Professional Documents
Culture Documents
Eczema Herpeticum in Atopic Dermatitis
Eczema Herpeticum in Atopic Dermatitis
DOI: 10.1111/all.14853
REVIEW
1
Division of Immunodermatology
and Allergy Research, Department of Abstract
Dermatology and Allergy, Hannover
Atopic dermatitis (AD) is one of the most common chronic inflammatory skin dis-
Medical School, Hannover, Germany
2
Cluster of Excellence RESIST (EXC 2155),
eases leading to pruritic skin lesions. A subset of AD patients exhibits a disseminated
Hannover Medical School, Hannover, severe HSV infection called eczema herpeticum (EH) that can cause life-threatening
Germany
complications. This review gives an overview of the clinical picture, and characteris-
Correspondence tics of the patients as well as the diagnosis and therapy of EH. A special focus lies on
Stephan Traidl, Hannover Medical
School (MHH), Department of
the pathophysiological hallmarks identified so far that predispose for EH. This aspect
Dermatology and Allergy, Carl-Neuberg- covers genetic aberrations, immunological changes, and environmental influences dis-
Str.1, 30625 Hannover, Germany.
Email: traidl.stephan@mh-hannover.de
playing a complex multifactorial situation, which is not completely understood. Type
2 skewing of virus-specific T cells in ADEH+ patients has been implicated in immune
profile abnormalities, along with impaired functions of dendritic cells and natural killer
cells. Furthermore, aberrations in interferon pathway-related genes such as IFNG and
IFNGR1 have been identified to increase the risk of EH. IL-4, IL-25, and thymic stromal
lymphopoietin (TSLP) are overexpressed in EH, whereas antimicrobial peptides like
human β-defensins and LL-37 are reduced. Concerning the epidermal barrier, single
nucleotide polymorphisms (SNPs) in skin barrier proteins such as filaggrin were identi-
fied in ADEH+ patients. A dysbalance of the skin microbiome also contributes to EH
due to an increase of Staphylococcus aureus, which provides a supporting role to the
viral infection via secreted toxins such as α-toxin. The risk of EH is reduced in AD pa-
tients treated with dupilumab. Further research is needed to identify and specifically
target risk factors for EH in AD patients.
KEYWORDS
Atopic dermatitis, eczema herpeticum, HSV, type 2 immune response, virus
1 | I NTRO D U C TI O N 85% of all cases manifest before the age of five, AD can occur lifelong
and the prevalence of AD is still high in adulthood.6-8 Surprisingly, recent
Atopic dermatitis (AD) is a chronic inflammatory skin disease, which is data based on two birth cohorts revealed that only 38% of adult AD pa-
characteristically associated with intense pruritus and eczematous le- tients in the United Kingdom reported a childhood onset of symptoms.9
sions.1 Robert Willan, an English dermatologist, was the first to describe Patients suffering from AD are prone to viral and bacterial in-
the disease in 1808.2 In most countries, over 20% of children are af- fections.5 Staphylococcus aureus (S. aureus) infections are particularly
fected at least once during a period of their lives.3-5 Despite the fact that common in AD patients, leading to superinfection.10
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in
any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
© 2021 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.
in patients with AD. The nomenclature of the rash matches the Simplexa
causative virus: eczema herpeticum (EH), eczema molluscatum, ec- Pemphigus Foliaceusb 33
Hodgkin's Diseaseb 50
zema verrucatum, eczema coxsackium (EC), and eczema vaccinatum Hailey-Hailey Disease b 34,137
Multiple Myeloma a 51
11
(EV), respectively. Whilst disseminated HPV and MCV infections Pityriasis Rubra Pilarisa 35
Wiskott-Aldrich 52
AD patients suffer more often from upper respiratory infections, Dermatitisa Patientsb
37
chest cold, and influenza than healthy individuals.14,15 Of note, no Staphylococcal Scalded
Skin Syndromea
increased prevalence of COVID-19 has been reported so far. The
treatment with dupilumab, an antibody directed against the α-chain Grover's Diseasea 38
of IL-4 and IL-13 receptors, appears to reduce the risk for EH.16,17 Psoriasisa 39
a 40
Additionally, no increased risk for COVID-19 infection was seen in Rosacea
AD patients treated with dupilumab.18,19 Patients With Skin 41
Graftsa
Burnsb 44,45
3 | H S V A N D EC ZE M A H E R PE TI CU M Trauma b 42
Cosmetic Proceduresb 43
Herpes simplex viruses are strict human pathogenic viruses affecting Ichthyosis b 46
mainly skin and mucosa. They can be distinguished into HSV-1 and atopic dermatitis
HSV-2. 20 HSV-1 primarily affects labial and oral regions, whereas
Note: The dichotomic differentiation is provided for a better overview.
HSV-2 most commonly affects the genital area. HSV-1 and 2 persist a
Virus was proved by culture, PCR, or immunofluorescence.
in sensory neurons, most notably in cells of the trigeminal ganglion b
Diagnosis was based on clinical appearance and/or Tzanck test.
for HSV-1 21 but also in the ciliary ganglion, 22 superior cervical gan-
glion, thoracic ganglia, and the ganglion of the vagus nerve. 23,24
HSV, which can induce recurrent herpes febrilis in healthy sub- has led to a controversial discussion on ichthyosis vulgaris as a pos-
jects, is able to cause a disseminated skin infection in patients with sible risk factor for EH..12,46,47 Hematological diseases affecting
AD.12 This was first described in 1887 by the Hungarian dermatolo- immune cells with a report of EH cover the spectrum of cutaneous
gist Moritz Kaposi with the term “eczema herpetiformis”. 25 The initial T-cell lymphoma,48 Sézary disease,49 Hodgkin's disease,50 multiple
name “herpetiformis” arose not from the knowledge that the disease myeloma,51 and Wiskott-Aldrich syndrome.52 EH was reported in
is caused by a herpes virus but the Greek word “herpein”, mean- an immune-suppressed patient treated with everolimus for a met-
ing “creeping”. EH is also known as “pustulosis acuta varioliformis” astatic renal cell carcinoma53 and in a patient with a phenytoin-
based on a publication of the German dermatologist Fritz Juliusberg induced drug rash.54 It should be mentioned that the diagnosis of
in 1898. 26 Likewise, the term “Kaposi's varicelliform eruption” was a history of AD has not been carried out very carefully in some of
used in this context as well. 27 Generalized HSV skin infections have these works. Regarding AD, the disease contains immunological ab-
also been reported in several other diseases. In order to group them, normalities as well as a disturbed skin barrier. Skin damaging factors
they may be subdivided according to whether they occur in diseases such as contact sports can contribute to the eruption of EH in AD
with predominant skin malfunctions or those with hematological/ patients.55 Laser resurfacing was described as a possible additional
immunological aberrations (Table 1). Concerning skin diseases, EH trigger of EH in a HIV-positive patient.56
28-31
has often been reported in Darier's disease in addition to AD.
