[DRESS as a rare differential diagnosis in eosinophilia, skin rash and acute hepatitis]. / DRESS als seltene Differentialdiagnose bei Eosinophilie, Hautexanthem und akuter Hepatitis.

A 21-year-old female patient presented with fever, pharyngitis, lymphadenopathy and generalized exanthema that had started 2 weeks prior. Allergies were not known, the family and travel history were negative. Due to depression, Duloxetine had been taken for 1.5 years, and due to bipolar disorder, a treatment with Lamotrigine was started four weeks prior but was stopped because of increased transaminase levels. Laboratory findings on admission showed eosinophilia (1.327 /nl), lymphocytosis and acute hepatitis (GOT 428 U/l, GPT 438 U/l) with deranged coagulation. Inflammatory parameters were increased. Ultrasound revealed hepatosplenomegaly with ascites. Acute viral or parasitic infection was excluded serologically. A skin biopsy showed a perivascular inflammatory infiltrate, compatible with a drug reaction. An inflammatory infiltrate was found in the liver biopsy, consistent with drug-induced hepatitis. Cough, dyspnea and pleural effusion occurred. In summary of the findings and with the help of the RegiSCAR-Score, the diagnosis of drug reaction with eosinophilia and systemic symptoms (DRESS) could be made. Under high-dose prednisolone therapy, a gradual decrease of transaminases and reconstitution of liver synthesis could be observed.In patients with eosinophilia, lymphadenopathy, acute hepatitis and generalized exanthema, DRESS is a rare but-due to its potentially life-threatening consequences-important differential diagnosis. The most important measure is to stop the suspected inducing medication immediately. Severe cases should be treated with high-dose systemic corticosteroids.

Loss-of-Function Myeloperoxidase Mutations Are Associated with Increased Neutrophil Counts and Pustular Skin Disease.

The identification of disease alleles underlying human autoinflammatory diseases can provide important insights into the mechanisms that maintain neutrophil homeostasis. Here, we focused our attention on generalized pustular psoriasis (GPP), a potentially life-threatening disorder presenting with cutaneous and systemic neutrophilia. Following the whole-exome sequencing of 19 unrelated affected individuals, we identified a subject harboring a homozygous splice-site mutation (c.2031-2A>C) in MPO. This encodes myeloperoxidase, an essential component of neutrophil azurophil granules. MPO screening in conditions phenotypically related to GPP uncovered further disease alleles in one subject with acral pustular psoriasis (c.2031-2A>C;c.2031-2A>C) and in two individuals with acute generalized exanthematous pustulosis (c.1705C>T;c.2031-2A>C and c.1552_1565del;c.1552_1565del). A subsequent analysis of UK Biobank data demonstrated that the c.2031-2A>C and c.1705C>T (p.Arg569Trp) disease alleles were also associated with increased neutrophil abundance in the general population (p = 5.1 × 10-6 and p = 3.6 × 10-5, respectively). The same applied to three further deleterious variants that had been genotyped in the cohort, with two alleles (c.995C>T [p.Ala332Val] and c.752T>C [p.Met251Thr]) yielding p values < 10-10. Finally, treatment of healthy neutrophils with an MPO inhibitor (4-Aminobenzoic acid hydrazide) increased cell viability and delayed apoptosis, highlighting a mechanism whereby MPO mutations affect granulocyte numbers. These findings identify MPO as a genetic determinant of pustular skin disease and neutrophil abundance. Given the recent interest in the development of MPO antagonists for the treatment of neurodegenerative disease, our results also suggest that the pro-inflammatory effects of these agents should be closely monitored.

Effects of dosage in new users of lamotrigine inducing epidermal necrolysis: Results of the German Registry of Severe Skin Reactions.

