ARTICLE
Auteur(s) :, AF
Nikkels1,*, F Beauthier2, P
Quatresooz1, GE Piérard1
1Department of Dermatopathology, University Hospital
Sart Tilman, B-4000 Liège, Belgium
2Department of Pathology, University Hospital of Liège,
Liège, Belgium
accepté le 20 Septembre 2004
Darier disease is an autosomal dominant disorder with variable
penetrance. It is related to mutations in the chromosome 12q23-24
located gene encoding for the endoplasmic reticulum (ER) Ca ATPase
ATP2A2. This defect results in impaired intercellular adhesion,
causing both dyskeratosic apoptosis and acantholysis [1]. The
predominant clinical features consist of small, sometimes profuse,
hyperkeratotic papules with a preferential localization on the
seborrheic areas of the trunk. Darier disease, either active or in
remission, predisposes to some infectious complications, such as
herpes simplex virus (HSV) [2-5], varicella-zoster virus (VZV)
[6-8], and pox virus infections [9]. The atypical clinical
presentations of these viral complications frequently delay their
recognition and postpone adequate antiviral treatment [2-5].
Whether this increased susceptibility to cutaneous viral infections
is related to impaired cellular and/or humoral immunity in Darier
disease or to the disease-associated epidermal alterations remains
unsettled [10, 11].HSV and VZV infections are usually self-limited
and self-healing diseases. However, these infections may
potentially progress to serious muco-cutaneous and systemic
involvement in immunocompetent patients [12, 13]. This condition
may prove to be more severe in an immunocompromised background
including pregnancy [14, 15], HIV infection [16], and organ
transplantation [17]. A fatal outcome is possible [12, 18-20].To
the best of our knowledge, we present the first case of lethal
systemic HSV type-2 infection in a patient under corticotherapy for
Darier disease. The pathomechanisms leading to the extension of the
cutaneous HSV infection and to the systemic dissemination in this
patient are reviewed.
Case report
Lifelong, a 67-year-old man had suffered from severe and extensive
Darier disease, predominantly involving the back, chest, groin,
forearms and arms, face, and intertriginous areas. In addition to
the hyperkeratotic papules, he had experienced several episodes of
extensive and coalescent crusted plaques and bullous lesions. His
medical history also included hypothyroidism and recurrent gastric
ulcers. He had been treated by bypass surgery for ischemic
cardiopathy. He had no allergy manifestations, and he did not
suffer from recurrent oro-labial or genital herpes infections. Over
the years, various topical agents, including tretinoin, squamolytic
agents and antimicrobial soaps and creams had been used without
significant therapeutic responses. The frequent bacterial
colonizations by Pseudomonas aeruginosa and Staphylococcus aureus
had been treated by topical antiseptics, antibiotic creams and oral
antibiotics. Due to the disease severity and the therapeutic
failures, the patient had been treated since 1978 by retinate
(Tigason®, 25-50 mg/d, Roche) and subsequently by
etretinate (Neotigason®, 25-50 mg, Roche), supplemented
by oral methylprednisolone (Medrol®, 16-32 mg/d).
Rapidly following the cardiac bypass surgery in 1997, the
patient developed a circumscribed herpetic infection of his Darier
disease on the back. A biopsy revealed a perivascular superficial
lympho-monocytic infiltrate with suprabasal acantholysis and
dyskeratotic keratinocytes, consistent with Darier disease, but did
not reveal any obvious cytological signs of herpes virus infection
( (figure 1) ).
However, using immunohistochemistry (IHC) [12] with polyclonal
anti-HSV type-1 and type-2 antibodies (Dakopatts®,
Denmark) a Tzanck smear revealed the presence of type-1 HSV
specific antigens ( (figure 2) ). VZV antigens
were not identified. Intravenous aciclovir (10 mg/kg/8 hours for 7
days) was administered followed by a progressive resolution of the
viral infection.
When the patient developed the most recent exacerbation of his
skin condition, the daily therapy consisted of dipyridamol 75 mg,
L-thyroxin 50 μg, atorvastatine 20 mg, acetylsalicylic acid 100 mg,
minocyclin 50 mg, methylprednisolone 32 mg and etretinate 50 mg, as
well as topical applications of antiseptics and betamethasone
dipropionate. Despite this treatment, the head, neck and trunk were
oozing and crusted.
