Raster-scanning optoacoustic mesoscopy biomarkers for atopic dermatitis skin lesions.

Atopic dermatitis (AD) is the most common chronic inflammatory skin disease worldwide. Its severity is assessed using scores that rely on visual observation of the affected body surface area, the morphology of the lesions and subjective symptoms, like pruritus or insomnia. Ideally, such scores should be complemented by objective and accurate measurements of disease severity to standardize disease scoring in routine care and clinical trials. Recently, it was shown that raster-scanning optoacoustic mesoscopy (RSOM) can provide detailed three-dimensional images of skin inflammation processes that capture the most relevant features of their pathology. Moreover, precise RSOM biomarkers of inflammation have been identified for psoriasis. However, the objectivity and validity of such biomarkers in repeated measurements have not yet been assessed for AD. Here, we report the results of a study on the repeatability of RSOM inflammation biomarkers in AD to estimate their precision. Optoacoustic imaging analysis revealed morphological inflammation biomarkers with precision well beyond standard clinical severity metrics. Our findings suggest that optoacoustic mesoscopy may be a good choice for quantitative evaluations of AD that are inaccessible by other methods. This could potentially enable the optimization of disease scoring and drug development.

Increasing the COVID-19 immunization rate through allergy testing.

BACKGROUND: Vaccination of the population is required to combat the COVID-19 pandemic. Allergy testing could reduce anxiety towards COVID-19 vaccination and thereby may increase vaccination rate, however, its effectiveness remains unclear. METHODS: One hundred and thirty prospective real-life patients in need of but not daring to get vaccinated asked for allergy workup for COVID-19 vaccine hypersensitivity in 2021/2022. Characterization of patients, identification of anxieties, decrease of patient's anxiety levels, overall vaccination rate and adverse reactions after vaccination were assessed. RESULTS: Tested patients were characterized by being female (91.5%) and having a high rate of previous allergies (e.g. to food 55.4%, drugs 54.6%, or previous vaccinations 50%) and dermatological disease (29.2%) but not always had medical contraindications for COVID-19 vaccination. Sixty one patients (49.6%) were highly concerned (4-6, Likert scale 0-6) about vaccination and 47 (37.6%) expressed resolving thoughts about vaccinaion anaphylaxis (3-6, Likert scale 0-6). However only 35 patients (28.5%) were scared of getting COVID-19 within 2 months (4-6, Likert scale 0-6) and only 11 (9%) patients had high expectations of getting COVID-19 (4-6, Likert scale 0-6). Allergy testing significantly (p < 0.01 to p < 0.05 respectively) reduced the median anxiety of allergic symptoms following vaccination: dyspnoea (4.2-3.1), to faint (3.7-2.7), long-term consequences (3.6-2.2), pruritus (3.4-2.6), skin rash (3.3-2.6) and death (3.2-2.6). After allergy testing, most patients (108/122, 88.5%) let themselves be vaccinated within 60 days. Revaccinated patients with previous symptoms experienced a reduction of symptoms (p < 0.05) upon revaccination. CONCLUSIONS: Patients not daring to get vaccinated have more anxiety towards vaccination than to acquire COVID-19. For those, allergy testing excludes vaccine allergy, and is a tool to increase vaccination willingness and thereby helps to combat vaccination hesitancy.

[Optoacoustic imaging-Applications and advancements of innovative imaging techniques]. / Optoakustische Bildgebung ­ innovative Bildgebungsverfahren auf dem Vormarsch.

Optoacoustic imaging (OAB) has developed steadily in recent years. By means of partly pulsed light, in a wide variety of wavelengths, different colour carriers (chromophores) are excited to form sound waves. These in turn are detected by the newly developed systems and converted into three-dimensional images by means of various algorithms. The technique is characterised by a good ratio between contrast and penetration depth and can create macro-, meso- and microscopic images due to its scalability. Optoacoustic macroscopy broadly irradiates the area to be examined with laser light. This can produce images with a high penetration depth, but only with a moderate resolution. Clinically interesting fields of application are for example the results of sentinel lymph nodes (SLNs) examined ex vivo using macroscopic optoacoustics. Due to the ability of OAB to visualise melanin, the detection rate of metastases was superior to previous methods, but not to histology. The ability to visualise dermal and epidermal structures, especially vessels, with good resolution makes optoacoustic mesoscopy useful in the examination of inflammatory skin diseases and could contribute to the verification of the success of therapy, e.g., with biologics for psoriasis vulgaris or atopic eczema (AE), in the future. Optoacoustic microscopy, which has so far been limited mainly to preclinical in vivo research, could be used in the future to detect even finer vascular structures and their changes. The clinical possibilities of OAB seem to be of great benefit and continue to be the subject of intensive research.

