Eczema Herpeticum Research Articles

Evaluation of Atopic Dermatitis and Cutaneous Infectious Disorders Using Sequential Pattern Mining: A Nationwide Population-Based Cohort Study

According to previous studies, the increased risk of cutaneous infectious disorders in patients with atopic dermatitis (AD) is related to impaired epidermal function, abnormal systemic immune function, and lower antimicrobial peptides. In this study, we analyzed the association between AD and cutaneous infectious disorders in the real world using sequential pattern mining (SPM). We analyzed National Health Insurance data from 2010–2013 using SPM to identify comorbid cutaneous infectious diseases and the onset durations of comorbidities. Patients with AD were at greater risk for molluscum contagiosum (adjusted odds ratio (aOR), 5.273), impetigo (aOR, 2.852), chickenpox (aOR, 2.251), otitis media (aOR, 1.748), eczema herpeticum (aOR, 1.292), and viral warts (aOR, 1.105). In SPM analysis, comorbidity of 1.06% shown in molluscum contagiosum was the highest value, and the duration of 77.42 days documented for molluscum contagiosum was the shortest onset duration among all the association rules. This study suggests that AD is associated with an increased risk of cutaneous infectious disorders. In particular, care should be taken regarding its high relevance with impetigo, molluscum contagiosum, and otitis media, which may help in preventing AD from worsening through appropriately preventing and managing the condition.

Extensive eczema herpeticum in a previously well child

BackgroundEczema herpeticum, also known as Kaposi varicelliform eruption, is a potentially life-threatening disseminated cutaneous viral infection. In the majority of cases, this condition develops as a complication in patients with atopic dermatitis. However, it may arise in a wide spectrum of pre-existing skin conditions, including psoriasis, seborrheic dermatitis, contact dermatitis, cutaneous T cell lymphoma, pemphigus vulgaris, and others.Case presentationWe present the case of a 2-year-old boy who was brought to the emergency department because of a high-grade fever and rash. The fever started 2 days before his presentation, and its maximum measurement was 39.6°C. The following day, the patient developed numerous painful, pruritic vesiculopustular eruptions, and oozing involving the lips, rendering the patient unable to tolerate oral feeding. The patient was seen by the dermatology team who diagnosed the child as having eczema herpeticum. The patient was commenced on antiviral and empirical antibiotic therapy in the form of intravenous acyclovir and cephalexin along with topical fusidic acid and panthenol. The patient showed clinical improvement with resolution of the fever and partial involution of the rash 2 days following the administration of the antimicrobial therapy.ConclusionEczema herpeticum is a rare clinical entity that can result in significant morbidity. The case highlights the importance of considering the diagnosis of eczema herpeticum in the appropriate clinical settings, even in patients who were not known to have any prior skin disorder.

An integrated analysis of herpes virus infections from eight randomized clinical studies of baricitinib in adults with moderate-to-severe atopic dermatitis.

