Human Papillomavirus-type distribution in anogenital lesions of prepubertal children.

BACKGROUND: In contrast to adults, only limited data are available on the human papillomavirus (HPV)-type spectrum in anogenital warts (AGW) of children. OBJECTIVE: This study aimed to evaluate the HPV-type spectrum in AGW of prepubertal children. MATERIALS & METHODS: In a retrospective German multicentre study, HPV genotyping was performed in AGW biopsies of 55 1- to 12-year-old children using HPV group-specific PCRs followed by hybridization with type-specific probes or sequence analysis. RESULTS: Human papillomavirus-DNA was found in 53 of the 55 AGW. In 58.5% (31/53) of the HPV-positive AGW, mucosal HPV types were detected. HPV6 (27/53, 50.9%) was the predominant type. 43.4% (23/53) of the lesions were induced by cutaneous HPV types (HPV2, HPV27, HPV57). Mucosal HPV types were significantly more common in children under 5 years of age than in children 5 years of age and older (22/25, 88.0% [95% CI: 70.0-95.8] vs. 9/28, 32.1% [95% CI: 17.9-50.7], P < 0.001). In contrast, cutaneous HPV types were significantly more prevalent in the 5- to 12-year age group (4/25, 16.0% [95% CI 6.4-34.7] vs. 19/28, 67.9% [95% CI 49.3-82.1], P < 0.001). CONCLUSION: Anogenital warts in 5- to 12-year-old children are frequently associated with cutaneous HPV types, possibly due to horizontal transmission. HPV typing, in addition to comprehensive clinical and psychosocial evaluation, can potentially help in the assessment of these cases.

PCR analysis is superior to histology for diagnosis of Whipple's disease mimicking seronegative rheumatic diseases.

OBJECTIVES: The diagnosis of Whipple's disease (WD) is commonly confirmed by histology demonstrating Periodic Acid Schiff (PAS)-positive macrophages in the duodenal mucosa. Analysis of intestinal tissue or other specimens using polymerase chain reaction (PCR) is a more sensitive method. However, the relevance of positive PCR findings is still controversial. Therefore, we evaluated the relevance of histology and PCR findings to establishing the diagnosis of WD in a series of WD patients initially presenting with suspected rheumatic diseases. METHOD: Between 2006 and 2014, 20 patients with seronegative rheumatic diseases tested positive for Tropheryma whipplei (Tw) by PCR and/or histology and were enrolled in a retrospective analysis of the diagnostic value of both procedures. RESULTS: Seven of the 20 cases (35%) were diagnosed with 'classic' WD as indicated by PAS-positive macrophages. In the remaining 13 patients, the presence of Tw was detected by intestinal (n = 10) or synovial PCR analysis (n = 3). Two of the 20 patients (10%) with evidence of Tw did not respond to antibiotic therapy. They were not considered to suffer from WD. Therefore, relying only on histological findings of intestinal biopsies would have missed 11 (61%) of the 18 patients with WD in our cohort. In comparison, PCR of intestinal biopsies detected Tw-DNA in 14 (93%) of the 15 WD patients evaluated. Patients with a positive histology did not differ from PCR-positive patients with regard to sex, age, or duration of disease, but more often presented with gastrointestinal symptoms. CONCLUSIONS: A substantial number of WD patients present without typical intestinal histology findings. Additional PCR analysis of intestinal tissue or synovial fluid increased the sensitivity of the diagnostic evaluation and should be considered particularly in patients presenting with atypical seronegative rheumatic diseases and a high-risk profile for WD.

[Lymphedema as initial manifestation of malignancy]. / Lymphödem als erstes Zeichen eines Malignoms.

Lymphedema may result from various benign or malignant causes. In particular rapidly progressing central or unilateral lymphedema (even in case of only discrete clinical findings) should initiate an extensive diagnostic workup to detect underlying malignancies in order to enable early therapy.

Photosensitive atopic dermatitis--a neglected subset: Clinical, laboratory, histological and photobiological workup.

