with the 180-kDa BP180 (lane 4). H) Immunoblotting
using concentrated HaCaT cell culture supernatant showing
IgA antibodies of positive control LABD serum (lane 1) and
the IgG antibodies of the present patients serum (lane 3) reacting with the 120-KDa LAD-1 and IgA antibodies of normal
control serum (lane 2) showing no specific reactivity.

BP180, BP230, desmoglein-1 and desmoglein-3 were negative. Immunoblotting demonstrated that the patients IgG
antibodies, but not IgA antibodies, reacted with BP180 in
normal human epidermal extracts (gure 1G) and the 120kDa LAD-1 in concentrated HaCaT cell culture supernatant
(gure 1H). Immunoblotting using dermal extracts, recombinant proteins of BP180 NC16a and C-terminal domains
and purified human laminin-332 did not show any positive
bands. Based on these findings, a diagnosis of BP due to IgG
antibodies to the 120-kDa LAD-1 was made. Oral administration of prednisolone (40 mg/day) was started and the

275