Atopic dermatitis (AD) is associated with an increased risk for viral infections including those caused by herpes simplex virus and varicella zoster virus. This study examined treatment-emergent (TE) herpes simplex infection including eczema herpeticum (EH), and herpes zoster (HZ), in adult patients with AD receiving ≥1 dose of baricitinib (BARI), an oral selective inhibitor of Janus kinase 1/2. We evaluated data from six double-blinded, randomized, placebo-controlled (PC) trials and two long-term extension studies, within three analysis sets: PC, 2-4-mg BARI extended and All-BARI-AD. Frequency, incidence rate (IR)/100 person-years (PYs) and clinical characteristics of TE-herpes simplex, EH and HZ were reported. In the All-BARI-AD dataset (n = 2531; 2247 PYs), herpes simplex was reported in 8.9% of patients (n = 224; IR = 10.3). Most herpes simplex events were rated as mild or moderate (93.3%), rarely led to permanent discontinuation (2.2%) and presented mostly as oral/perioral herpes simplex (51.3%). TE-EH occurred at a low frequency (All-BARI-AD 1.7% n = 43; IR = 2.0) and were reported in 0.5%, 0.2% and 1.4% of patients receiving placebo, 2-mg or 4-mg BARI respectively. In the All-BARI-AD dataset, most events were investigator-rated as mild/moderate (79.1%), affected ≤2% of the body surface area (74.2%) and occurred as single events (88.4%). Serious TE-EH (n = 11) occurred exclusively in patients with poor disease control (vIGA-AD™ score ≥3) at infection onset. TE-HZ was reported in 2.1% of BARI patients (n = 53; IR = 2.3), without a dose relationship during the PC period (IR = 2.7 and IR = 0.0) or the extended dataset (IR = 3.7 and IR = 1.7) for 2- or 4-mg BARI respectively. TE-herpes simplex was common, while occurrence of EH was uncommon. Most events of EH were localized with involvement of a small BSA and were linked to poor disease control. Events of HZ were rare in the PC dataset and without a dose dependent increase in frequency.

Conditions That Simulate the Environment of Atopic Dermatitis Enhance Susceptibility of Human Keratinocytes to Vaccinia Virus.

Individuals with underlying chronic skin conditions, notably atopic dermatitis (AD), are disproportionately affected by infections from members of the herpesviridae, papovaviridae, and poxviridae families. Many patients with AD experience recurrent, widespread cutaneous viral infections that can lead to viremia, serious organ complications, and even death. Little is known about how the type 2 inflammatory environment observed in the skin of AD patients impacts the susceptibility of epidermal cells (keratinocytes) to viral pathogens. Herein, we studied the susceptibility of keratinocytes to the prototypical poxvirus, vaccinia virus (VV)—the causative agent of eczema vaccinatum—under conditions that simulate the epidermal environment observed in AD. Treatment of keratinocytes with type 2 cytokines (IL-4 and -13) to simulate the inflammatory environment or a tight junction disrupting peptide to mirror the barrier disruption observed in AD patients, resulted in a differentiation-dependent increase in susceptibility to VV. Furthermore, pan JAK inhibition was able to diminish the VV susceptibility occurring in keratinocytes exposed to type 2 cytokines. We propose that in AD, the increased viral susceptibility of keratinocytes leads to enhanced virus production in the skin, which contributes to the rampant dissemination and pathology seen within patients.

Signaling sphingolipids are biomarkers for atopic dermatitis prone to disseminated viral infections

Life-threatening viral diseases such as eczema herpeticum (EH) and eczema vaccinatum (EV) occur in <5% of individuals with atopic dermatitis (AD). The diagnosis of AD, however, excludes all individuals with AD from smallpox vaccination. We sought to identify circulatory and skin lipid biomarkers associated with EH and EV. Stratum corneum and plasma samples from 15 subjects with AD and a history of EH, 13 age- and gender-matched subjects with AD and without EH history, and 13 healthy nonatopic (NA) controls were analyzed by liquid chromatography tandem mass spectrometry for sphingolipid content. Sphingosine-1-phosphate (S1P) and ceramide levels were validated in plasma samples from the Atopic Dermatitis Vaccinia Network/Atopic Dermatitis Research Network repository (12 NA, 12 AD, 23 EH) and plasma from 7 subjects with EV and 7 matched subjects with AD. S1P lyase was downregulated in human primary keratinocytes to evaluate its effect on herpes simplex virus 1 (HSV-1) replication invitro. The stratum corneum of patients with EH demonstrated significantly higher levels of free sphingoid bases than those in patients who were NA, indicating enhanced sphingolipid turnover in keratinocytes (P< .05). Plasma from 2 independent cohorts of patients with EH had a significantly increased S1P/ceramide ratio in subjects with EH versus those with AD and or who were NA (P< .01). The S1P level in plasma from subjects with EV was twice the level in plasma from subjects with AD (mean= 1,533 vs 732 pmol/mL; P< .001). Downregulation of S1P lyase expression with silencing RNA led to an increased S1P level and doubled HSV-1 titer in keratinocytes. Our data point to long-term abnormalities in the S1P signaling system as a biomarker for previous disseminated viral diseases and a potential treatment target in recurring infections.