Case histories have also been published for a variety of other
skin diseases such as epidermolysis bullosa simplex,32 pemphigus 4 | C LI N I C A L PI C T U R E A N D PATI E NT S ’
foliaceus,33 Hailey-Hailey disease,34 pityriasis rubra pilaris,35 irri- C H A R AC TE R I S TI C S
tant contact dermatitis,36 staphylococcal scalded skin syndrome,37
Grover's disease,38 psoriasis,39 rosacea,40 patients with skin grafts,41 The clinical manifestation of EH is characterized by disseminated non-
42
trauma, cosmetic procedures such as follicular hair unit ex- grouped vesicular eruptions and pustules on erythematous lesions,
traction,43 and severe burns.44,45 EH has also been described in two preferentially affecting the head, neck, chest, and arm (Figure 1).
patients with ichthyosis vulgaris and a history of AD. Interestingly, These vesicles potentially lead to erosions after 2-7 days.57-59 The
in these cases, EH appeared in a period when AD was absent, which skin morphology is often accompanied by general symptoms such
TRAIDL et al. | 3
as fever, malaise, and headache along with lymphadenopathy.60,61 of cases in winter and spring was observed in other studies.11,71
Furthermore, the clinical picture can be exacerbated by bacte- Accordingly, Rerinck et al. suggested an association between in-
rial superinfections, most notably with streptococci and staphylo- creased AD severity in these seasons and the slightly increased oc-
cocci.62,63 It was shown that patients suffering from acute EH exhibit currence.77 Furthermore, ADEH+ patients seem to exhibit a general
64
lower levels of lymphocytes and higher levels of monocytes. EH susceptibility for pathogens as they manifest cutaneous infections
can be accompanied by herpes encephalitis or hepatitis, which can with MCV or S. aureus more often than ADEH−patients.13
65,66
also occur in immune-competent patients. Additionally, EH is
also reported in pregnancy.67
At least 20% of EH patients report recurrent herpes infections 5 | D I AG N OS I S A N D D I FFE R E NTI A L
in their medical history. In a smaller group of patients, the recur- D I AG N OS I S
rent HSV infections appear generalized.68 Recently, Seegräber et al.
published a retrospective European multicenter study analyzing 224 EH is often diagnosed clinically, yet established criteria for its diag-
EH cases that identified a recurrence rate of 26.5%.69 Recurrence nosis are not currently available. Diagnosis can be reinforced by the
was associated with an earlier onset of AD; however, no differences high sensitive detection of HSV-DNA by means of the polymerase
were seen concerning total IgE. Many patients exhibited AD lesions chain reaction (PCR) allowing the discrimination of HSV type 1 and
without EH, yet skin absent of AD lesions was never affected by her- 2.12,78 PCR is, however, unable to differentiate between active vi-
69
petic lesions. Wheeler et al. demonstrated that recurrent EH is less rions and virus proteins. Detecting HSV in virus culture can prove
70
severe compared to the first manifestation. The mean age of adult active virions, however, this requires 60-130 additional hours com-
EH patients was estimated at 22.5 years.72,73 In 1985, Wutzler et al. pared to PCR.79 The use of indirect immunofluorescence to detect
provided the information that the majority of EH was due to HSV-1 HSV antigens is regularly applied.80 Additionally, methods such as
73
infection, which is often confirmed by the experiences of most cli- direct detection of HSV by electronic microscopy or Tzanck test are
nicians; however, no current data of the distribution between HSV-1 also available but rarely used.70 The latter represents a practical and
and HSV-2 in EH is available. Patients with AD and EH have a sig- quick method that shows giant viral multinucleated cells but is not
nificantly earlier onset of AD.71,72 Increased total IgE levels, asthma frequently performed due to the comprehensive availability of PCR
frequency and sensitizations to aeroallergens, food, and Malassezia and the lack of specific detection of HSV. Tzanck test cannot differ-
13,74
sympodialis indicate stronger type 2 immune responses. entiate HSV and varicella-zoster virus (VZV) infections of the skin. A
A case report published by Lübbe et al documented EH in two histological analysis of a punch biopsy shows signs of an HSV infec-
AD patients using the topical immunomodulatory substance tacro- tion as the virus induces a cytopathic effect in the keratinocytes as
limus,75 although this was not evident in studies oftacrolimus using well as multinuclear giant cells with intranuclear inclusions.
76
larger cohorts. Treatment of AD with corticosteroids was not iden- Concerning the diagnosis based on clinical morphology, EH can
tified as a risk factor following a cohort study by Wollenberg et al. be confused with EC, a recently described complication of coxsackie
This study was also unable to identify any significant seasonal dif- infection in AD patients (Figure 2).81 EC is most commonly caused
72
ferences in the incidence of EH. However, a slight accumulation by coxsackievirus A6. In 2013 Mathes et al. proclaimed vesicles and
erosions in areas of AD as clinical hallmarks for EC. Additionally,
coxsackievirus A6-associated eruptions provide several further clin-
(A) (B)
ical characteristics: widespread vesiculobullous and erosive erup-
tion, a Gianotti Crosti–like eruption with acrofacial papulovesicles
and erosions, a petechial and purpuric rash, and delayed cutaneous
manifestations as acral desquamation.81 In the case of an unclear
clinical picture, diagnostic PCR from skin lesions for both HSV and
(A) (B)
Clinical characteristics
1. Non-grouped vesicular eruptions
2. Vesicles and erosions focused on predominant AD lesions
3. Fever, malaise
4. EH episode in the patient history
Diagnostic tests
1. HSV PCR
2. Virus culture
3. Virus protein detection in the skin by labeled antibodies
(immunofluorescence)
4. Electronic microscopy
5. Tzanck test
6. Histology
F I G U R E 4 Molecular and genetic characteristics of EH patients leading to viral susceptibility. Abnormalities in the immunological
response, skin barrier dysfunction, and environmental factors contribute to the complex pathogenesis of EH. ANKRD1: ankyrin repeat
domain 1, CLDN1: claudin-1, DC: dendritic cell, FLG: filaggrin gene, HSV: herpes simplex virus, IDO1: indoleamine 2,3-dioxygenase, IFN:
interferon, IFNGR1: interferon γ receptor 1, IRF: interferon regulatory factors, NK: natural killer cell, S. aureus: Staphylococcus aureus, STAT:
signal transducer and activator of transcription, Tc: cytotoxic T cell, Th: T helper cell, TJs: tight junctions, TSLP: thymic stromal lymphopoietin
more unrestrained viral spread, maybe speculated.87 Regarding identification of patients at risk of EH and allow intervention with
filaggrin, Kim et al. analyzed skin biopsies of ADEH+, ADEH−, and specific preventive approaches.