BACKGROUND: Photosensitive atopic dermatitis (PhAD) is a scarcely reported entity characterized clinically by a photodistributed rash in patients who fulfil the criteria for atopic dermatitis (AD). OBJECTIVES: The aim of this retrospective study is to define significant clinical, laboratory and immunological parameters as well as photobiological features for diagnosing PhAD. METHODS: We conducted a single-centre retrospective analysis of 17 patients with long-standing AD who in the disease course suddenly developed photosensitivity. All patients with suspected PhAD treated in our department between 2009 and 2014 were included in the study. Diagnostic methods were immunological parameters, prick and patch testing, histology and phototesting procedures. RESULTS: Onset of photosensitivity was observed during spring, summer and during exposure to artificial UVR (Ultraviolet radiation) as part of the patients' treatment regimen. Symptoms appeared 31.5 months on average after AD diagnosis was established. Although the MED (Minimal erythematous dose) was normal compared to a control group, all patients tested with photoprovocation methods exhibited a positive reaction. Two types of reactions were observed: papular and eczematous reactions, both types having similar histology. The wavelength spectrum most commonly involved was UVA. The disease seems to affect women more often than men. Predilection sites included face, neck, exposed trunk areas and arms. Patients with PhAD had coexistent eczematous lesions in non-sun-exposed skin. IgE levels were elevated in 11/17 patients (65%), with a median value of 269 kU/L. CONCLUSION: PhAD is an underreported subset of atopic dermatitis, which is rarely diagnosed. This study suggests that several features including atopic diathesis, eczematous lesions in UVR exposed body regions and positive photoprovocation reaction are suggestive of PhAD as the likely diagnosis. Typically, the atopic eczema starts without a sign of photosensitivity, however, in a subgroup of AD patients after a few months to years, a switch occurs leading to PhAD.

State of the art: systemic rosacea management.

Based on numerous trials, oral tetracyclines and most commonly their second-generation derivative doxycycline have become the main pillar in systemic rosacea treatment. However, the only preparation that has been approved so far in this setting is 40 mg doxycycline in an anti-inflammatory dosage and with a modified release formulation. With the introduction of this once-daily, non-antibiotic dosing of doxycycline, oral therapy is more commonly prescribed as first-line treatment in moderate to severe papulopustular rosacea. In addition, topical and oral strategies are often used in combination due to the more substantial improvements compared to monotherapy. Although several other non-approved oral agents like macrolides, isotretinoin, and carvedilol have been evaluated for systemic treatment and showed promising results, yet the experience with these drugs in rosacea is limited, and thus they should be reserved for special situations.

Aktueller Stand der systemischen Rosazea-Therapie.

Basierend auf den Daten zahlreicher Studien sind orale Tetracycline - und hier insbesondere Doxycyclin als Tetracyclin der zweiten Generation - die Grundpfeiler der systemischen Rosazea-Therapie. Bisher ist dafür jedoch nur Doxycyclin 40 mg in antientzündlicher Dosierung mit veränderter Wirkstofffreisetzung zugelassen. Seit Einführung der Therapie mit Doxycyclin einmal täglich in nicht antibiotischer Dosierung wird die orale Therapie häufiger als Erstbehandlung bei mittelschwerer bis schwerer papulopustulöser Rosazea verschrieben. Oft wird diese Behandlung aufgrund der besseren Wirksamkeit im Vergleich zur Monotherapie auch mit einer topischen Behandlung kombiniert. Obwohl in der Systemtherapie weitere, nicht zugelassene Wirkstoffe wie Makrolide, Isotretinoin und Carvedilol mit viel versprechenden Ergebnissen untersucht wurden, ist die vorliegende Erfahrung bisher begrenzt, so dass diese Substanzen speziellen Situationen vorbehalten bleiben sollten.

Pathogenesis and clinical presentation of rosacea as a key for a symptom-oriented therapy.

