Acute Generalized Exanthematous Pustulosis: Clinical Characteristics, Pathogenesis, and Management.

BACKGROUND: Acute generalized exanthematous pustulosis (AGEP) is a potentially severe adverse cutaneous drug reaction, which typically occurs within 24-48 h after the intake of the culprit drug. SUMMARY: AGEP is characterized by numerous sterile subcorneal pustules on erythematous skin and in less than a third of cases it can be associated with organ manifestations possibly leading to life-threatening symptoms (e.g., cholestasis, nephritis, and lung and bone marrow involvement). In contrast to generalized pustular psoriasis, it can involve mucosal regions and typically resolves rapidly if the culprit drug is removed, and adequate therapy with topical or systemic steroids administered. Diagnosis based on patient history, clinical signs, and characteristic cutaneous histology is rarely challenging. Identification of the culprit drug may be aided by patch testing or lymphocyte transformation tests that are of limited value. KEY MESSAGES: Recent experimental data reviewed herein are supportive of an early role of drug-induced innate immune activation and innate cytokines such as interleukin (IL)-1, IL-36, and IL-17 in the pathogenesis of AGEP. This explains the rapid onset and neutrophilic character of the cutaneous inflammation, but also provides new avenues for in vitro tests aimed at better identifying the culprit drug.

Cutaneous lichenoid drug eruptions: A narrative review evaluating demographics, clinical features and culprit medications.

Cutaneous lichenoid drug eruptions (LDE) are adverse drug reactions (ADR) characterized by symmetric, erythematous, violaceous papules reminiscent but rarely fully characteristic of lichen planus (LP). We aimed to analyse the literature describing cases of LDE within the last 20 years to provide additional insight into culprit drugs, typical latency to onset of the eruption, the spectrum of clinical presentations, severity and management. A literature search was conducted in MEDLINE between January 2000 and 27 January 2021. The keywords 'lichenoid drug rash' and 'lichenoid drug eruption' were used. Cases were included if LDE diagnosis was made, and culprit drugs were identified. A total of 323 cases with LDE were identified from 163 published case reports and studies. The mean patient age was 58.5 years (1 month to 92 years), and 135 patients (41.8%) were female. Checkpoint inhibitors (CKI) were the most frequently reported culprit drugs (136 cases; 42.1%), followed by tyrosine kinase inhibitors (TKI) (39 cases; 12.0%) and anti-TNF-α-monoclonal antibodies (13 cases; 4.0%). The latency between initiation of the drug and manifestation was 15.7 weeks (range: 0.1-208 weeks). After discontinuing the culprit drug, the median time to resolution was 14.2 weeks (range: 0.71-416 weeks). One hundred thirty-six patients (42.1%) were treated with topical, and 54 patients (16.7%) with systemic glucocorticoids. Overall, we conclude that, albeit rare, LDE is challenging to diagnose ADR induced by mostly CKI, TKI, and biologics. Treatment modalities resemble that of lichen planus, and the culprit drugs had to be discontinued in only 26%, which is low compared with other types of adverse drug reactions. This is probably due to the low risk of aggravation (e.g. toxic epidermal necrolysis) if the drug is continued and the benefit/risk ratio favouring the drug, as is often the case in cancer therapy.

Contact allergy to the Dexcom G6 glucose monitoring system-Role of 2,2'-methylenebis(6-tert-butyl-4-methylphenol) monoacrylate in the new adhesive.

BACKGROUND: Skin reactions to the glucose monitoring systems Dexcom G5 and G6 have been rare. In 2019, the components of the adhesive were exchanged for better skin fixation. Since then, more and more patients experienced severe skin reactions. A few months ago, 2,2'-methylenebis(6-tert-butyl-4-methylphenol) monoacrylate (MBPA) was identified as a new component in the adhesive of the G6 model. Furthermore, it was suspected that isobornyl acrylate (IBOA) was also a component of the exchanged adhesive. OBJECTIVES: Our objective was to investigate if MBPA plays a major role in the increasing skin problems of patients without a history of IBOA-sensitization. Furthermore, our aim was to examine whether IBOA is contained in the newer model adhesive and may also contribute to allergic contact dermatitis (ACD). PATIENTS AND METHODS: Five patients with a newly occurred ACD caused by the glucose monitoring system Dexcom G6 were investigated. Patch testing including MBPA in three different concentrations, as well as IBOA, were performed. Gas chromatography-mass spectrometry of the newer system Dexcom G6 was carried out. RESULTS: All patients were shown to be sensitized to MBPA, while MBPA 0,5% showed the strongest reaction. On the other hand, IBOA was tested negative. CONCLUSION: In our study group, MBPA was observed to be the triggering allergen of the recently changed adhesive.

Environmental Mycobacterium avium subsp. hominissuis have a higher probability to act as a recipient in conjugation than clinical strains.