Classifying atopic dermatitis: a systematic review of phenotypes and associated characteristics.

Atopic dermatitis is a heterogeneous disease, accompanied by a wide variation in disease presentation and the potential to identify many phenotypes that may be relevant for prognosis and treatment. We aimed to systematically review previously reported phenotypes of atopic dermatitis and any characteristics associated with them. Ovid EMBASE, Ovid MEDLINE and Web of Science were searched from inception till 12 February 2021 for studies attempting to classify atopic dermatitis. Primary outcomes are atopic dermatitis phenotypes and characteristics associated with them in subsequent analyses. A secondary outcome is the methodological approach used to derive them. In total, 8511 records were found. By focussing only on certain clinical phenotypes, 186 studies were eligible for inclusion. The majority of studies were hospital‐based (59%, 109/186) and cross‐sectional (76%, 141/186). The number of included patients ranged from seven to 526 808. Data‐driven approaches to identify phenotypes were only used in a minority of studies (7%, 13/186). Ninety‐one studies (49%) investigated a phenotype based on disease severity. A phenotype based on disease trajectory, morphology and eczema herpeticum was investigated in 56 (30%), 22 (12%) and 11 (6%) studies respectively. Thirty‐six studies (19%) investigated morphological characteristics in other phenotypes. Investigated associated characteristics differed between studies. In conclusion, we present an overview of phenotype definitions used in literature for severity, trajectory, morphology and eczema herpeticum, including associated characteristics. There is a lack of uniform and consistent use of atopic dermatitis phenotypes across studies.

Wearables and smart skin as new tools for clinical practice and research in dermatology

Wearables and smart skin as new tools for clinical practice and research in dermatology

Th1 regulatory events by infectious pathogens, herpes zoster and herpes simplex viruses: prospects for therapeutic options for atopic eczema.

Infections caused by viral and bacterial pathogens are typically perceived as harmful, such as in cases of herpes zoster and herpes simplex virus infections. However, clinical observation of an improvement in atopic skin lesions upon herpes virus infection has been noted, particularly at the site of varicella and Kaposi’s varicelliform eruption. Th1 immune cells and cytokines, mobilized and induced for protection against infectious pathogens, are expected to improve Th2 dominant atopic symptoms. This study focuses on Th1 immunoregulatory events mediated by infectious pathogens, particularly herpes viruses. Immunoregulatory events induced by herpes viruses may have a potential therapeutic value for treating atopic eczema.

Herpes Zoster Duplex Symmetricus along with Ramsay Hunt Syndrome in an Acute Abdomen

Herpes zoster (HZ) duplex symmetricus is an extremely rare variant of multidermatomal HZ where there is the involvement of bilaterally symmetrical dermatomes. This generally occurs in immuno-compromised individuals and is unusual in immunocompetent host. When occurring over the face, it can be associated with Ramsay Hunt syndrome. Bilateral symmetrical lesions present a unique diagnostic dilemma owing to morphological similarities with Eczema Herpeticum and rarely enteroviral infections. In such cases, correct interpretation of serological tests helps in the diagnosis of the condition. Here, we present the case of HZ duplex symmetricus occurring in an immune-competent individual over bilateral V1 3 and C4 dermatome (left) along with facial palsy.