Rosacea is a common chronic inflammatory skin disorder that typically occurs in adults and affects the face. Synonyms of rosacea include "acne rosacea", "couperose" and "facial erythrosis", in German also "Kupferfinne" and "Rotfinne". The disorder is characterised by a chronic and flaring course and is caused by a genetically predisposed, multifactorial process. A higher incidence is seen in people with fair skin and a positive family history. The characteristic rosacea symptoms manifest primarily, but not exclusively centrofacially, with forehead, nose, chin and cheeks significantly affected. Based on the various main symptoms a classification of the individual clinical pictures can be performed. However, a classification often does not reflect the clinical reality, since the various symptoms commonly coexist. The present review provides an introduction on pathogenesis and clinical manifestations of rosacea and prefers a symptom-oriented therapy approach.

Rosazea-Management: Update über allgemeine Maßnahmen und topische Therapieoptionen.

Obwohl bislang für die Rosazea keine kurative Therapie besteht, können verschiedene Optionen zur Behandlung der Symptome und zur Vorbeugung von Exazerbationen empfohlen werden. Neben Selbsthilfemaßnahme wie der Vermeidung von Triggerfaktoren und einer geeigneten Hautpflege sollte das Rosazea-Management bei Patienten mit erythematöser und leichter bis schwerer papulopustulöser Rosazea die Anwendung topischer Präparate als First-Line-Therapie umfassen. Da Überlappungen der charakteristischen Rosazea-Symptome im klinischen Alltag die Regel sind, sollte die medikamentöse Therapie auf die individuellen Symptome zugeschnitten werden; auch eine Kombinationstherapie kann erforderlich sein. Zu den für die Behandlung der Hauptsymptome der Rosazea zugelassenen Wirkstoffen gehören Brimonidin gegen das Erythem sowie Ivermectin, Metronidazol oder Azelainsäure gegen entzündliche Läsionen. Ihre Wirksamkeit wurde in zahlreichen validen, gut kontrollierten Studien belegt. Darüber hinaus existieren verschiedene nicht zugelassene topische Behandlungsmöglichkeiten, deren Wirksamkeit und Sicherheit noch in größeren, kontrollierten Studien zu untersuchen ist.

Pathogenese und Klinik der Rosazea als Schlüssel für eine symptomorientierte Therapie.

Rosazea ist eine häufige chronisch-entzündliche Hauterkrankung, die typischerweise bei Erwachsenen vorkommt und das Gesicht betrifft. Synonyme der Rosazea sind Acne rosacea, Kupferfinne, Rotfinne, Couperose und Rosacea. Die Erkrankung ist durch einen chronischen und schubartigen Verlauf gekennzeichnet und wird durch ein genetisch prädisponiertes, multifaktorielles Geschehen bedingt. Ein vermehrtes Auftreten wird bei hellem Hauttyp und positiver Familienanamnese verzeichnet. Die charakteristischen Rosazea-Symptome manifestieren sich vorwiegend, aber nicht ausschließlich zentrofazial, wobei Stirn, Nase, Kinn und die Wangen maßgeblich betroffen sind. Dabei werden unterschiedliche Hauptsymptome voneinander unterschieden, anhand derer eine Klassifikation der verschiedenen klinischen Bilder vorgenommen werden kann. Eine Klassifizierung wird oftmals jedoch nicht der klinischen Realität gerecht, da die verschiedenen Symptome häufig gemeinsam auftreten. Diese Übersichtarbeit führt in die Pathogenese und Klinik der Rosazea ein und plädiert für einen symptomorientierten Therapieansatz.

Rosacea Management: Update on general measures and topical treatment options.

Although there is presently no cure for rosacea, there are several recommended treatment options available to control many of the symptoms and to prevent them from getting worse. In addition to self-help measures like avoidance of trigger factors and proper skin care, rosacea management should include topical medications as one of the first-line choices for patients with erythematous and mild to severe papulopustular rosacea. Since mixed forms of characteristic rosacea symptoms are more common, medical treatment must be symptom-tailored for each individual case and will often involve a combination therapy. Approved topical agents for the major symptoms of rosacea encompass brimonidine for erythema and ivermectin, metronidazole or azelaic acid for inflammatory lesions, all of which have shown their efficacy in numerous valid, well-controlled trials. In addition, there are several other, not approved topical treatments which are possible options that require further validation in larger well-controlled studies.