OBJECTIVE: This study was undertaken to determine the impact of dosage in new users of lamotrigine (LTG) and the concomitant intake of valproic acid (VPA) on epidermal necrolysis (EN). METHODS: A total of 102 EN cases with exposure to LTG were identified (1992-2018) in the German Registry of Severe Skin Reactions. All cases are validated by an independent expert committee. Six cases were excluded due to lack of exposure in the relevant time frame. Causality assessment was performed with ALDEN (Algorithm for Assessment of Drug Causality in EN) on definite/probable cases (≥12 years; n = 84). Evaluation of dosing regimen was restricted to cases with complete LTG dosing history (n = 74). RESULTS: Demography showed a mean age of 42.4 years, female predominance (69%), and low mortality (7.3%). Epilepsy was the indication for use in 87.5%. LTG was the very probable cause in 71.4% and probable cause in 28.6%. On average, one additional antiseizure medication was taken, most frequently VPA (43/84). Combined LTG/VPA treatment showed no statistically significant difference in morbidity or mortality. Mean time latency from initiation of LTG to reaction onset was 24.2 days, varying between 21 days with high initial dose and 29.2 days with low initial dose. Low initial LTG dose (n = 9) revealed higher mortality (22.2%) and higher severity (5/9) than high initial dose (n = 35, mortality = 14.3%, 14/35 higher severity). No patient died when the starting dose was as recommended. The highest mortality (25%) was found in patients with no dose increase (n = 8), which correlated with higher age. Despite the recommended or low initial dose, 52.7% of patients developed EN, in contrast to 39.2% with a slow, recommended, or no dose escalation. SIGNIFICANCE: Neither the initial dose, dose escalation, nor the combination with VPA seems to influence the general occurrence of EN. However, EN patients with the recommended starting dose and the recommended dose escalation had the best outcome in terms of clinical severity and mortality.

Epidermal necrolysis in the context of immuno-oncologic medication as well as kinase inhibitors and biologics.

BACKGROUND: Stevens-Johnson syndrome and toxic epidermal necrolysis are severe, primarily drug-induced reactions of skin and mucosa. Since they differ in the extent of skin detachment but not in etiology, they are grouped together as epidermal necrolysis (EN). Due to nationwide registration, representative data are available at the German Center for the Documentation of Severe Skin Reactions (dZh). Here, an increasing number of case notifications in the context with new immuno-oncologic drugs, kinase inhibitors and biologics have been observed. MATERIAL AND METHODS: Of 4,150 cases notifications between January 2003 and February 2019, 102 cases with exposure to these drug groups underwent systematic analysis, validation and causality assessment. RESULTS: Two cases of EN to vemurafenib were confirmed and one case to afatinib and pembrolizumab, respectively. In 14 EN cases other drugs - predominantly allopurinol or cotrimoxazole - were the causative agent. Fourteen cases were EN-like reactions: six bullous lichenoid drug eruptions (DE) to pembrolizumab (2), obinutuzumab, nivolumab, rituximab, infliximab/nivolumab, and eight multiforme-like DE to rituximab (2), adalimumab, ramucirumab, bevacizumab, vemurafenib, sorafenib (2). Lichenoid DE were differentiated from EN through histopathology and by the protracted course of EN, multiforme-like DE by variable skin manifestations with only sparse epidermolysis or mucosal involvement. CONCLUSIONS: A correct diagnosis is highly relevant in terms of prognosis and use of these drugs in malignoma treatment. Re-exposure is contraindicated in EN, but possible in other DE after rigorous risk-benefit evaluation.

Severe drug-induced skin reactions: clinical features, diagnosis, etiology, and therapy.

Drugs can induce severe skin reactions that differ in clinical presentation, prognosis, and therapy. The spectrum of these reactions not only includes bullous reactions such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and generalized bullous fixed drug eruption (GBFDE) but also acute generalized exanthematous pustulosis (AGEP) and drug reaction with eosinophilia and systemic symptoms (DRESS). If AGEP or DRESS is suspected, the diagnosis should be confirmed by thorough clinical examination, a skin biopsy, and specific laboratory tests. Crucial for the patient's prognosis, the causative agent should be rapidly identified and discontinued. It is therefore important to know the most frequent triggers of severe drug reactions, some of which may induce various reaction patterns. Depending on the clinical diagnosis, symptomatic and adequate supportive therapy, as well as systemic immunomodulatory treatments are used. The prognosis in SJS/TEN is often poor and depends on the patient's age and underlying conditions as well as the extent of skin detachment. The prognosis of GBFDE is somewhat better, but recurrences may lead to more severe disease manifestations. In DRESS, protracted and recurrent courses have been described, whereas AGEP usually resolves without problems.