+
healthy individuals. IL-25was augmented in ADEH skin compared
to ADEH− and healthy skin biopsies. Furthermore, it has been shown
that HSV-1 replication is enhanced as an indirect result of IL-25 in- 8 | I M M U N E S YS TE M A N D TH E RO LE O F
hibiting filaggrin expression.88 A D T Y PI C A L T Y PE 2 I M M U N E R E S P O N S E
Besides filaggrin, claudins, which take part in the determination
of tight junctions’ resistance, were identified to be associated with The immune response in AD is characterized by T helper (Th) 2 cell-
AD. It was shown by gene expression analysis that claudin-1 and −23 driven inflammation.1 Raychaudhuri et al. were the first to investi-
are expressed in lower amounts in AD patients compared to healthy gate the role of Th2 cytokines in viral defense, showing that IL-4
89
individuals. De Benedetto et al. identified specific single nucleo- increases the extent of cytopathic effected cells in HSV-infected cell
tide polymorphisms (SNP) in CLDN1 associated with EH: In European culture and decreases the production of IFN-γ.90 Several studies em-
+
American ADEH patients rs3774032 (OR = 0.44, 95% CI: 0.22-0.85) phasized the enhanced replication of the virus in the presence of IL-4
and rs3732923 (OR = 1.93, 95% CI: 1.21-3.07) 89 and in African- and IL-13 and the worsening of HSV infections under the influence
Americansrs3954259 (OR = 2.16, 95% CI: 1.02-4.59). Silencing of of IL-4 in animal models.88,91
Claudin-1 by siRNA, and a subsequent reduction of >50% of tran- Additionally, it was shown that IL-4 and IL-13 downregulate fil-
scripts, mirrored the conditions of AD skin. It was shown that kerat- aggrin, which may contribute to viral susceptibility as previously de-
inocytes with silenced claudin-1 were more susceptible to infection scribed.88 IL-4 and IL-13 act via the signal transducer and activator
with HSV-1 in an in vitro approach.89 of transcription (STAT) 6, which itself plays a role in the adaptive
Pertaining to the skin barrier, several risk factors for the devel- immune system.92,93 Howell et al compared 20 ADEH+ patients with
opment of EH were identified in AD patients that may enable the 55 ADEH− patients demonstrating thatSTAT6 SNPs (rs3024975,
6 | TRAIDL et al.
rs841718, rs167769, and rs703817) were associated with EH; the for EH in AD patients. These results underlined the finding of Leung
haplotypes rs167769 and rs324013 increased the risk for EH three et al showing an increased risk for EH in patients with specific
times (OR: 3.33, 95% CI: 1.39-8.55).94 IFN-γ and IFNGR1 SNPs.84 Of note, Gao et al identified seven com-
Analysis of the epigenome in AD patients with EH identified mon IFNGR1 SNPs (rs11914, rs17175127, rs1327475, rs10457655,
several sites of the genome with significant differential methylation rs7749390, rs2234711, and rs28515059) to be accompanied with a
95
when compared to healthy controls. Interestingly, two differen- reduced risk for EH.
tially methylated CpGs were revealed to be associated with IL-4 and Beside the IFN-γ receptor 1, interferon regulatory factors (IRF)
IL-13 in AD patients; ADEH+ and ADEH− patients, however, could play an important role as transcription factors in intracellular signal-
not be distinguished based on these findings. ing pathways. By analyzing the transcriptome of PBMCs after HSV-1
T cells are central to cell-mediated adaptive immunity and have stimulation, Bin et al. revealed that IRF3 and IRF7 are downregulated
been characterized in AD lesions in detail. Type 2 polarization is an im- in ADEH+ patients in comparison with ADEH− and healthy individ-
portant hallmark of the T-cell infiltrate in AD lesions. Investigating the uals.101 This led to a downstream decrease in expression of type
T-cell mediated antiviral immune response in AD patients, we recently I and type III interferon genes. Additionally, Bin et al showed that
+
showed that T-cell lines from ADEH individuals reactive to HSV anti- ankyrin repeat domain 1 (ANKRD1) is reduced in PBMCs of ADEH+
96
gens secrete higher levels of IL-4 as compared to healthy individuals. patients.101 Upon further investigation, it was shown that ANKRD1
+ +
Investigation of antigen-activated CD154 subsets in ADEH patients forms a protein complex with IRF3 and IRF7, contributing to an an-
revealed that increased frequencies of HSV-specific Th2 cells were tiviral innate immune signaling pathway.102 Moreover, several SNPs
present. Moreover, these patients were found to have elevated HSV- in the IRF2 encoding gene, depending on ethnic background, are
1-specific cytotoxic (Tc) 2 cells and decreased numbers of Tc1 cells. associated with a higher risk of developing EH.103 In conclusion, nu-
Additionally, elevated expression of IL-4 by HSV-1-specific T cells was merous gene expression patterns and SNPs were determined to lead
observed upon staining with HSV-1-specific MHC class I tetramers.96 to an impaired IFN-signaling pathway, resulting in a weakened viral
In addition to Th and Tc cells, the role that regulatory T cells defense.
(Tregs) might have in ADEH has also gained interest over the last In addition to IFNGR, human leukocyte antigen (HLA) is also en-
decade. Tregs are a subset of CD4+ T cells characterized by immu- coded by chromosome 6. Interestingly, HLA B7 was identified to be
nosuppressive properties. In particular, induced Tregs (iTregs) with associated with EH, approximately doubling the risk of developing
skin-homing capacity were increased in patients with acute EH com- the condition (OR: 1.91, 95% CI: 1.10-3.31).104
− +
pared to ADEH patients. Analysis of their role in ADEH patients has Regarding other immune cells, a decreased amount of plasmacy-
shown that their suppressive capacity to inhibit the proliferation of toid dendritic cells can be detected in AD. These cells are known as
effector T cells is similar to that of healthy individuals. Investigating physiological producers of IFN-α and β, and thus, take part in viral
the cytokine expression of different lymphocyte subsets revealed defense. The reduced presence of plasmacytoid dendritic cells in
reduced IFN-γ and TNF-α production in acute ADEH+ by T-helper the skin may, therefore, lead to a higher susceptibility to HSV.105
cells, cytotoxic T cells, and NK cells compared to healthy controls. Indoleamine 2,3-dioxygenase (IDO1), a tryptophan catabolizing en-
As the depletion of Tregs from HSV-1 infected PBMCs restored the zyme, is a product of dendritic cells. Analyzing the role of IDO1 in
production of IFN-γ, it was hypothesized that Tregs may contribute ADEH+ patients, Staudacher et al. revealed an increased activity of
97
to the initiation and progression of EH in AD patients. IDO1 during acute EH.106 Additionally, increased IDO1 expression
As previously mentioned, IL-4 and IL-5 are upregulated in acute and activity was revealed in Langerhans cells (LC) from ADEH+ pa-
12,73
AD lesions, leading to a decrease in IFN-γ production. With the tients and acute EH individuals. Stimulating ADEH+ patient-derived
knowledge that IFN-γ plays a decisive role in viral defense, its re- LC in vitro resulted in an exaggerated IDO1 expression and activ-
duction may induce susceptibility to HSV.98,99 Additionally, serum ity. Notably, IDO inhibits T-cell proliferation and IFN-γ production,
levels of IFN-β and IFN-γ were found to be reduced in AD patients, meaning the increased IDO1 activity in ADEH+ patients may contrib-
+
although it is worth noting that IFN-γ was reduced in both ADEH ute to HSV susceptibility.107
and ADEH− subjects.74 Furthermore, significantly decreased levels Furthermore, skin-derived antimicrobial peptides (AMP) are in-
of IFN-γ in T-cell lines of AD patients, particularly ADEH+ patients, volved in local protection against pathogens, for example, viruses
were observed following stimulation with HSV proteins and pep- and bacteria. Interestingly, some of these AMPs are reduced in AD
tides.96 In addition, transcriptome analyses of PBMCs from ADEH+ patients.108,109 Howell et al demonstrated that, in antiviral assays,
patients displayed a reduced IFN-γ and IFN-γ receptor gene expres- the AMP LL-37, in particular, exhibited anti-HSV activity.110 ADEH+
− 84
sion compared to ADEH patients. patients express significantly lower levels of LL-
37in their skin,
Gao et al. investigated the interferon-pathway in ADEH+ pa- which may contribute to HSV susceptibility.110 Notably, an inverse
tients in detail by sequencing relevant genes (IFNG, IFNGR1, IFNAR1, correlation of total IgE and LL-37 was detected identifying a possible
100
and IL12RB1) and subsequently delineated six rare missense- surrogate parameter.