Transient memory impairment and transient global amnesia induced by photodynamic therapy.

Photodynamic therapy (PDT) is a commonly used and effective treatment option for nonmelanoma skin cancer. Apart from local side-effects such as pain, oedema and erythema, no major adverse events occur in the majority of cases. Here we report on five patients who developed memory deficits such as transient global amnesia immediately after PDT for actinic keratosis. All PDT treatments were performed according to standard therapy protocols. The reported patients had a memory gap for the entire procedure, as well as for the consecutive emergency medical care. Other common neurological causes such as stroke or epileptic seizures were excluded. No focal neurological deficits were detectable. The symptoms had a fairly rapid onset following red-light illumination and were reversible without sequelae within 1-24 h. No correlation of the condition and pain during the illumination could be revealed. Magnetic resonance imaging of the brain revealed punctuated lesions in the hippocampus as a potential morphological correlate in one patient. The association between amnestic syndromes and PDT is novel and has not previously been reported. Even though PDT is considered a safe treatment modality, the possibility of neurological adverse events, albeit rare, should be kept in mind.

Brimonidine gel 0.33% rapidly improves patient-reported outcomes by controlling facial erythema of rosacea: a randomized, double-blind, vehicle-controlled study.

BACKGROUND: Facial redness contributes to impaired psychosocial functioning in rosacea patients and the only approved treatment for erythema is topical brimonidine gel 0.33%. OBJECTIVES: To evaluate patient-reported outcomes, as well as efficacy and safety, in subjects with self-perceived severe erythema treated with brimonidine gel 0.33% compared to vehicle. METHODS: An 8-day multicenter, randomized study comparing once-daily brimonidine gel 0.33% with vehicle gel using a facial redness questionnaire, subject satisfaction questionnaire and a patient diary of facial redness control to assess patient-reported outcomes. RESULTS: Of the 92 included subjects with self-perceived severe erythema, very few were satisfied with their appearance at baseline (4.2% brimonidine group, 0 vehicle group). On Day 8, significantly more brimonidine group subjects were satisfied with their facial appearance compared to vehicle group (36.9% vs. 21.5%; P < 0.05), with the overall treatment effect (69.6% vs. 40.4%; P < 0.01), and with the improvement in their facial redness (67.4% vs. 33.3%; P < 0.001). More brimonidine group subjects were able to control their facial redness daily (e.g. 83.0% vs. 38.9% on Day 1). On Day 8, significantly more brimonidine group subjects than vehicle group had at least a one-grade improvement from baseline in the Clinician Erythema Assessment score (71.7% vs. 35.7%; P = 0.0011) and Patient Self-Assessment score (76.1% vs. 47.6%; P = 0.004). More subjects in the brimonidine group (29.2%) reported treatment-related adverse events than in the vehicle group (15.9%) but most were mild and transient. CONCLUSIONS: Once-daily brimonidine gel 0.33% allowed patients to rapidly control their facial redness and significantly improved patient-reported outcomes in the treatment of persistent facial erythema of rosacea.

[Allergic contact eczema to a long-used cosmetic: Methylisothiazolinon, a type IV-allergen]. / Allergisches Kontaktekzem auf ein langjährig angewandtes Kosmetikum : Methylisothiazolinon als Typ-IV-Allergen.

Methylisothiazolinone was permitted in 2004 as preservative in rinse-off and leave-on products by the European cosmetics directive. This led to a dramatic increase in contact eczemas induced by MI in the past few years. Here, we report a patient who developed a spreading contact eczema of the face, neck and proximal arms mimicking a photodermatosis. The reaction was caused by use of a facial ointment that only recently started to contain MI. Type IV-sensitization to MI was verified by patch testing.

The autoimmune pathogenesis of multiple sclerosis.