ETFAD/EADV Eczema task force 2020 position paper on diagnosis and treatment of atopic dermatitis in adults and children.

Atopic dermatitis (AD) is a highly pruritic, chronic inflammatory skin disease. The diagnosis is made using evaluated clinical criteria. Disease activity and burden are best measured with a composite score, assessing both objective and subjective symptoms, such as SCORing Atopic Dermatitis (SCORAD). AD management must take into account clinical and pathogenic variabilities, the patient's age and also target flare prevention. Basic therapy includes hydrating and barrier-stabilizing topical treatment universally applied, as well as avoiding specific and unspecific provocation factors. Visible skin lesions are treated with anti-inflammatory topical agents such as corticosteroids and calcineurin inhibitors (tacrolimus and pimecrolimus), which are preferred in sensitive locations. Topical tacrolimus and some mid-potency corticosteroids are proven agents for proactive therapy, which is defined as the long-term intermittent anti-inflammatory therapy of frequently relapsing skin areas. Systemic anti-inflammatory or immunosuppressive treatment is a rapidly changing field requiring monitoring. Oral corticosteroids have a largely unfavourable benefit-risk ratio. The IL-4R-blocker dupilumab is a safe, effective and licensed, but expensive, treatment option with potential ocular side-effects. Other biologicals targeting key pathways in the atopic immune response, as well as different Janus kinase inhibitors, are among emerging treatment options. Dysbalanced microbial colonization and infection may induce disease exacerbation and can justify additional antimicrobial treatment. Systemic antihistamines (H1R-blockers) only have limited effects on AD-related itch and eczema lesions. Adjuvant therapy includes UV irradiation, preferably narrowband UVB or UVA1. Coal tar may be useful for atopic hand and foot eczema. Dietary recommendations should be patient-specific, and elimination diets should only be advised in case of proven food allergy. Allergen-specific immunotherapy to aeroallergens may be useful in selected cases. Psychosomatic counselling is recommended to address stress-induced exacerbations. Efficacy-proven 'Eczema school' educational programmes and therapeutic patient education are recommended for both children and adults.

Recurrent eczema herpeticum - a retrospective European multicenter study evaluating the clinical characteristics of eczema herpeticum cases in atopic dermatitis patients.

BACKGROUND: Eczema herpeticum (EH) is a disseminated viral infection of eczematous skin disease with the herpes simplex virus. Knowledge on clinical characteristics, risk factors and recurrent disease is limited. Our aim was to better define clinical characteristics and risk factors for EH and especially for recurrent EH. METHODS: A retrospective analysis of EH cases assessed the history, clinical signs, prior treatment and laboratory results using a predefined questionnaire. RESULTS: A total of 224 EH cases from eight European centres were included. Extrinsic AD was identified as risk factor for EH, and only one patient suffered from intrinsic AD. Early onset of AD was identified as risk factor for recurrent EH. Pretreatment with topical steroids, systemic steroids, topical calcineurin inhibitors or plain emollients reflected standard therapy. Many patients showed AD lesions without EH, but skin without AD lesions was never affected by herpetic lesions. CONCLUSION: Patients with clinically active, extrinsic AD are at risk of EH. Recurrent EH is associated with confounders of severe atopic distortion and requires active AD lesions for clinical manifestation. Recurrent eczema herpeticum mainly affects patients with early onset of AD.

European task force on atopic dermatitis position paper: treatment of parental atopic dermatitis during preconception, pregnancy and lactation period.