mutations inIFNGR1 located on chromosome 6 (Val14Met, Val61Ile, The keratinocyte-derived thymic stromal lymphopoietin (TSLP),
Val264Ile, His335Pro, Tyr397Cys, and Leu467Pro). These mutations which stimulates DCs to induce Th2 cell, polarization was analyzed
were associated with an IFN-γ Receptor 1 deficiency predisposing by Gao et al.111 Investigating the TSLP pathway, an association
TRAIDL et al. | 7
For AD, some recent phase II or phase III studies have been cells and a malfunction of the IFN-pathway. Additionally, a detailed
communicated as full papers for baricitinib, upadacitinib, and abroc- understanding of the contributing genetic factors may lead to the
itinib.127-131 So far, no significant increases have been observed for ability to identify AD patients at risk of developing EH. New thera-
EH or other herpes infections with any of these JAK inhibitors in peutic approaches such as dupilumab or other anti-t ype 2 inflamma-
those studies. It should be mentioned; however, that a history of tion drugs may represent a specific prevention measure, particularly
EH was defined as an exclusion criterion in most of the studies. in patients with recurrent EH episodes.
Additionally, studies on efficacies of novel drugs are usually under-
powered with respect to the evaluation of rare adverse events. In ORCID
the regulatory text of baricitinib, which has been approved in the Stephan Traidl https://orcid.org/0000-0003-4806-599X
European Union for AD in November 2020, a history of EH is not Lennart Roesner https://orcid.org/0000-0001-6651-0458
included as a contraindication. However, JAK inhibitors should be
used with caution in ADEH+ patients. REFERENCES
1. Werfel T, Allam J-P, Biedermann T, et al. Cellular and molecular im-
munologic mechanisms in patients with atopic dermatitis. J Allergy
Clin Immunol 2016;138(2):336-3 49.
10 | PR E V E NTI O N A N D O U TLO O K
2. Willan R. On cutaneous diseases. Johnson 1808.
3. Flohr C, Mann J. New insights into the epidemiology of childhood
Primary prevention in the context of EH in AD patients would re- atopic dermatitis. Allergy 2014;69(1):3-16.
quire the prevention of initial HSV infection. A possible approach to 4. Leung DY, Boguniewicz M, Howell MD, Nomura I, Hamid QA. New
insights into atopic dermatitis. J Clin Invest 2004;113(5):651-657.
achieve this would be the vaccination of AD patients against HSV. In
5. Bieber T. Atopic dermatitis. N Engl J Med 2008;358(14):1483-1494.
the last three decades, immunization against HSV has been the focus 6. Illi S, von Mutius E, Lau S, et al. The natural course of atopic der-
of a multitude of publications. A pivotal protein synthesized by herpes matitis from birth to age 7 years and the association with asthma.
simplex viruses is glycoprotein D, which is encoded in both HSV types J Allergy Clin Immunol 2004;113(5):925-931.
7. Garmhausen D, Hagemann T, Bieber T, et al. Characterization of
but not VZV.132 A vaccination containing glycoprotein D was brought
different courses of atopic dermatitis in adolescent and adult pa-
to clinical trials for the prevention of genital HSV-1 and HSV-2 infec-
tients. Allergy 2013;68(4):498-506.
tions in seronegative women. The vaccine, whilst successful against 8. Barbarot S, Auziere S, Gadkari A, et al. Epidemiology of atopic
HSV-1, did not provide protection against HSV-2.133 Recent studies dermatitis in adults: Results from an international survey. Allergy
investigating an HSV live attenuated vaccine demonstrated effec- 2018;73(6):1284-1293.
9. Abuabara K, Ye M, McCulloch CE, et al. Clinical onset of atopic
tiveness in a guinea pig genital HSV-2 infection model.134
eczema: Results from 2 nationally representative British
As described above, a multitude of genetic aberrations have birth cohorts followed through midlife. J Allergy Clin Immunol
been identified that predispose for EH in AD patients. The use of 2019;144(3):710-719.
genetic sequencing to identify AD patients at risk of developing EH 10. Langan SM, Irvine AD, Weidinger S. Atopic dermatitis. Lancet
2020;396(10247):345-360.
may be part of a prevention strategy in the future.
11. Wollenberg A, Wetzel S, Burgdorf WH, Haas J. Viral infections in
Our recent results revealed a type 2 skewing of virus-specific T atopic dermatitis: pathogenic aspects and clinical management. J
cells in ADEH+ patients; most notably an increase in IL-4.96 Fleming Allergy Clin Immunol 2003;112(4):667-674.
et al provided a meta-analysis investigating the risk of EH during 12. Wetzel S, Wollenberg A. Eczema herpeticatum. Hautarzt
2004;55(7):646-652.
treatment with dupilumab, a human monoclonal IgG4 antibody tar-
13. Beck LA, Boguniewicz M, Hata T, et al. Phenotype of atopic der-
geting the α-chain of the IL-4 and IL-13 receptor.135 This study, which matitis subjects with a history of eczema herpeticum. J Allergy Clin
included eight randomized controlled trials with 2706 participants in Immunol 2009;124(2):260-269.e7.
total, identified a risk reduction of nearly 70% for EH in dupilumab 14. Rystedt I, Strannegard IL, Strannegard O. Recurrent viral infections
in patients with past or present atopic dermatitis. Br J Dermatol
treated AD patients, yet no risk reduction was shown for overall her-
1986;114(5):575-582.
pesvirus infections.17 Further investigation is needed to determine 15. Strom MA, Silverberg JI. Association between atopic derma-
whether the decreased risk of developing EH upon treatment with titis and extracutaneous infections in US adults. Br J Dermatol
dupilumab is based on an improvement of the skin, the reduced type 2017;176(2):495-497.