Mycobacterium avium subsp. hominissuis (MAH) is a widespread opportunistic pathogen that can be isolated from environment (dust, soil and water) and patients with lung or lymphnode infection. In our previous research we revealed the pronounced genetic diversity in MAH by identifying eight different types of a newly described genomic island. In order to identify mechanisms of such horizontal gene transfer we now analyzed the ability of 47 MAH isolates to inherit the conjugative plasmid pRAW from M. marinum. A higher percentage of environmental isolates (22.7%) compared to clinical isolates (8%) had the capacity to function as recipient in conjugal plasmid transfer. Genetic analysis showed additionally that environmental isolates contained more genes homologous to genes present on conjugative mycobacterial plasmids than clinical isolates. Comparative analysis of the genomes of the isolates pointed to a possible association between the ability to act as recipient in conjugation and the structure of a genomic region containing the radC gene and a type I restriction/modification system. Finally we found that uptake of pRAW decreased the resistance against various antibiotics.

Selected Ion Monitoring for Orbitrap-Based Metabolomics.

Orbitrap mass spectrometry in full scan mode enables the simultaneous detection of hundreds of metabolites and their isotope-labeled forms. Yet, sensitivity remains limiting for many metabolites, including low-concentration species, poor ionizers, and low-fractional-abundance isotope-labeled forms in isotope-tracing studies. Here, we explore selected ion monitoring (SIM) as a means of sensitivity enhancement. The analytes of interest are enriched in the orbitrap analyzer by using the quadrupole as a mass filter to select particular ions. In tissue extracts, SIM significantly enhances the detection of ions of low intensity, as indicated by improved signal-to-noise (S/N) ratios and measurement precision. In addition, SIM improves the accuracy of isotope-ratio measurements. SIM, however, must be deployed with care, as excessive accumulation in the orbitrap of similar m/z ions can lead, via space-charge effects, to decreased performance (signal loss, mass shift, and ion coalescence). Ion accumulation can be controlled by adjusting settings including injection time and target ion quantity. Overall, we suggest using a full scan to ensure broad metabolic coverage, in tandem with SIM, for the accurate quantitation of targeted low-intensity ions, and provide methods deploying this approach to enhance metabolome coverage.

Assessment of Treatment Approaches and Outcomes in Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: Insights From a Pan-European Multicenter Study.

IMPORTANCE: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe drug reactions associated with a high rate of mortality and morbidity. There is no consensus on the treatment strategy. OBJECTIVE: To explore treatment approaches across Europe and outcomes associated with the SJS/TEN disease course, as well as risk factors and culprit drugs. DESIGN, SETTING, AND PARTICIPANTS: A retrospective pan-European multicenter cohort study including 13 referral centers belonging to the ToxiTEN ERN-skin subgroup was conducted. A total of 212 adults with SJS/TEN were included between January 1, 2015, and December 31, 2019, and data were collected from a follow-up period of 6 weeks. MAIN OUTCOMES AND MEASURES: Risk factors for severe acute-phase complications (acute kidney failure, septicemia, and need for mechanical ventilation) and mortality 6 weeks following admission were evaluated using a multivariable-adjusted logistic regression model. One tool used in evaluation of severity was the Score of Toxic Epidermal Necrolysis (SCORTEN), which ranges from 0 to 7, with 7 the highest level of severity. RESULTS: Of 212 patients (134 of 211 [63.7%] women; mean [SD] age, 51.0 [19.3] years), the mean (SD) body surface area detachment was 27% (32.8%). In 176 (83.0%) patients, a culprit drug was identified. Antibiotics (21.2%), followed by anticonvulsants (18.9%), nonsteroidal anti-inflammatory drugs (11.8%), allopurinol (11.3%), and sulfonamides (10.4%), were the most common suspected agents. Treatment approaches ranged from best supportive care only (38.2%) to systemic glucocorticoids (35.4%), intravenous immunoglobulins (23.6%), cyclosporine (10.4%), and antitumor necrosis factor agents (3.3%). Most patients (63.7%) developed severe acute-phase complications. The 6-week mortality rate was 20.8%. Maximal body surface area detachment (≥30%) was found to be independently associated with severe acute-phase complications (fully adjusted odds ratio [OR], 2.49; 95% CI, 1.21-5.12; P = .01) and SCORTEN greater than or equal to 2 was significantly associated with mortality (fully adjusted OR, 10.30; 95% CI, 3.82-27.78; P < .001). Cyclosporine was associated with a higher frequency of greater than or equal to 20% increase in body surface area detachment in the acute phase (adjusted OR, 3.44; 95% CI, 1.12-10.52; P = .03) and an increased risk of infections (adjusted OR, 7.16; 95% CI, 1.52-33.74; P = .01). Systemic glucocorticoids and intravenous immunoglobulins were associated with a decreased risk of infections (adjusted OR, 0.40; 95% CI, 0.18-0.88; P = .02). No significant difference in 6-week mortality was found between treatment groups. CONCLUSIONS AND RELEVANCE: This cohort study noted differences in treatment strategies for SJS/TEN in Europe; the findings suggest the need for prospective therapeutic studies to be conducted and registries to be developed.