Eczema herpeticum subsequent to septic shock in early pregnancy: a first case report

BackgroundEczema herpeticum (EH) is a severe skin complication caused by human simplex virus (HSV) infection concomitant with immune dysfunction and dermatological conditions, mainly atopic dermatitis. We present the first case of EH subsequent to sepsis-related immunological suppression in pregnancy.Case presentationSeptic shock developed in a 30-year-old primiparous woman at 14 weeks of pregnancy during admission for hyperemesis gravidarum. Although her life-threatening status due to sepsis improved by prompt treatment, on day 3 of treatment in the intensive care unit, blisters suddenly erupted on her face and neck and spread over her body. EH was diagnosed according to HSV type-1 antigen positivity and a past medical history of EH and atopic dermatitis. Antiviral agents were administered immediately, with positive results. Her general condition improved quickly, without central nervous system defects. This is the first report of EH following septic shock in early pregnancy. At present, we speculate that EH develops as a complication due to immunological changes in the late phase of sepsis because sepsis is mainly characterized by both an inflammatory state in the acute phase and an immunosuppressive state in the late phase. Pregnancy can also contribute to its pathogenesis, as it causes an immunosuppressive state. Mortality due to EH is relatively high; in this case, a history of EH and atopic dermatitis contributed to the initiation of prompt medical interventions for the former, with improvement in the patient’s severe condition. The combination of immunological changes in sepsis and pregnancy can cause HSV reactivation, resulting in EH recurrence.ConclusionsIn conclusion, if dermatological symptoms develop in a pregnant woman with a history of EH and/or atopic dermatitis treated for sepsis, EH should be suspected based not only on clinical features but also on immunological changes along with sepsis, and prompt medical interventions should be initiated.

Phototherapy for atopic eczema.

Phototherapy for atopic eczema.

122 Ex vivo infection of skin from atopic dermatitis patients reveals facilitated invasion of herpes simplex virus 1

During primary infection, herpes simplex virus 1 (HSV-1) enters human skin or mucosa and establishes lifelong latency in sensory neurons. The skin is normally well protected from invading pathogens as the epithelium forms effective barriers. How HSV-1 can overcome this barrier in vivo remains to be shown. One prominent example for successful HSV-1 skin invasion is eczema herpeticum, a disseminated HSV-1 infection and severe complication of atopic dermatitis (AD). In lesional skin of AD patients, the mechanical skin barrier consisting of the stratum corneum and tight junctions in the stratum granulosum is impaired.

Eczema Herpeticum in an Infant

A 3-month-old otherwise healthy girl with known eczema presented to the Department of Pediatrics with acute onset of a facial rash and fever of 39 °C. On examination, the infant was systemically well and stable hemodynamically. She had confluent areas of skin crusting and weeping over the entire face, with disseminated monomorphic, umbilicated, vesiculopapular lesions (Figure 1, A). Facial edema and cervical lymphadenopathy were also present. Despite therapy with oral cefaclor (30 mg/kg/d, 3 times daily) and cetirizine hydrochloride liquid drops (0.25 mg/kg/d, twice daily) for 3 consecutive days, eczema lesions worsened.

Safety considerations of systemic Janus kinase inhibitors in atopic dermatitis applications.

Janus kinase (JAK) inhibitors are emerging treatments for atopic dermatitis (AD). Due to this novel role as a therapeutic option for patients with AD, we aimed to review current evidence on the pathophysiology and the safety and adverse effects (AEs) of oral JAK inhibitors for the treatment of AD utilizing the key terms atopic dermatitis, JAK inhibitors, and adverse effect or event. Our study indicated that oral JAK inhibitors have a moderate safety profile for use in AD in several reviews and phase II or III clinical trials. Headaches, nausea, and nasopharyngitis are the most commonly reported systemic AEs. Furthermore, acne, herpes simplex, herpes zoster, and eczema herpeticum are the most commonly recorded dermatological AEs. Current evidence indicates JAK inhibitors may also have less association with some of the serious AEs, although there is potential for increased risk of asthma, acute pancreatitis, neutropenia, and thrombocytopenia. Whereas data remain limited for the long-term safety of JAK inhibitor use in patients with AD, many ongoing clinical trials have promising preliminary results.