16. Eichenfield LF, Bieber T, Beck LA, et al. Infections in dupilumab
2 polarized inflammation in the skin, or both. This may lead to the
clinical trials in atopic dermatitis: a comprehensive pooled analysis.
hypothesis that dupilumab, or other anti-t ype 2 inflammation drugs, Am J Clin Dermatol 2019;20(3):443-456.
can be used for tertiary prevention of EH in patients with recurrent 17. Fleming P, Drucker AM. Risk of infection in patients with atopic
episodes, or even perhaps as secondary prevention in patients with dermatitis treated with dupilumab: a meta-analysis of randomized
an increased risk. Nowadays, a prophylaxis with acyclovir 200 mg controlled trials. J Am Acad Dermatol 2018;78(1):62-69.e1.
18. Carugno A, Raponi F, Locatelli AG, et al. No evidence of increased
twice daily or valaciclovir 500 mg per day over several months is
risk for COVID-19 infection in patients treated with Dupilumab for
recommended in ADEH+ patients with recurrent episodes.12,136 atopic dermatitis in a high-epidemic area -Bergamo, Lombardy,
In conclusion, EH depicts a severe complication in patients with Italy. J Eur Acad Dermatol Venereol. 2020.
AD. It is caused by specific barrier dysfunctions as well as immu- 19. Wollenberg A, Flohr C, Simon D, et al. European Task Force on
Atopic Dermatitis (ETFAD) statement on severe acute respiratory
nological aberrations such as a type 2 skewing of virus-specific T
TRAIDL et al. | 9
syndrome coronavirus 2 (SARS-Cov-2)-infection and atopic der- 42. Grossman JA, Berger R, Hoehn RJ. Kaposi's varicelliform eruption
matitis. J Eur Acad Dermatol Venereol 2020. complicating local facial trauma. Case report. Plast Reconstr Surg
20. Buxbaum S, Geers M, Gross G, Schofer H, Rabenau HF, Doerr HW. 1975;55(5):615-617.
Epidemiology of herpes simplex virus types 1 and 2 in Germany: 43. Mansur AT, Demirci GT, Uzunismail MA, Yildiz S. A rare complica-
what has changed? Med Microbiol Immunol 2003;192(3):177-181. tion of follicular hair unit extraction: Kaposi's varicelliform erup-
21. Baringer JR, Swoveland P. Recovery of herpes-simplex virus from tion. Dermatol Pract Concept 2016;6(1):15-17.
human trigeminal ganglions. N Engl J Med 1973;288(13):648-650. 44. Nishimura M, Maekawa M, Hino Y, Mihara K, Kohda H. Kaposi's
22. Bustos DE, Atherton SS. Detection of herpes simplex virus varicelliform eruption. Development in a patient with a healing
type 1 in human ciliary ganglia. Invest Ophthalmol Vis Sci second-degree burn. Arch Dermatol 1984;120(6):799-8 00.
2002;43(7):2244-2249. 45. Bartralot R, Garcia-Patos V, Rodriguez-C ano L, Castells A. Kaposi's
23. Warren KG, Brown SM, Wroblewska Z, Gilden D, Koprowski H, varicelliform eruption in a patient with healing second degree
Subak-Sharpe J. Isolation of latent herpes simplex virus from the burns. Clin Exp Dermatol 1996;21(2):127-130.
superior cervical and vagus ganglions of human beings. N Engl J 46. Verbov J, Munro DD, Miller A. Recurrent eczema herpeticum asso-
Med 1978;298(19):1068-1069. ciated with ichthyosis vulgaris. Br J Dermatol 1972;86(6):638-6 40.
24. Mahalingam R, Wellish MC, Dueland AN, Cohrs RJ, Gilden DH. 47. Santmyire-Rosenberger BR, Nigra TP. Psoriasis herpeticum: three
Localization of herpes simplex virus and varicella zoster virus DNA cases of Kaposi's varicelliform eruption in psoriasis. J Am Acad
in human ganglia. Ann Neurol 1992;31(4):444-4 48. Dermatol 2005;53(1):52-56.
25. Kaposi M. Pathologie und Therapie der Hautkrankheiten für prak- 48. Masessa JM, Grossman ME, Knobler EH, Bank DE. Kaposi's var-
tische Ärzte und Studirende. 3rd ed. Wien: Urban & Schwarzenberg; icelliform eruption in cutaneous T cell lymphoma. J Am Acad
1887. Dermatol 1989;21(1):133-135.
26. Juliusberg F. Über Pustulosis acuta varioliformis. Arch. f. Derm. u. 49. Brion N, Guillaume JC, Dubertret L, Touraine R. Disseminated cu-
Syph. 1898;46:21-28. taneous herpes of the adult and Sezary syndrome (author's transl).
27. Nahmias AJ, Roizman B. Infection with herpes-simplex viruses 1 Ann Dermatol Venereol 1981;108(6–7 ):517-521.
and 2. 1. N Engl J Med 1973;289(13):667-674. 50. Muller SA, Herrmann EC Jr, Winkelmann RK. Herpes simplex infec-
28. Walker K, Martini A, Philips H, Sharp L, Thomas K, Tarbox M. tions in hematologic malignancies. Am J Med 1972;52(1):102-114.
Darier disease with disseminated herpes simplex virus type 2 in- 51. Fukuzawa M, Oguchi S, Saida T. Kaposi's varicelliform eruption
fection. Dermatol Online J 2019;25(4). of an elderly patient with multiple myeloma. J Am Acad Dermatol
29. Higgins PG, Crow KD. Recurrent Kaposi's varicelliform eruption in 2000;42(5 Pt 2):921-922.
Darier's disease. Br J Dermatol 1973;88(4):391-394. 52. St. Geme JW, Prince JT, Burke BA, Good RA, Krivit W. Impaired
30. Hazen PG, Eppes RB. Eczema herpeticum caused by herpesvi- cellular resistance to herpes-simplex virus in Wiskott-Aldrich syn-
rus type 2. A case in a patient with Darier disease. Arch Dermatol drome. N Engl J Med 2016;273(5):229-234.
1977;113(8):1085-1086. 53. Hong S, Kim EH, Cho SB, Rha SY. Kaposi's Varicelliform-like erup-
31. Tayabali K, Pothiwalla H, Lowitt M. Eczema herpeticum in Darier's tion in a patient treated with everolimus for metastatic renal cell
disease: a topical storm. J Community Hosp Intern Med Perspect carcinoma: report of a rare case. Case Rep Oncol 2014;7(2):337-3 42.