Structure-activity analysis of the dermcidin-derived peptide DCD-1L, an anionic antimicrobial peptide present in human sweat.

Dermcidin encodes the anionic amphiphilic peptide DCD-1L, which displays a broad spectrum of antimicrobial activity under conditions resembling those in human sweat. Here, we have investigated its mode of antimicrobial activity. We found that DCD-1L interacts preferentially with negatively charged bacterial phospholipids with a helix axis that is aligned flat on a lipid bilayer surface. Upon interaction with lipid bilayers DCD-1L forms oligomeric complexes that are stabilized by Zn(2+). DCD-1L is able to form ion channels in the bacterial membrane, and we propose that Zn(2+)-induced self-assembly of DCD-1L upon interaction with bacterial lipid bilayers is a prerequisite for ion channel formation. These data allow us for the first time to propose a molecular model for the antimicrobial mechanism of a naturally processed human anionic peptide that is active under the harsh conditions present in human sweat.

Case report: Generalized bullous fixed drug eruption mimicking epidermal necrolysis.

Generalized bullous fixed drug eruption (GBFDE) is the most severe form of fixed drug eruption and can be misdiagnosed as epidermal necrolysis (EN). We report the case of a 42-year-old male patient presenting with more than 50% skin detachment without defined areas of exanthema or erythema and a history of one prior event of EN caused by acetaminophen (paracetamol), allopurinol, or amoxicillin 1.5 years ago. The initial diagnosis was GBFDE or EN. The histology of a skin biopsy was unable to distinguish between the two diseases. The course of the disease, the later clinical presentation, and the medical and medication history, however, were in favor of a diagnosis of GBFDE with two potentially culprit drugs: metamizole and ibuprofen. Moxifloxacin, enoxaparin sodium, hydromorphone, and insulin human were administered concomitantly, which makes them suspicious as well. Unfortunately, the patient received an additional dose of metamizole, one of the possible causative drugs, and he developed another bullous reaction within 1 month. This led to the diagnosis of GBFDE due to metamizole. This report highlights the challenges of distinguishing two rare diseases and elucidates the importance of distinct clinical presentation and detailed medication history.

Dermcidin-derived peptides show a different mode of action than the cathelicidin LL-37 against Staphylococcus aureus.

Dermcidin (DCD) is an antimicrobial peptide which is constitutively expressed in eccrine sweat glands. By postsecretory proteolytic processing in sweat, the DCD protein gives rise to anionic and cationic DCD peptides with a broad spectrum of antimicrobial activity. Many antimicrobial peptides induce membrane permeabilization as part of their killing mechanism, which is accompanied by a loss of the bacterial membrane potential. In this study we show that there is a time-dependent bactericidal activity of anionic and cationic DCD-derived peptides which is followed by bacterial membrane depolarization. However, DCD-derived peptides do not induce pore formation in the membranes of gram-negative and gram-positive bacteria. This is in contrast to the mode of action of the cathelicidin LL-37. Interestingly, LL-37 as well as DCD-derived peptides inhibit bacterial macromolecular synthesis, especially RNA and protein synthesis, without binding to microbial DNA or RNA. Binding studies with components of the cell envelope of gram-positive and gram-negative bacteria and with model membranes indicated that DCD-derived peptides bind to the bacterial envelope but show only a weak binding to lipopolysaccharide (LPS) from gram-negative bacteria or to peptidoglycan, lipoteichoic acid, and wall teichoic acid, isolated from Staphylococcus aureus. In contrast, LL-37 binds strongly in a dose-dependent fashion to these components. Altogether, these data indicate that the mode of action of DCD-derived peptides is different from that of the cathelicidin LL-37 and that components of the bacterial cell envelope play a role in the antimicrobial activity of DCD.