Atopic dermatitis (AD) is a common inflammatory skin disease that affects both children and adults, including a large number of adults of reproductive age. Several guidelines for the treatment of AD exist, yet specific recommendations for the treatment of pregnant or lactating women and for adults planning to have a child are often lacking. This position paper from the European Task force on Atopic Dermatitis (ETFAD) is based on up-to-date scientific literature on treating pregnant and lactating women as wells as adults with AD planning to have a child. It is based on the expert opinions of members of the ETFAD and on existing safety data on the proposed treatments, many of which are derived from patients with other inflammatory diseases or from transplantation medicine. For treating future parents, as well as pregnant and lactating women with AD, the use of topical treatments including moisturizers, topical corticosteroids, tacrolimus, antiseptics such as chlorhexidine, octenidine, potassium permanganate and sodium hypochlorite (bleach) is deemed to be safe. Ultraviolet (UV) therapy may also be used. Systemic treatment should be prescribed only after careful consideration. According to the opinion of the ETFAD, treatment should be restricted to systemic corticosteroids and cyclosporine A, and, in selected cases, azathioprine.

Variable response to low-dose naltrexone in patients with Darier disease: a case series.

BACKGROUND: Darier disease is a rare autosomal-dominant genodermatosis with a loss of function of a Ca2+ -ATPase pump (SERCA2-pump). Clinically, the disease is characterized by red-brown keratotic papules mainly in seborrhoeic areas and has only limited and unsatisfactory treatment options. Previously, low-dose naltrexone was described as a successful treatment option in Hailey-Hailey disease, a genodermatosis with a genetic mutation coding for a similar loss of function of a Ca2+ -ATPase pump (hSPCA1-pump). OBJECTIVE: To assess the efficacy of low-dose naltrexone as a treatment option in Darier disease. METHODS: Six patients with biopsy-proven Darier disease (four had severe, one had moderate and one mild clinical manifestations). The patients received off-label therapy with naltrexone [5 mg per os (p.o.)] and magnesium [200 mg p.o.]. Patients were followed up every 4 weeks for minimally 12 weeks. Upon clinical presentation, the disease severity and subjective pain and itch scores were assessed, and standardized photographs were obtained. RESULTS: The clinical response to naltrexone varied after 12 weeks. The four patients with severe Darier disease showed worsening after initial improvement during the first 4 weeks, whereas the two patients with a mild to moderate clinical manifestation clearly improved, showing almost full remission after 12 weeks with complete flattening of the keratotic papules. CONCLUSION: Low-dose naltrexone did not have an effect on severe Darier disease compared to Hailey-Hailey disease, but it was beneficial in mild to moderate forms of the disease. Further studies are needed to confirm these observations of variable responses.

[Pruritus in Germany-a Google search engine analysis]. / Pruritus in Deutschland ­ eine Google-Suchmaschinenanalyse.

BACKGROUND: Because affected persons often do not visit a doctor, the prevalence of chronic and acute pruritus in the general population is difficult to determine. OBJECTIVES: The aim of this study is to estimate the frequency and the most common locations of pruritus in German internet users, who-with 62.4 million persons-represent a large majority of the German population, by analysing the Google search volume. MATERIALS AND METHODS: Relevant keywords for the subject "pruritus" were identified and analysed using the Google AdWords Keyword Planner. The assessment period was January 2015 to December 2016. RESULTS: In total the Google AdWords Keyword Planner identified 701 keywords for the topic "Juckreiz" (German lay word for pruritus), resulting in 7,531,890 pruritus-related Google searches during the assessment period. Most common search terms were the German lay term for atopic eczema ("Neurodermitis", 23.7%), the German lay term for psoriasis ("Schuppenflechte", 17.8%) and "psoriasis" (13%). The German lay term for pruritus ("Juckreiz") was only the sixth most searched term (3%). Most searches (72%) focused on influencing factors for pruritus, especially on skin diseases and skin conditions. The most commonly searched location was pruritus on the whole body, followed by anal pruritus. Analysis of the temporal course showed a higher monthly search volume during winter. CONCLUSION: With its unconventional methodology, a Google search engine analysis, this study allows a rough estimation of the medical need of pruritus in the German general population, which seems to be higher than expected. Especially pruritus in the anal area was identified as an unmet medical need.

Non-invasive imaging in dermatology and the unique potential of raster-scan optoacoustic mesoscopy.

In recent years, several non-invasive imaging methods have been introduced to facilitate diagnostics and therapy monitoring in dermatology. The microscopic imaging methods are restricted in their penetration depth, while the mesoscopic methods probe deeper but provide only morphological, not functional, information. 'Raster-scan optoacoustic mesoscopy' (RSOM), an emerging new imaging technique, combines deep penetration with contrast based on light absorption, which provides morphological, molecular and functional information. Here, we compare the capabilities and limitations of currently available dermatological imaging methods and highlight the principles and unique abilities of RSOM. We illustrate the clinical potential of RSOM, in particular for non-invasive diagnosis and monitoring of inflammatory and oncological skin diseases.