One of the major goals of biomedical research is to reveal the pathomechanisms that lead to a disease on a level on which diagnostic criteria and causal therapies can be designed. The understanding and treatment of multiple sclerosis (MS) is still far from this goal, but exciting developments are on the way. MS is thought to be an autoimmune disease that is mediated by brain tissue-reactive lymphocytes, T cells and B cells, but so far these lymphocytes could not be reliably detected. This article highlights recent developments that permit the detection of autoreactive B cells in MS, the implications of this finding for early diagnosis of the disease, monitoring its activity, and eventually for gaining insight into the specific immune pathology that drives MS.

Photoperiodic effects on diapause-associated gene expression trajectories in European Leptinotarsa decemlineata populations.

Behavioural and physiological changes during diapause, an important strategy of insects for surviving harsh seasonal conditions, have been intensively studied. The genetic and molecular mechanisms underpinning diapause development are less well known. We took a candidate gene approach to study prediapause gene expression patterns in the Colorado potato beetle (Leptinotarsa decemlineata), an invasive insect that has rapidly spread northwards to high seasonality environments. Newly eclosed beetles originating from southern (Italy) and northern (Russia) Europe were reared under short- [12 h light (L):12 h dark (D)] and long-day (18L:6D) photoperiods for 10 days. This time period includes the sensitive period for the photoperiodic induction and initiation of diapause. Gene expression trajectories of 12 diapause-related genes (regulatory, metabolic and stress-resistance) were analysed from 0-, 5- and 10-day-old beetles. Gene expression differences increased with age, deviating significantly between populations and photoperiods in 10-day-old beetles. The gene expression profiles, particularly those related to energy metabolism and stress-resistance, indicate that beetles originating from Russia also prepare for diapause under the long-day photoperiod and show qualitative differences in the diapausing phenotype. Our study shows that population-dependent differences seen in behavioural and physiological traits connected with diapause in L. decemlineata are also evident in the expression trajectories of diapause-related genes.

Course and treatment of chronic hepatitis E virus infection in lung transplant recipients.

OBJECTIVE: Persistent hepatitis E virus (HEV) infections have been described in various transplant cohorts. However, the frequency and the course of HEV infection in lung transplant recipients (Lu-Tr) are not well defined. METHODS: We retrospectively analyzed serum from 95 Lu-Tr for HEV RNA and anti-HEV immunoglobulin-G (IgG) (with the MP assay). Anti-HEV seroprevalence was compared to that of 537 healthy individuals. Prospective HEV screening was subsequently initiated in Lu-Tr. RESULTS: Elevated liver enzymes were observed in 44/95 (46.3%) patients. Anti-HEV IgG was present in 5/95 patients (5.3%), revealing a slightly higher prevalence compared to controls (2%, 11/537; P = 0.07). Chronic HEV infection with detectable viral replication was confirmed by polymerase chain reaction in 3 (3.2%) patients, all of whom demonstrated clinical and biochemical features of active liver disease (maximum alanine aminotransferase [ALTmax ] 89, 215, and 270 IU/L, respectively). One patient had died from multi-organ failure in combination with liver cirrhosis before HEV diagnosis. Two additional patients with chronic hepatitis E were identified during prospective screening (ALTmax 359 and 318 IU/L). All patients still alive commenced ribavirin therapy for 5 months, with dose adjustment (400-600 mg/day) according to renal function and hemoglobin level. Sustained resolution of HEV infection occurred in 2 patients. One patient is still under treatment, and the fourth died from graft failure considered unrelated to ribavirin therapy. CONCLUSION: Chronic hepatitis E should be considered in the differential diagnosis of elevated liver enzymes, which are commonly seen in Lu-Tr. We observed 1 case of end-stage liver cirrhosis and death in an HEV-infected subject, who was not treated with ribavirin. Given this potentially devastating consequence, ribavirin therapy of persistent HEV infection appears to be acceptably safe and effective in Lu-Tr. However, larger prospective studies are warranted.