Fever in Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in Pediatric Cases: Laboratory Work-up and Antibiotic Therapy.

Fever is a symptom that often accompanies skin eruptions, especially in children. It can be a sign of an infectious condition presenting with exanthems or it may precede an exanthematous eruption. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe reactions affecting skin and mucosa with blisters and erosions. High fever occurs in these conditions, frequently before the skin and/or mucosa is affected.

Severe Drug Hypersensitivity Reactions: Clinical Pattern, Diagnosis, Etiology and Therapeutic Options.

Severe cutaneous adverse reactions (SCAR) are known for a high morbidity and mortality. They may be life-threatening for the affected patient and difficult to accomplish for the patient's family and the treating physician. Such conditions include not only bullous reactions like toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), but also acute generalized exanthematous pustulosis (AGEP) and drug reaction with eosinophilia and systemic symptoms (DRESS). Since clinical pattern, etiology, prognosis and treatment differ among these severe skin reactions, a clear diagnosis based on a comprehensive clinical examination, skin biopsy, and specific laboratory tests is necessary. Because most of these reactions are caused by drug intake, a thorough history of medication use has to be obtained. However, there are cases with an infectious or idiopathic cause. In any case it is crucial to identify the most likely cause and rapidly discontinue the inducing agent, if a drug cause is suspected. This is associated with the patient`s prognosis which is often poor for bullous reaction. In addition, patient's age, underlying conditions, and the extent of skin detachment play a major role in terms of prognosis. Severe cutaneous adverse reactions are T-cell-mediated reactions, and certain alleles of human leukocyte antigens (HLA) are involved in the activation of T-cells with cytotoxic effect. The therapeutic options depend on the clinical diagnosis. For all reactions a symptomatic and adequate supportive therapy is necessary, in some cases a systemic immunomodulating therapy can be useful.

Management of nonimmediate hypersensitivity reactions to drugs.

Nonimmediate hypersensitivity to drugs has a huge diversity of clinical presentations affecting exclusively or predominantly a single organ (most often the skin) or multiple organs. The latter is the rule with drug reaction with eosinophilia and systemic symptoms, and with drug-induced vasculitis. The management includes a dozen successive steps. Finally, the patient should be provided clear information on the suspected cause of the reaction, recommendations for follow-up after severe reactions associated with a risk of sequelae, and clear recommendations for future use of medications. Pharmacovigilance networks should be informed.

The role of antimicrobial peptides in human skin and in skin infectious diseases.

Antimicrobial peptides or proteins (AMPs) represent an ancient and efficient innate defense mechanism which protects interfaces from infection with pathogenic microorganisms. In human skin AMPs are produced mainly by keratinocytes, neutrophils, sebocytes or sweat glands and are either expressed constitutively or after an inflammatory stimulus. In several human skin diseases there is an inverse correlation between severity of the disease and the level of AMP production. Skin lesions of patients with atopic dermatitis show a diminished expression of the beta-defensins and the cathelicidin LL-37. Furthermore, these patients have a reduced amount of the AMP dermcidin in their sweat which correlates with an impaired innate defense of human skin in vivo. In addition, decreased levels of AMPs are associated with burns and chronic wounds. In contrast, overexpression of AMPs can lead to increased protection against skin infections as seen in patients with psoriasis and rosacea, inflammatory skin-diseases which rarely result in superinfection. In other skin diseases, e.g. in patients with acne vulgaris, increased levels of AMPs are often found in inflamed or infected skin areas indicating a role of these peptides in the protection from infection. These data indicate that AMPs have a therapeutical potential as topical anti-infectives in several skin diseases. The broad spectrum of antimicrobial activity, the low incidence of bacterial resistance and their function as immunomodulatory agents are attractive features of AMPs for their clinical use.