ARTICLE
Urticaria is characterized by the circumscribed, raised, erythematous,
usually pruritic evanescent areas of edema that involve the superficial
portion of dermis [1]. An acute episode of urticaria generally lasts only
several hours. The various causes of urticaria include soluble antigens
in foods, drugs or insect venom, contact allergens, physical stimuli such
as pressure, vibration, solar radiation, cold temperature, occult infections
and malignancies, and some hereditary syndromes. When individual lesions
persist for more than 24 hours, we consider non-usual urticarial reactions
such as urticarial reaction accompanied by eosinophilia, urticarial vasculitis,
delayed pressure urticaria and urticarial reaction caused by late phase
reaction.
We encountered three patients who showed urticarial reaction lasting
more than 24 hours, possibly caused by late phase reaction. We discuss
the unique features of this condition.
Case reports
Case 1
A 66-year-old man was referred to our dermatological clinic complaining
of recurrent, painful and pruritic erythema. The episode which began 3
weeks before, initiated at the wrists and spread over the upper limbs.
Physical examination revealed indurated erythema with a dull border on
the upper limbs and the back. Individual lesions lasted more than 24 hours.
Skin biopsy revealed interstitial superficial dermal edema and a perivascular
infiltrate predominated by eosinophils and some mononuclear cells. Leukocytoclastic
vasculitis was not observed. Immunofluorescent studies showed no deposition
of immunoglobulins or complements on the vessel wall. The total white
blood cell counts were as high as 8,100 with 2.1% eosinophils. Laboratory
findings including electrolyte levels and chemistry panels revealed no
abnormalities. Serum levels of C3, C4 and CH50 were normal. Proteinurea
or joint pain was not observed. The patient was treated with oral betamethasone
of 1.5 mg/day which was tapered gradually, in combination with oral epinastine
hydrochloride 20 mg/day. Skin lesions improved day by day.
Case 2
A 44-year-old man had experienced recurrent pruritic erythema on his
face and body for 2 months. The individual lesions lasted more than 24
hours. He had been treated with betamethasone, 1.0 mg/day, without sustained
improvement. Physical examination revealed edematous erythema with a sharp
border on his face and body (Fig. 1). On skin biopsy, interstitial
dermal edema and a perivascular infiltrate with a lot of eosinophils and
some neutrophils were observed in the upper dermis. Leukocytoclastic vasculitis
was not observed. The total white blood cell count was as high as 8,700
with 2.0% eosinophils. Laboratory findings revealed no abnormalities.
Serum levels of C3, C4 and CH50 were normal. Proteinurea was not found.
The patient was treated with paramethasone acetate 4 mg/day orally for
14 days and 3 mg/day for another 14 days. Cetirizine hydrochloride 10
mg/day and d-chlorpheniramine maleate 12 mg/day were also given. His condition
improved gradually.
Case 3
A 76-year-old man was admitted to our hospital because of recurrent
and pruritic erythematous wheals, which had begun 6 months before. The
lesion started at the medial side of the right thigh and spread over the
extremities. Individual lesions lasted about 72 hours. He noticed systemic
pruritus, especially at the waist and the ankles. He had been treated
with epinastine hydrochloride 20 mg/day orally without much effect. Physical
examination revealed indurative erythema on the right lower limb and the
thigh. Skin biopsy revealed interstitial dermal edema around the vessels
and a perivascular infiltrate (Fig. 2A) mainly with eosinophils
(Fig. 2B). Leukocytoclastic vasculitis was not observed. By immunofluorescent
studies, perivascular deposits of immunoglobulins or complements were
not found. Total white bood cell count was 5,800 with 1,067 eosinophils.
He disclosed no abnormalities on laboratory findings. Serum levels of
C3, C4 and CH50 were normal. Proteinurea or joint pain was not found.
The patient had been suffering from hypertension and diabetes mellitus,
which is known to be worsened by glucocorticoid. We compared the benefit
of treating skin lesions with glucocorticoid with its risk, and decided
not to give glucocorticoid to him. He had been treated with epinastine
hydrochloride 20 mg/day and d-chlorpheniramine maleate 12 mg/day. His
erythema did not improve, but the pruritus improved a little.