The patient was admitted to the intensive care unit for severe
acute respiratory distress syndrome (ARDS), abdominal and
dorso-lumbar pains, nausea and vomiting, severe dehydration, and
fever. At admission, blood analysis showed corticosteroid-related
hyperleukocytosis (24120/mm3, 87.7% neutrophils),
hypercalcemia (2.86 mmol/L), inflammatory syndrome (CRP: 250 mg/L,
fibrinogen: 13.12 g/L), increased TSH: 6.99 μUI/L, total CPK: 560
μg/L, CPK/MB: 15.6 μg/L, renal insufficiency (urea: 0.64 g/L,
creatinine: 20 mg/L) and hyperglycemia (1.96 g/L). The coagulation
parameters were in the normal range. No other biological
alterations of the hepatic, pancreatic and cardiac functions were
observed. CT scan of the abdomen and pelvis revealed
spondylodiscitis of the D12-L1 junction. Thorax X-ray showed a
retrocardiac condensation. ECG revealed left a ventricular
hypertrophy and tachycardia (113/min). Transthoracic cardiac
ultrasound assessment confirmed the presence of a left ventricular
hypertrophy, ventricular inferior hypokinesis, without any sign of
pericarditis. Numerous and widespread smelly hemorrhagic keratotic
papules, and small bullous lesions involved more than 50% of the
skin surface, clinically suggested an exacerbation of Darier
disease. Furthermore, there were severe neurological alterations
caused by dehydration. One week later, after fluid replenishment,
the renal function progressively improved and the patient’s general
condition was stabilized. In an attempt to control the extensive
Darier disease, the above-mentioned topical and systemic therapies
for his Darier disease were initiated again. The patient was then
transferred from the intensive care unit to the rheumatology ward
to investigate the D12-L1 spondylodiscitis.
For the next two weeks, numerous painful, smelly, hemorrhaghic,
and oozing bullous skin lesions progressively extended, accompanied
by increasing fever. Swabs and cultures of several skin lesions
revealed the presence of an abnormal biocene composed of
multiresistant Staphylococcus aureus, Escherichia coli, Pseudomonas
aeruginosa, and Proteus mirabilis. Viral cultures revealed no
evidence of HSV infection. To eradicate the bacterial load of the
Darier disease lesions, intravenous ciprofloxacin 200 mg/mL/d and
clindamycin 900 mg/d were administered. In addition, topical
applications of fusidic acid (Fucidin® cream) and
betamethasone dipropionate (Diprosone® cream) were
performed. A 3-day therapy failed to bring any clinical
improvement. The skin surface involved was still expanding over the
entire trunk, the genital area, the ears, the lips and the palate.
Due to the widespread affected skin surface, the patient was
transferred to the burns unit. A skin biopsy was performed
revealing a superficial perivascular lymphoid infiltrate with
diffuse acantholysis, large keratinocytes and necrotic cells (
(figure 3) ).
These histological alterations suggested an α-herpesvirus infection
of Darier disease. Viral identification by IHC using polyclonal
anti-HSV type-1 and type-2 antibodies revealed the presence of
type-2 HSV ( (figure
4) ). Complementary IHC examinations revealed positivity
for the type-2 HSV specific antibody HH2 (Seralab), while the HSV
type-1 specific antibody IBD4 (Seralab) remained negative. IHC
using the VL8 anti-VZV monoclonal antibody [12] as well as the
controls respecting primary antibody omission remained negative.
Positive controls consisted of sections from cutaneous HSV
infections of other patients. The final diagnosis was a type-2 HSV
infection of Darier disease. Intravenous acyclovir (10 mg/kg/8
hours) was administered, beginning on the 5th day of
hospitalisation in the burns unit. Serology was consistent with
past-HSV infection (IgG+, IgM–), but type-specific HSV
identification was not performed. Meanwhile, the pulmonary status
of the patient was still worsening with the production of abundant
sputum. One day later, oxygen saturation continued to worsen and
the patient was placed under assisted ventilation. Thorax
radiography revealed bilateral basal condensation with an
interstitial syndrome. The next day, severe melena developed,
oxygen saturation dramatically fell, and the hemodynamic status
deteriorated. Despite intensive medical assistance, ARDS rapidly
worsened and the patient passed away a few hours later.
At autopsy, extensive erosions were observed on the trunk and
thighs ( (figure
5) ). Macroscopic examination revealed a diffusely dense
pulmonary parenchyma with numerous white-yellowish abcesses ( (figure 6) ). The
visceral pleura showed fibrinous deposits. Hypertrophic
cardiopathy, vascular atherosclerosis, and myocardal past
infarction were evidenced.
Histological examination showed cutaneous erosions covered by a
fibrino-leukocytic exsudate. The epidermal architecture was
completely disrupted. The bronchioles and alveolar spaces were
filled by inflammatory cells, predominantly neutrophils. The
pulmonary parenchyma was studded by multiple abscesses. The
GI-tract showed congestion of the mucosal layer. A thorough search
for HSV type-1, type-2 and VZV antigens was performed by IHC on the
autopsy material. Primary antibody omission, and HSV- and VZV-
positive control slides were used as negative and positive
controls, respectively. Positive type-2 HSV immunostaining was
evidenced in keratinocytes showing strong intracellular staining
and a more diffuse signal inside the epidermal blisters. Type-2 HSV
antigens were evidenced in foci of bronchopneumonia exhibiting a
diffuse staining pattern in suppurative areas ( (figure 7) ). The mucosal
layer of the GI-tract also presented a HSV type 2 immunostaining,
in particular in the congested and ulcerated zones. No histological
and IHC clues of HSV infection were found in the kidneys, liver,
pancreas and spleen.