Efficacy and Safety of Upadacitinib vs Dupilumab in Adults With Moderate-to-Severe Atopic Dermatitis

Atopic dermatitis (AD) is a chronic, recurrent, inflammatory skin disease with an unmet need for treatments that provide rapid and high levels of skin clearance and itch improvement. To assess the safety and efficacy of upadacitinib vs dupilumab in adults with moderate-to-severe AD. Heads Up was a 24-week, head-to-head, phase 3b, multicenter, randomized, double-blinded, double-dummy, active-controlled clinical trial comparing the safety and efficacy of upadacitinib with dupilumab among 692 adults with moderate-to-severe AD who were candidates for systemic therapy. The study was conducted from February 21, 2019, to December 9, 2020, at 129 centers located in 22 countries across Europe, North and South America, Oceania, and the Asia-Pacific region. Efficacy analyses were conducted in the intent-to-treat population. Patients were randomized 1:1 and treated with oral upadacitinib, 30 mg once daily, or subcutaneous dupilumab, 300 mg every other week. The primary end point was achievement of 75% improvement in the Eczema Area and Severity Index (EASI75) at week 16. Secondary end points were percentage change from baseline in the Worst Pruritus Numerical Rating Scale (NRS) (weekly average), proportion of patients achieving EASI100 and EASI90 at week 16, percentage change from baseline in Worst Pruritus NRS at week 4, proportion of patients achieving EASI75 at week 2, percentage change from baseline in Worst Pruritus NRS (weekly average) at week 1, and Worst Pruritus NRS (weekly average) improvement of 4 points or more at week 16. End points at week 24 included EASI75, EASI90, EASI100, and improvement of 4 points or more in Worst Pruritus NRS from baseline (weekly average). Safety was assessed as treatment-emergent adverse events in all patients receiving 1 or more dose of either drug. Of 924 patients screened, 348 (183 men [52.6%]; mean [SD] age, 36.6 [14.6] years) were randomized to receive upadacitinib and 344 were randomized to receive dupilumab (194 men [56.4%]; mean [SD] age, 36.9 [14.1] years); demographic and disease characteristics were balanced among treatment groups. At week 16, 247 patients receiving upadacitinib (71.0%) and 210 patients receiving dupilumab (61.1%) achieved EASI75 (P = .006). All ranked secondary end points also demonstrated the superiority of upadacitinib vs dupilumab, including improvement in Worst Pruritus NRS as early as week 1 (mean [SE], 31.4% [1.7%] vs 8.8% [1.8%]; P < .001), achievement of EASI75 as early as week 2 (152 [43.7%] vs 60 [17.4%]; P < .001), and achievement of EASI100 at week 16 (97 [27.9%] vs 26 [7.6%]; P < .001). Rates of serious infection, eczema herpeticum, herpes zoster, and laboratory-related adverse events were higher for patients who received upadacitinib, whereas rates of conjunctivitis and injection-site reactions were higher for patients who received dupilumab. During 16 weeks of treatment, upadacitinib demonstrated superior efficacy vs dupilumab in patients with moderate-to-severe AD, with no new safety signals. ClinicalTrials.gov Identifier: NCT03738397.

Ophthalmic Involvement in pediatric eczema herpeticum

Ophthalmic Involvement in pediatric eczema herpeticum

Staphylococcal TSST-1 Association with Eczema Herpeticum in Humans.