2019;9(4):347-350. 54. Ajith C, Dogra S, Handa S. Kaposi's varicelliform eruption in
32. Huguen J, Fraitag S, Misery L, Abasq-Thomas C. Kaposi varicelli- a patient with phenytoin- induced drug rash. Int J Dermatol
form eruption in a patient with epidermolysis bullosa simplex gen- 2006;45(12):1452-1453.
eralized severe. JAAD Case Rep 2016;2(3):209-211. 55. Shenoy R, Mostow E, Cain G. Eczema herpeticum in a wrestler. Clin
33. Martins-C astro R, Proenca N, de Salles-Gomes LF. On the associ- J Sport Med 2015;25(1):e18-e19.
ation of some dermatoses with South American pemphigus folia- 56. Rodriguez- Serna M, Mercader P, Pardo J, Fortea- Baixauli JM,
ceus. Int J Dermatol 1974;13(5):271-275. Aliaga A. Kaposi's varicelliform eruption in an HIV- positive
34. Schirren H, Schirren CG, Schlupen EM, Volkenandt M, Kind P. patient after laser resurfacing. J Eur Acad Dermatol Venereol
Exacerbation of Hailey-Hailey disease by infection with herpes 2004;18(6):711-712.
simplex virus. Detection with polymerase chain reaction. Hautarzt 57. Braun-Falco O, Plewig G, Wolff HH, Burgdorf W, Landthaler M,
1995;46(7):494-497. editors. Braun-Falco's Dermatologie, Venerologie und Allergologie.
35. Ng SK, Ang CB, Tham A. Kaposi's varicelliform eruption in a pa- 5th ed. Heidelberg: Springer; 2005.
tient with pityriasis rubra pilaris. J Am Acad Dermatol 1992;27(2 Pt 58. David TJ, Lakhani PK, Haeney MR. Severe atopic eczema, recur-
1):263. rent pneumococcal meningitis and recurrent eczema herpeticum.
36. Morganroth GS, Glick SA, Perez MI, Castiglione FM Jr, Bolognia JL. J R Soc Med 1984;77(8):696-697.
Kaposi's varicelliform eruption complicating irritant contact der- 59. Higgins CR, Schofield JK, Tatnall FM, Leigh IM. Natural history,
matitis. J Am Acad Dermatol 1992;27(6 Pt 1):1030-1031. management and complications of herpes labialis. J Med Virol
37. Barrio J, Lazaro P, Barrio JL. Kaposi's varicelliform eruption 1993;41:22-26.
and staphylococcal scalded skin syndrome in adults. J Am Acad 60. David TJ, Longson M. Herpes simplex infections in atopic eczema.
Dermatol 1997;37(3 Pt 1):510-511. Arch Dis Child 1985;60(4):338-3 43.
38. Kosann MK, Fogelman JP, Stern RL. Kaposi's varicelliform erup- 61. Chen YP, Wu YC. Eczema herpeticum in three siblings: clinical fea-
tion in a patient with Grover's disease. J Am Acad Dermatol tures and acyclovir treatment. J Dermatol 1986;13(5):334-338.
2003;49(5):914-915. 62. Ring J. Handbook of Atopic Eczema. Berlin/Heidelberg/New York:
39. Saraswat A, Ratho RK, Kumar B. Two unusual cases of Kaposi's Springer; 2006.
varicelliform eruption. Acta Derm Venereol 2002;82(2):138-139. 63. Swart RN, Vermeer BJ, van Der Meer JW, Enschede FA, Versteeg
40. Kucukyilmaz I, Alpsoy E, Yazar S. Kaposi's varicelliform erup- J. Treatment of eczema herpeticum with acyclovir. Arch Dermatol
tion in association with rosacea. J Am Acad Dermatol 2004;51(5 1983;119(1):13-16.
Suppl):S169-S172. 64. Hinz T, Zaccaro D, Byron M, et al. Atopic dermo-respiratory syn-
41. Manders SM, Chetty BV. Eczema herpeticum occurring in auto- drome is a correlate of eczema herpeticum. Allergy 2011;66(7):
grafted skin. J Am Acad Dermatol 1991;24(3):509-510. 925-933.
10 | TRAIDL et al.
65. Okamoto M, Takahagi S, Tanaka A, Ogawa A, Nobuki H, Hide M. 86. Howell MD, Kim BE, Gao P, et al. Cytokine modulation of atopic
A case of Kaposi varicelliform eruption progressing to herpes dermatitis filaggrin skin expression. J Allergy Clin Immunol
simplex virus hepatitis in an immunocompetent patient. Clin Exp 2007;120(1):150-155.
Dermatol 2018;43(5):636-638. 87. Gao PS, Rafaels NM, Hand T, et al. Filaggrin mutations that confer
66. Yeh TC, Lin YK, Chiu WY, Tzeng NS, Lin TY. Kaposi's varicelli- risk of atopic dermatitis confer greater risk for eczema herpeticum.
form eruption in herpes simplex encephalitis. Intern Emerg Med J Allergy Clin Immunol. 2009;124:507-513.
2016;11(6):885-887. 88. Kim BE, Bin L, Ye YM, Ramamoorthy P, Leung DY. IL-25 enhances
67. Gurvits GE, Nord JA. Eczema herpeticum in pregnancy. Dermatol HSV-1 replication by inhibiting filaggrin expression, and acts syn-
Reports 2011;3(2):e32. ergistically with Th2 cytokines to enhance HSV-1 replication. J
68. Hata S. Recurrent eczema herpeticum in an adult. J Dermatol Invest Dermatol 2013;133(12):2678-2685.
1985;12(4):372-374. 89. De Benedetto A, Slifka MK, Rafaels NM, et al. Reductions
69. Seegräber M, Worm M, Werfel T, et al. Recurrent eczema herpe- in claudin- 1 may enhance susceptibility to herpes simplex
ticum -a retrospective European multicenter study evaluating the virus 1 infections in atopic dermatitis. J Allergy Clin Immunol
clinical characteristics of eczema herpeticum cases in atopic derma- 2011;128(1):242-246.e5.
titis patients. J Eur Acad Dermatol Venereol 2019;34(5):1074-1079. 90. Raychaudhuri SP, Raychaudhuri SK. Revisit to Kaposi's varicelli-
70. Wheeler CE Jr, Abele DC. Eczema herpeticum, primary and recur- form eruption: role of IL-4. Int J Dermatol 1995;34(12):854-856.
rent. Arch Dermatol 1966;93(2):162-173. 91. Ikemoto K, Pollard RB, Fukumoto T, Morimatsu M, Suzuki F. Small
71. Bork K, Brauninger W. Increasing incidence of eczema her- amounts of exogenous IL-4 increase the severity of encephalitis
peticum: analysis of seventy- five cases. J Am Acad Dermatol induced in mice by the intranasal infection of herpes simplex virus
1988;19(6):1024-1029. type 1. J Immunol 1995;155(3):1326-1333.