Discussion
Darier disease, either clinically active or in remission, is prone
to HSV skin infections [2-5]. Any unusual disease exacerbations
and/or sudden therapeutic failures should prompt to search for a
viral complication. The frequently atypical clinical presentations
of these viral infections often delay clinical recognition and
adequate therapeutic measures [2-5]. This situation occurred in the
patient presented here, because the diagnosis of type-2 HSV
infection of Darier disease was only reached after histological and
IHC examinations. The IHC search for HSV or VZV-specific antigens
on Tzanck smears or skin biopsies is currently available for rapid,
sensitive and type-specific diagnosis [21]. Diagnosis can also be
reached using PCR [22, 23] or viral culture and identification
[24]. However, these methods are time-consuming compared to IHC
search.
The herpetic infection in 1997 was related to the type-1 HSV,
which represents the usual agent of Darier disease-related HSV
infection [2-5]. Surprisingly, type-2 HSV antigens were identified
in the most recent episode using polyclonal and monoclonal type-2
HSV specific antibodies both in the skin and internal organs. The
patient had no history of recurrent genital or oro-labial herpes.
Serology was IgG+, IgM– for HSV, but no type-specific serological
distinction was performed. Although some patients with widespread
herpes infection present recurrent labial HSV infections [2-5],
others do not, and it is currently not established whether
recurrent oro-labial and genital HSV infections represent a risk
factor for developing HSV infection of Darier disease.
The pathomechanisms of the Darier disease-associated
susceptibility to herpesvirus infection remain unclear. First, it
has been postulated that this event was related to impaired
cellular immunity in Darier disease [10, 25]. However, other
authors never evidenced any immune impairment associated with this
disease [11, 26]. Second, it is unlikely that Darier dyskeratosis
is by itself capable of HSV reactivation in the ganglion. It can be
postulated that the suprabasal acantholysis provides a favorable
environment for HSV disease, by mimicking acantholysis present in
cutaneous HSV infection. Third, there may be a deficiency in, or
the presence of, non-functional defensins, another non-immune
innate host defence line of the skin, displaying antibacterial and
antiviral properties [27]. This hypothesis is supported by the
variety of different bacterial species colonizing the cutaneous
surface of the Darier lesions. Finally, in the present patient,
both topical and oral glucocorticoids probably presented an
additional risk for HSV cutaneous extension followed by further
internal dissemination.
The mechanisms of the skin viral extension and internal
dissemination by glucocorticoids are better understood.
Experimental evidence showed the reactivation of bovine herpes
virus 1 (BHV-1) by means of corticosteroids in an intranasal rabbit
model [28]. By contrast, extension of focal HSV encephalitis in a
rat model was not increased after administration of systemic
glucocorticoids [29]. There is no clinical evidence that HSV is
reactivated or induced by the use of topical glucocorticoids.
However, inappropriate topical glucocorticoid treatment of HSV skin
infection is known to lead to severe expanding infections, often
leading to scarring. Through binding to glucocorticoid receptors,
the topical corticosteroids may affect about 10-100 genes leading
to altered rate of transcription, repressing or inducing mRNA
production and protein synthesis. By inhibiting NαB factor, there
is a reduction of the inflammatory process including various
cytokines, adhesion molecules, inflammatory enzymes and growth
factors including TNFα, GM-CSF, IL1, IL2, IL6, IL8, ICAM-1,
E-selectin and cyclo-oxygenase. By inhibiting some of these
factors, such as ICAM-1, TNF-α, IL1, IL2, and IL6, the predominant
Th1 profile [30-32] of the anti-HSV host defense line is inhibited,
allowing extension of the infection. Sudden glucocorticoid
withdrawal has also been described as a risk factor for HSV
infection [33]. In brief, topical glucocorticoids do not seem to
reactivate or induce HSV skin infection. However, once HSV
infection is present, they can seriously impair innate as well as
adaptive anti-HSV host immune responses, leading to extensive
infections.
Although HSV infection of Darier disease is not uncommon, a
fatal outcome has, to the best of our knowledge, never been
reported. Lethal outcome following extensive cutaneous and internal
HSV infection has been documented in an atopic dermatitis patient
[19], in burn patients [20] and in 2 cases of pemphigus vulgaris
[18]. The cause of death in the present patient was severe ARDS.
Type-2 HSV was found in cytolytic areas of the lungs, in
keratinocytes of the epidermal blisters and in the congested and
ulcerated zones of the GI-tract mucosal layer. The cytopathic
effects associated with the virological findings correlate with the
clinical findings of severe ARDS, skin infection and melena. These
data confirm earlier findings showing that the HSV disease
expression is clearly correlated with histologically recognizable
cytopathic effects associated with positive HSV immunostaining
[12].
In conclusion, atypical exacerbations and/or sudden therapeutic
failure in Darier disease should prompt for a thorough search for
herpes viridae infection. Both topical and systemic
immunosuppressive therapies of Darier disease represent additional
risks. Systemic antiviral therapy should be initiated as soon as
possible, limiting the risks of further cutaneous and/ or internal
dissemination.
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