ABSTRACTAtopic dermatitis (AD) is a condition affecting 30 million persons in the United States. AD patients are heavily infected with Staphylococcus aureus on the skin. A particularly severe form of AD is eczema herpeticum (ADEH), where the patients’ AD is complicated by S. aureus and herpes simplex virus (HSV) infection. This study examined the S. aureus strains from 15 ADEH patients, provided blinded, and showed a high association of ADEH with strains that produce toxic shock syndrome toxin-1 (TSST-1; 73%) compared to 10% production by typical AD isolates from patients without EH and those from another unrelated condition, cystic fibrosis. The ADEH isolates produced the superantigens associated with TSS (TSST-1 and staphylococcal enterotoxins A, B, and C). This association may in part explain the potential severity of ADEH. We also examined the effect of TSST-1 and HSV-1 on human epithelial cells and keratinocytes. TSST-1 used CD40 as its receptor on epithelial cells, and HSV-1 either directly or indirectly interacted with CD40. The consequence of these interactions was chemokine production, which is capable of causing harmful inflammation, with epidermal/keratinocyte barrier disruption. Human epithelial cells treated first with TSST-1 and then HSV-1 resulted in enhanced chemokine production. Finally, we showed that TSST-1 modestly increased HSV-1 replication but did not increase viral plaque size. Our data suggest that ADEH is associated with production of the major TSS-associated superantigens, together with HSV reactivation. The superantigens plus HSV may damage the skin barrier by causing harmful inflammation, thereby leading to increased symptoms.IMPORTANCE Atopic dermatitis (eczema, AD) with concurrent herpes simplex virus infection (eczema herpeticum, ADEH) is a severe form of AD. We show that ADEH patients are colonized with Staphylococcus aureus that primarily produces the superantigen toxic shock syndrome toxin-1 (TSST-1); however, significantly but to a lesser extent the superantigens staphylococcal enterotoxins A, B, and C are also represented in ADEH. Our studies showed that TSST-1 uses the immune costimulatory molecule CD40 as its epithelial cell receptor. Herpes simplex virus (HSV) also interacted directly or indirectly with CD40 on epithelial cells. Treatment of epithelial cells with TSST-1 and then HSV-1 resulted in enhanced chemokine production. We propose that this combination of exposures (TSST-1 and then HSV) leads to opening of epithelial and skin barriers to facilitate potentially serious ADEH.

BI19: Eczema herpeticum in a patient with severe combined immunodeficiency

BI19: Eczema herpeticum in a patient with severe combined immunodeficiency

Eczema herpeticum in atopic dermatitis.

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases leading to pruritic skin lesions. A subset of AD patients exhibits a disseminated severe HSV infection called eczema herpeticum (EH) that can cause life-threatening complications. This review gives an overview of the clinical picture, and characteristics of the patients as well as the diagnosis and therapy of EH. A special focus lies on the pathophysiological hallmarks identified so far that predispose for EH. This aspect covers genetic aberrations, immunological changes, and environmental influences displaying 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 identified 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 patients treated with dupilumab. Further research is needed to identify and specifically target risk factors for EH in AD patients.

Herpes simplex virus 1 proteins can induce skin inflammation in an atopic dermatitis-like mouse model.

Herpes simplex virus type 1 (HSV-1) can induce in certain individuals with atopic dermatitis (AD) severe cutaneous infections that can spread throughout the entire body, a condition named as AD complicated by eczema herpeticum (ADEH). It has been recently found that ADEH patients can produce specific IgE against HSV-1 proteins, which may contribute to lower protection against HSV-1. However, little is known about the capacity of these HSV-1 proteins to produce an inflammatory response at the skin level. In this study, using a mouse model of AD-like dermatitis, three HSV-1 proteins (glycoprotein D -gD-, glycoprotein B -gB- and VP22) were applied on tape-stripped back skin mice in three exposures periods. Ovalbumin (OVA) and 0.9% NaCl were used as positive and negative controls, respectively. Skin samples were obtained for analysis of specific cell components of skin infiltration. The results showed that the viral protein gD induced a statistically significant increase in the number of dermal infiltrating CD3+, CD4+ cells and mast cells compared with the negative control group. gD was also able to induce epidermal thickening and epidermal infiltration of T cells closely related to the one produced in mice sensitized with OVA. However, VP22 and gB contributed to a lesser extent to skin inflammation. These results showed that proteins from HSV-1, especially gD, can have per se an important T cell and mast cell-driven inflammatory potential at the skin level.