72. Wollenberg A, Zoch C, Wetzel S, Plewig G, Przybilla B. Predisposing 92. Chen H, Sun H, You F, et al. Activation of STAT6 by STING is critical
factors and clinical features of eczema herpeticum: a retrospective for antiviral innate immunity. Cell 2011;147(2):436-4 46.
analysis of 100 cases. J Am Acad Dermatol 2003;49(2):198-205. 93. Howell MD, Gallo RL, Boguniewicz M, et al. Cytokine milieu of
73. Wutzler P, Sauerbrei A, Sprossig M, Hadlich J, Ulbricht A, Thiel KD. atopic dermatitis skin subverts the innate immune response to
Clinical and virological studies of eczema herpeticum. Dermatol vaccinia virus. Immunity 2006;24(3):341-3 48.
Monatsschr 1985;171(4):222-229. 94. Howell MD, Gao P, Kim BE, et al. The signal transducer and ac-
74. Peng WM, Jenneck C, Bussmann C, et al. Risk factors of atopic tivator of transcription 6 gene (STAT6) increases the propensity
dermatitis patients for eczema herpeticum. J Invest Dermatol of patients with atopic dermatitis toward disseminated viral skin
2007;127(5):1261-1263. infections. J Allergy Clin Immunol 2011;128(5):1006-1014.
75. Lübbe J, Pournaras CC, Saurat JH. Eczema herpeticum during 95. Boorgula MP, Taub MA, Rafaels N, et al. Replicated methylation
treatment of atopic dermatitis with 0.1% tacrolimus ointment. changes associated with eczema herpeticum and allergic response.
Dermatology 2000;201(3):249-251. Clin Epigenetics. 2019;11(1).
76. Reitamo S, Rustin M, Ruzicka T, et al. Efficacy and safety of tac- 96. Traidl S, Kienlin P, Begemann G, et al. Patients with atopic der-
rolimus ointment compared with that of hydrocortisone butyrate matitis and history of eczema herpeticum elicit herpes simplex
ointment in adult patients with atopic dermatitis. J Allergy Clin virus-specific type 2 immune responses. J Allergy Clin Immunol
Immunol 2002;109(3):547-555. 2018;141(3):1144-1147.e5.
77. Rerinck HC, Kamann S, Wollenberg A. Eczema herpeticum: 97. Takahashi R, Sato Y, Kurata M, Yamazaki Y, Kimishima M,
Pathogenesis and therapy. Hautarzt 2006;57(7):586-591. Shiohara T. Pathological role of regulatory T cells in the initia-
78. LeGoff J, Péré H, Bélec L. Diagnosis of genital herpes simplex virus tion and maintenance of eczema herpeticum lesions. J Immunol
infection in the clinical laboratory. Virol J. 2014;11(1):11-83. 2014;192(3):969-978.
79. Marshall DS, Linfert DR, Draghi A, McCarter YS, Tsongalis GJ. 98. Leib DA, Harrison TE, Laslo KM, Machalek MA, Moorman NJ, Virgin
Identification of herpes simplex virus genital infection: compari- HW. Interferons regulate the phenotype of wild-t ype and mutant
son of a multiplex PCR assay and traditional viral isolation tech- herpes simplex viruses in vivo. J Exp Med 1999;189(4):663-672.
niques. Mod Pathol 2001;14(3):152-156. 99. Pasieka TJ, Cilloniz C, Lu B, et al. Host responses to wild-t ype and
80. Korting HC, Abeck D, Schmoeckel C. Comparative evaluation of attenuated herpes simplex virus infection in the absence of Stat1.
herpes virus detection using fluorescence-labeled monoclonal an- J Virol 2009;83(5):2075-2087.
tibodies and electron microscopy negative contrast technic in der- 100. Gao LI, Bin L, Rafaels NM, et al. Targeted deep sequencing identi-
matovenereologic diseases. Results of a pilot study of 30 patients. fies rare loss-of-function variants in IFNGR1 for risk of atopic der-
Hautarzt 1987;38(12):723-726. matitis complicated by eczema herpeticum. J Allergy Clin Immunol
81. Mathes EF, Oza V, Frieden IJ, et al. "Eczema coxsackium" and un- 2015;136(6):1591-1600.
usual cutaneous findings in an enterovirus outbreak. Pediatrics 101. Bin L, Edwards MG, Heiser R, et al. Identification of novel gene sig-
2013;132(1):e149-e157. natures in patients with atopic dermatitis complicated by eczema
82. Irvine AD, McLean WH, Leung DY. Filaggrin mutations as- herpeticum. J Allergy Clin Immunol 2014;134(4):848-855.
sociated with skin and allergic diseases. N Engl J Med 102. Bin L, Li X, Richers B, et al. Ankyrin repeat domain 1 regulates innate
2011;365(14):1315-1327. immune responses against herpes simplex virus 1: a potential role
83. van den Oord RA, Sheikh A. Filaggrin gene defects and risk of de- in eczema herpeticum. J Allergy Clin Immunol 2018;141(6):2085-
veloping allergic sensitisation and allergic disorders: systematic 2093.e1.
review and meta-analysis. BMJ 2009;339:b2433. 103. Gao P-S, Leung DYM, Rafaels NM, et al. Genetic variants in in-
84. Leung DY, Gao PS, Grigoryev DN, et al. Human atopic der- terferon regulatory factor 2 (IRF2) are associated with atopic der-
matitis complicated by eczema herpeticum is associated with matitis and eczema herpeticum. J Invest Dermatol 2012;132(3 Pt
abnormalities in IFN- gamma response. J Allergy Clin Immunol 1):650-657.
2011;127(4):965-973.e1-5. 104. Mathias RA, Weinberg A, Boguniewicz M, et al. Atopic dermati-
85. Henderson J, Northstone K, Lee SP, et al. The burden of disease as- tis complicated by eczema herpeticum is associated with HLA B7
sociated with filaggrin mutations: a population-based, longitudinal and reduced interferon-?-producing CD8+ T cells. Br J Dermatol
birth cohort study. J Allergy Clin Immunol 2008;121(4):872-877.e9. 2013;169(3):700-703.
TRAIDL et al. | 11
105. Wollenberg A, Günther S, Moderer M, et al. Plasmacytoid den- 124. Bechman K, Subesinghe S, Norton S, et al. A systematic review
dritic cells: a new cutaneous dendritic cell subset with dis- and meta- a nalysis of infection risk with small molecule JAK
tinct role in inflammatory skin diseases. J Invest Dermatol inhibitors in rheumatoid arthritis. Rheumatology 2019;58(10):
2002;119(5):1096-1102. 1755-1766.