Discussion
Our three cases showed urticarial reaction lasting more than 24 hours
which were unaffected by antihistamines, but effectively treated by corticosteroids
in case 1 and 2. The histological findings were characterized by interstitial
dermal edema and a perivascular infiltrate predominated by eosinophils
with little epidermal change. No immunoglobulin and complement deposition
was found on the vessel wall. Eosinophil counts and serum complements
were within normal range. Proteinurea or joint pain was not found. For
the wheal lasting more than 24 hours, urticarial reaction with eosinophilia
such as Well's syndrome, Gleich syndrome and parasitic diseases, and urticarial
vasculitis, delayed pressure urticaria, urticarial reaction caused by
late phase reaction are included in the differential diagnosis. Our patients
had normal eosinophil counts and flame figures were not observed in histological
findings, and so we can exclude urticarial reaction with eosinophilia
such as Well's syndrome, Gleich syndrome and parasitic diseases.
Urticarial vasculitis is a syndrome consisting of recurrent episodes
of urticarial lesions often associated with systemic symptoms such as
fever, arthralgia, abdominal pain and sometimes with glomerulonephritis
[2]. Individual lesions last more than 24 hours and produce burning or
stinging sensations [3]. Leukocytoclastic vasculitis of small vessels,
and deposition of immunoglobulins and complement around vessel walls and
basement membrane are usually observed. Low levels of complements in serum,
elevated erythrocyte sedimentation rate and CRP, and proteinurea are frequently
observed [4]. Our three cases did not show clinical or laboratory signs
of immune complex diseases. None of them showed leukocytoclastic vasculitis,
deposition of immunoglobulins or complements on their biopsy specimens.
These findings indicate that they are not diagnosed as urticarial vasculitis.
Delayed pressure urticaria is characterized by the delayed onset of
painful, non-pruritic swelling in areas exposed to pressure [5, 6]. The
lesions are observed four to eight hours after pressure challenge and
disappear within 24 to 32 hours after challenge [7]. The histological
features of delayed pressure urticaria lesions are edema of the dermis,
a mild perivascular infiltrate composed of mononuclear cells with neutrophils
and eosinophils, though the ratio of infiltrating cells varied among reports,
possibly because of the timing of the biopsy [7-9]. Usually, predominance
of eosinophil infiltrates are observed at sites of early lesions, and
perivasuclar neutrophils are observed in later lesions [10]. The cellular
infiltrate in delayed pressure urticaria is more prominent in the deeper
layers of the dermis and is not associated with a marked increase in mast
cell numbers. Immunofluorescent studies show non-specific deposition of
immunoglobulins and complement, as any site of inflammation may have the
same finding [7]. The lesions do not respond to various combinations of
antihistamines. Although addition of non-steroidal anti-inflammatory drugs
provides some improvement, most patients with delayed pressure urticaria
require oral glucocorticoids [7].
Our patients' clinical features, histological findings and laboratory
findings are very similar to delayed pressure urticaria. However, there
was no preceding mechanical pressure in our patients. Mekori et al.
indicated a resemblance between delayed pressure urticaria and late phase
reaction [7], in that individual wheals lasted more than 24 hours, histological
findings were characterized by interstitial dermal edema and a perivascular
infiltration predominanted by eosinophils and glucocorticoid was effective
but not anti-histamines. These findings indicate our cases resemble "persistent
urticaria" which are possibly caused by late phase reaction.
Recently, the pathogenesis of late phase reaction is becoming clear.
T helper type 2 (Th2) cells produce IL-4 and IL-5. In addition, activated
mast cells secrete several multifunctional cytokines, including IL-4,
IL-5 and TNF-alpha [11] which induce adhesion molecules that attract lymphocytes
and eosinophils to cutaneous sites of inflammation. These cytokines activate
eosinophils, T lymphocytes and endothelial cells. IL-4 may be important
for selective recruitment of eosinophils and induction of IgE synthesis.
IL-5 represents one of the most important cytokines for eosinophil differentiation
and proliferation. Mast cells play crucial roles in late phase reaction
followed by the infiltration of eosinophils, which are believed to be
of major importance as effector cells mediating the pathogenetically relevant
late phase reaction [12]. Eosinophil release toxic proteins, such as major
basic protein (MBP) and eosinophil cationic protein (ECP), as well as
toxic oxygen metabolites inducing tissue injury to the neighbouring cells
[13]. Massey et al. reported that steroids block the late phase
reaction and inhibit the eosinophil and basophil infiltration [14].
We, as well as other dermatologists [15, 16], often encounter similar
cases to the present cases, which can be called "persistent urticaria".
However, such a clinical entity has not yet been recognized in dermatological
textbooks [1, 17]. In these cases, the delayed development of wheal and
persistent presence of a typical urticaria-like wheal make the precise
and prompt diagnosis as well as treatment difficult. Thus we agree to
recognize such urticarial reaction as a clinical entity different from
usual urticaria, because clinical and histological findings and treatment
are quite different. *
Article accepted on 12/4/01
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