Long-term (6 and 12 months) follow-up of two prospective, randomized, controlled phase III trials of photodynamic therapy with BF-200 ALA and methyl aminolaevulinate for the treatment of actinic keratosis.

BACKGROUND: Two phase III trials of photodynamic therapy (PDT) with BF-200 ALA, a recently approved nanoemulsion formulation of 5-aminolaevulinic acid (ALA) demonstrated high clearance rates in mild-to-moderate actinic keratosis (AK). The comparison to a registered methyl aminolaevulinate (MAL) cream demonstrated significantly superior total patient clearance rates. OBJECTIVES: To evaluate long-term efficacy and safety of PDT for AK 6 and 12 months after the last PDT with BF-200 ALA, MAL or placebo. METHODS: The follow-up phase (FUP) was performed with patients of two phase III studies. Both studies compared BF-200 ALA with placebo, one of the studies additionally with MAL. Overall recurrence rates and various subgroups (light source, lesion severity, lesion location, complete responders after first PDT) were assessed 6 and 12 months after the last PDT. RESULTS: Recurrence rates were similar for BF-200 ALA and MAL, with a tendency to lower recurrence rates for BF-200 ALA. The proportion of patients who were fully cleared during PDT and remained completely clear for at least 12 months after PDT were 47% for BF-200 ALA (both studies) and 36% for MAL treatment. The subgroup that was illuminated with narrow wavelength LED lamps reached 69% and 53% for BF-200 ALA (both studies, respectively) and 41% for MAL. No safety concerns were reported. CONCLUSIONS: The FUP data confirmed the high efficacy and safety of PDT with BF-200 ALA. The slightly lower recurrence rates after BF-200 ALA treatment compared with MAL treatment enhanced the better treatment outcome due to the significantly superior efficacy.

[Phototherapy in the era of biologicals]. / Stellenwert der phototherapie im zeitalter der biologicals.

The development of biologicals had led to a dramatic change in the therapy of psoriasis, making necessary a re-evaluation of conventional therapeutic strategies. Four parameters must be evaluated: efficacy, economic burden, side effects and practicability. As for efficacy, according to published meta-analyses Infliximab reaches the efficiency of PUVA therapy, whereas the other biologicals, although being very effective, are inferior. Biologicals have a clear advantage in treating psoriatic arthritis. All published pharmacoeconomic studies demonstrate a significant advantage of phototherapy over biologicals. Severe and atypical (masked) infections, demyelinizing diseases, possible induction of lymphomas (not definitely established), and autoimmune phenomena are troublesome and feared side effects of biologicals. The risk of photocarcinogenesis after long-term use is the most significant side effect of phototherapy. However, considering the experience of 5 decades of good controlled clinical evaluation of phototherapy, this option has to be considered as safer than Biologicals. Looking at practicability, biologicals have undoubtedly a significant advantage compared to phototherapy.

[Rosacea: Clinical features and classification]. / Klinik und Klassifikation der Rosazea.

Rosacea is a frequent chronic dermatological disorder mainly affecting the face. Since it affects the appearance, it can be very distressing for the patient leading to psychosocial disturbances. Rosacea occurs in adults, peaking between 40 and 50 years of age. The course of rosacea is quite variable and the disease may stop at any stage. Generally, three main stages are differentiated: erythemato-teleangiectatic rosacea (rosacea stage I), papulopustular rosacea (rosacea stage II), hyperglandular-hypertrophic rosacea (rosacea stage III). Besides these main manifestations numerous special forms exist, which often lead to difficulties in the differential diagnoses and require specific therapeutic strategies. These include rosacea conglobata, rosacea fulminans, granulomatous rosacea, persisting edema, (Morbihan disease), gram negative rosacea, ocular rosacea, and steroid rosacea. Recently increasing numbers of patients have been observed, whose rosacea was were induced by inhibitors of epidermal growth factors (cetuximab, geftinib) used as chemotherapy in patients with different malignancies. These side effects have been described as acneiform eruptions but at least some of the described patients have a rosacea-like appearance; therefore, this form can be classified as a subset of drug induced rosacea.