106. Staudacher A, Hinz T, Novak N, von Bubnoff D, Bieber T. 125. Curtis JR, Xie F, Yang S, et al. Risk for herpes zoster in tofacitinib-
Exaggerated IDO1 expression and activity in Langerhans cells treated rheumatoid arthritis patients with and without con-
from patients with atopic dermatitis upon viral stimulation: a po- comitant methotrexate and glucocorticoids. Arthritis Care Res
tential predictive biomarker for high risk of Eczema herpeticum. 2019;71(9):1249-1254.
Allergy 2015;70(11):1432-1439. 126. Curtis JR, Xie F, Yun H, Bernatsky S, Winthrop KL. Real-world
107. Müller A, Heseler K, Schmidt SK, Spekker K, Mackenzie comparative risks of herpes virus infections in tofacitinib and
CR, Däubener W. The missing link between indoleamine biologic-treated patients with rheumatoid arthritis. Ann Rheum Dis
2,3-dioxygenase mediated antibacterial and immunoregulatory 2016;75(10):1843-1847.
effects. J Cell Mol Med 2009;13(6):1125-1135. 127. Guttman- Yassky E, Silverberg JI, Nemoto O, et al. Baricitinib
108. Harder J, Bartels J, Christophers E, Schroder JM. A peptide antibi- in adult patients with moderate- to-
severe atopic dermatitis: a
otic from human skin. Nature 1997;387(6636):861. phase 2 parallel, double-blinded, randomized placebo-controlled
109. Ong PY, Ohtake T, Brandt C, et al. Endogenous antimicrobial multiple-dose study. J Am Acad Dermatol 2019;80(4):913-921.e9.
peptides and skin infections in atopic dermatitis. N Engl J Med 128. Guttman- Yassky E, Thaçi D, Pangan AL, et al. Upadacitinib in
2002;347(15):1151-1160. adults with moderate to severe atopic dermatitis: 16-week results
110. Howell M, Wollenberg A, Gallo R, et al. Cathelicidin deficiency from a randomized, placebo-controlled trial. J Allergy Clin Immunol
predisposes to eczema herpeticum. J Allergy Clin Immunol 2020;145(3):877-884.
2006;117(4):836-8 41. 129. Gooderham MJ, Forman SB, Bissonnette R, et al. Efficacy and
111. Gao PS, Rafaels NM, Mu D, et al. Genetic variants in TSLP are as- safety of oral janus kinase 1 inhibitor abrocitinib for patients
sociated with atopic dermatitis and eczema herpeticum. J Allergy with atopic dermatitis: a phase 2 randomized clinical trial. JAMA
Clin Immunol 2010;125(6):1403-1407.e4. Dermatol 2019;155(12):1371-1379.
112. Kawakami Y, Ando T, Lee J-R , et al. Defective natural killer cell 130. Silverberg JI, Simpson EL. Association between obesity and ec-
activity in a mouse model of eczema herpeticum. J Allergy Clin zema prevalence, severity and poorer health in US adolescents.
Immunol 2017;139(3):997-1006.e10. Dermatitis 2014;25(4):172-181.
113. Schreiber A, Rösner L, Begemann G, et al. Cytotoxic immune re- 131. Simpson EL, Lacour J, Spelman L, et al. Baricitinib in patients with
sponse of CD8+ T cells and NK cells in patients suffering from moderate-to-severe atopic dermatitis and inadequate response to
atopic dermatitis with a history of eczema herpeticum. Allergo J topical corticosteroids: results from two randomized monother-
2018;27(51):58. apy phase III trials. Br J Dermatol. 2020;183(2):242-255.
114. Cabanillas B, Weighardt H, Izquierdo E, Forster I, Novak N. 132. Geraghty RJ, Jogger CR, Spear PG. Cellular expression of alpha-
IgE reactivity against herpes simplex virus 1 in patients with herpesvirus gD interferes with entry of homologous and heter-
atopic dermatitis complicated by eczema herpeticum. Allergy ologous alphaherpesviruses by blocking access to a shared gD
2020;75(1):226-229. receptor. Virology 2000;268(1):147-158.
115. Mikolajczyk R, Roesner LM. General aspects regarding the skin 133. Belshe RB, Leone PA, Bernstein DI, et al. Efficacy results of a trial
microbiome. Hautarzt 2019;70(6):400-4 06. of a herpes simplex vaccine. N Engl J Med 2012;366(1):34-43.
116. Reiger M, Schwierzeck V, Traidl-Hoffmann C. Atopic eczema and 134. Bernstein DI, Pullum DA, Cardin RD, Bravo FJ, Dixon DA,
microbiome. Hautarzt 2019;70(6):407-415. Kousoulas KG. The HSV-1 live attenuated VC2 vaccine provides
117. Bin L, Kim BE, Brauweiler A, et al. Staphylococcus aureus alpha- protection against HSV-2 genital infection in the guinea pig model
toxin modulates skin host response to viral infection. J Allergy Clin of genital herpes. Vaccine 2019;37(1):61-68.
Immunol 2012;130(3):683-691.e2. 135. Simpson EL, Bieber T, Guttman-Yassky E, et al. Two phase 3 tri-
118. Yoshida M, Umene K. Close association of predominant genotype als of dupilumab versus placebo in atopic dermatitis. N Engl J Med
of herpes simplex virus type 1 with eczema herpeticum analyzed 2016;375(24):2335-2348.
using restriction fragment length polymorphism of polymerase 136. Dekio I, Chinuki Y, Furumura M, Morita E. Recurrent Kaposi's var-
chain reaction. J Virol Methods 2003;109(1):11-16. icelliform eruption successfully controlled by low-dose oral valac-
119. Umene K, Yoshida M, Sakaoka H. Comparison of the association iclovir. J Dermatol 2012;39(2):197-199.
with eczema herpeticum in the two predominant genotypes of 137. Lee GH, Kim YM, Lee SY, Lee JS, Park YL, Whang KU. A case of
herpes simplex virus type 1. J Med Virol 1996;49(4):329-332. eczema herpeticum with hailey- hailey disease. Ann Dermatol
120. Schaeffer HJ, Beauchamp L, de Miranda P, Elion GB, Bauer DJ, 2009;21(3):311-314.
Collins P. 9-(2-Hydroxyethoxymethyl) guanine activity against vi-
ruses of the herpes group. Nature 1978;272(5654):583-585.
121. Wood AJJ, Whitley RJ, Gnann JW. Acyclovir: a decade later. N Engl
How to cite this article: Traidl S, Roesner L, Zeitvogel J,
J Med 1992;327(11):782-789.
Werfel T. Eczema herpeticum in atopic dermatitis. Allergy.
122. Frobert E, Burrel S, Ducastelle-Lepretre S, et al. Resistance of her-
pes simplex viruses to acyclovir: an update from a ten-year survey 2021;00:1–11. https://doi.org/10.1111/all.14853
in France. Antiviral Res 2014;111:36-41.
123. He H, Guttman-Yassky E. JAK inhibitors for atopic dermatitis: an
update. Am J Clin Dermatol 2019;20(2):181-192.