Assessing nailfold microvascular structure with ultra-wideband raster-scan optoacoustic mesoscopy.

Nailfold capillaroscopy, based on bright-field microscopy, is widely used to diagnose systemic sclerosis (SSc). However it cannot reveal information about venules and arterioles lying deep under the nailfold, nor can it provide detailed data about surface microvasculature when the skin around the nail is thick. These limitations reflect the fact that capillaroscopy is based on microscopy methods whose penetration depth is restricted to about 200 µm. We investigated whether ultra-wideband raster-scan optoacoustic mesoscopy (UWB-RSOM) can resolve small capillaries of the nailfold in healthy volunteers and compared the optoacoustic data to conventional capillaroscopy examinations. We quantified UWB-RSOM-resolved capillary density and capillary diameter as features that relate to SSc biomarkers, and we obtained the first three-dimensional, in vivo images of the deeper arterioles and venules. These results establish the potential of UWB-RSOM for analyzing SSc-relevant markers.

Application of recombinant antigen 5 allergens from seven allergy-relevant Hymenoptera species in diagnostics.

BACKGROUND: Hymenoptera stings can cause severe anaphylaxis in untreated venom-allergic patients. A correct diagnosis regarding the relevant species for immunotherapy is often hampered by clinically irrelevant cross-reactivity. In vespid venom allergy, cross-reactivity between venoms of different species can be a diagnostic challenge. To address immunological IgE cross-reactivity on molecular level, seven recombinant antigens 5 of the most important Vespoidea groups were assessed by different diagnostic setups. METHODS: The antigens 5 of yellow jackets, hornets, European and American paper wasps, fire ants, white-faced hornets, and Polybia wasps were recombinantly produced in insect cells, immunologically and structurally characterized, and their sIgE reactivity assessed by ImmunoCAP, ELISA, cross-inhibition, and basophil activation test (BAT) in patients with yellow jacket or Polistes venom allergy of two European geographical areas. RESULTS: All recombinant allergens were correctly folded and structural models and patient reactivity profiles suggested the presence of conserved and unique B-cell epitopes. All antigens 5 showed extensive cross-reactivity in sIgE analyses, inhibition assays, and BAT. This cross-reactivity was more pronounced in ImmunoCAP measurements with venom extracts than in sIgE analyses with recombinant antigens 5. Dose-response curves with the allergens in BAT allowed a differentiated individual dissection of relevant sensitization. CONCLUSIONS: Due to extensive cross-reactivity in various diagnostic settings, antigens 5 are inappropriate markers for differential sIgE diagnostics in vespid venom allergy. However, the newly available antigens 5 from further vespid species and the combination of recombinant allergen-based sIgE measurements with BAT represents a practicable way to diagnose clinically relevant sensitization in vespid venom allergy.

Defining pollen exposure times for clinical trials of allergen immunotherapy for pollen-induced rhinoconjunctivitis - an EAACI position paper.

BACKGROUND: Clinical efficacy of pollen allergen immunotherapy (AIT) has been broadly documented in randomized controlled trials. The underlying clinical endpoints are analysed in seasonal time periods predefined based on the background pollen concentration. However, any validated or generally accepted definition from academia or regulatory authorities for this relevant pollen exposure intensity or period of time (season) is currently not available. Therefore, this Task Force initiative of the European Academy of Allergy and Clinical Immunology (EAACI) aimed to propose definitions based on expert consensus. METHODS: A Task Force of the Immunotherapy and Aerobiology and Pollution Interest Groups of the EAACI reviewed the literature on pollen exposure in the context of defining relevant time intervals for evaluation of efficacy in AIT trials. Underlying principles in measuring pollen exposure and associated methodological problems and limitations were considered to achieve a consensus. RESULTS: The Task Force achieved a comprehensive position in defining pollen exposure times for different pollen types. Definitions are presented for 'pollen season', 'high pollen season' (or 'peak pollen period') and 'high pollen days'. CONCLUSION: This EAACI position paper provides definitions of pollen exposures for different pollen types for use in AIT trials. Their validity as standards remains to be tested in future studies.