ARTICLE
Erythema multiforme (EM) is an acute, self-limiting dermatosis, characterized
by distinctive "target" lesions and which may be caused by allergy to
drugs or various infections. In particular, herpes simplex virus (HSV)
is recognized as the most common precipitator of EM [1]. However, the
relationship between varicella-zoster virus (VZV) and EM is rarely documented
in the literature [2-4]. EM following herpes zoster was first described
in 1998 by Weismann et al. [4]. Here, we report a further case.
Case report
A 49-year-old Japanese man was admitted to Kyoto Min-iren Central Hospital
for evaluation of acute illness with slight fever to 38° C, headache
and erythematous skin lesions. These eruptions had started on his hands
4 days earlier, with slight fever, and progressed rapidly over his extremities
and trunk. The patient's past history revealed that, about 4 weeks prior
to this onset, he had been suffering from cervical zoster, which was treated
with intravenous acyclovir 500 mg (6.6 mg/kg) once daily for 1 week in
the outpatient department. The treatment prevented the progression of
new lesions and reduced acute zoster pain. Since then he had taken no
medicine. The family history was not remarkable.
On admission, physical examination revealed red, oedematous papules
and up to coin-sized round erythemas, with concentric colour changes,
which in part were confluent to form large erythematous maculae and were
distributed symmetrically over the extremities and trunk (Fig.
1). There was no mucous membrane involvement or lymphadenopathy and
a clinical diagnosis of EM was made. Urinalysis was normal except for
a glucose level of 1.0 g/dl. Laboratory results were: leucocytes 8,800/mm3
with 75.5% neutrophils, 0.7% eosinophils, and 17.9% lymphocytes; c-reactive
protein 6.4 mg/dl (normal range: < 0.6); aspartate aminotransferase
29 IU/l (< 38); alanine aminotransferase 89 IU/l (< 44); lactic
dehydrogenase 207 IU/l (< 211); alkaline phosphatase 265 IU/l (<
338); gamma-glutamyltranspeptidase 143 IU/l (< 66); and glucose 191
mg/dl. The results of urinalysis and routine chemistry profile showed
mild diabetes and mild alcoholic liver dysfunction. Positive serum titers
of IgG-type antibodies to VZV and HSV were found by Enzyme Immunoassay
(SRL, Tokyo, Japan) at the levels of 115.0 and 12.1, respectively (normal
< 2.0). A positive titer of IgM-type to VZV was found at the level
of 1.19, but IgM-type antibody to HSV was negative, with a titer of 0.37
(normal < 0.80). Serological reactions to cytomegalovirus and mycoplasma
were negative, and antinuclear antibodies also were negative.
A biopsy specimen from the "target" lesion on the back revealed hydropic
degeneration of basal cells, tagging of lymphocytes along the dermoepidermal
junction, and a sparse, superficial, perivascular lymphoid infiltrate
with a few eosinophils. Necrosis of individual keratinocytes and mild
spongiosis were seen in the epidermis (Fig.
2). The upper dermis showed a slight oedema and a few infiltrating
neutrophils in the capillary lumen. Based on these data, a final diagnosis
of EM was confirmed.
All signs and symptoms resolved within 10 days with medication with
antihistamines and topical steroids. Only the flesh-coloured scars, following
herpes zoster, remained unchanged on his right neck and upper arm (Fig.
3). Five months after resolution, IgM-type antibodies to both VZV
and HSV were negative. IgG-type antibodies to VZV and HSVwere positive,
with lower titers of 36.0 and 5.4, respectively. There have been no recurrences
of EM during two years of follow-up.
Discussion
According to the present classification, the clinical spectrum of EM
comprises at least two distinct subsets: the common HSV-associated EM
(HAEM) and the infrequent and severe Stevens-Johnson syndrome/toxic epidermal
necrosis (SJS/TEN) that is most often related to drug intolerance [5].
Both share two morphological features: target lesions - circular erythemas
or urticarial plaques with strikingly concentric features such as blisters,
necrosis and hemorrhage; and satellite cell (or more widespread) necrosis
of the epidermis. HAEM is characterized by a marked inflammatory infiltrate
of the papillary dermis, chiefly composed of CD4-positive T lymphocytes
and monocytes [6] and microvascular damage [7], whereas there is only
little inflammation in SJS/TEN ("silent dermis").
HSV-DNA has been found, using the polymerase chain reaction, in skin
lesions and peripheral blood mononuclear cells (PBMC) from patients with
HAEM [8]. Furthermore, HSV-1 infected PBMC play a pivotal role in the
pathogenesis of HAEM [9]. HSV-1 infected PBMC not only adhere much more
efficiently to endothelial cells but also induce these to upregulate their
adhesion molecule and HLA class I synthesis, at both the mRNA and protein
levels, thus setting the stage for the dermal inflammatory response characteristic
for HAEM (which is absent in SJS/TEN because the offensive drugs are transported
freely and not via PBMC). Further recent evidence shows that HAEM is mechanistically
distinct from drug-induced EM: IFN-gamma is expressed in HAEM lesions,
whilst TNF-alpha is expressed in drug-induced EM lesions [10].
It has been proposed that cutaneous reactions at sites of resolved varicella-zoster
lesions may be caused by an atypical delayed hypersensitivity reaction
to the virus [11]. There was only one case of SJS caused by acyclovir;
however, the patient developed fever and rash 1 day after taking the drug
[12]. This case showed typical EM lesions and was thought to be related
more closely with herpes zoster than with well-documented precipitating
factors like herpes simplex, mycoplasma infection and drugs, including
acyclovir. The EM in our case was less florid than the VZV-associated
EM in previously reported adult cases [3, 4]. There are two forms of VZV-associated
EM: varicella- [2, 3] and zoster-associated [4]. Although VZV DNA has
been shown to persist in blood mononuclear cells of patients with varicella
or zoster up to six weeks after the development of rash [13], it seems
curious that varicella-associated EM occurred almost simultaneously with
varicella, but the occurrence of EM after zoster was delayed. In the first
reported cases of post-zoster EM, the time lag was 10 to 14 days [4].
At the onset of EM, those patients received oral acyclovir, 800 mg five
times daily for 7 days, a regimen used worldwide for zoster, but which
appears to have little impact on the course of EM. The EM in our case
occurred much longer after VZV manifestations than would be expected.
Our patient received intravenous acyclovir in a relatively low dose only
once daily at the time of the herpes zoster. Although it is not normally
considered appropriate therapy for herpes zoster, we believe it is more
effective than oral acyclovir on outpatients with zoster. It is likely
that our acyclovir therapy might have some influence on the disease severity
and time lag ; nevertheless both our case and the first reported cases
demonstrated histologically "silent dermis".
Varicella-associated EM seems to occur with
a similar pathogenesis to HSV in HAEM because of the simultaneous occurrence.
It would be interesting to perform polymerase chain reaction determination
of VZV DNA in varicella-associated EM, although it could not be done in
our case. In contrast, the delay in the occurrence of EM and histologically
"silent dermis" suggests that post-zoster EM may occur with a similar
pathogenesis to that in drug-induced EM, via TNF-alpha.
Finally, our case supports strongly the view that zoster should be implicated
as a possible cause of EM.
Article accepted on 12/4/02
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