Summary
Background
Drug reaction with eosinophilia and systemic symptoms (DRESS) is a condition caused by a drug‐induced immune response. Previous reports have found that CXCL10, also known as ...interferon‐γ‐induced protein (IP)‐10, may participate in the pathogenesis of cutaneous adverse drug reactions. However, the exact role of IP‐10 in DRESS and Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) has remained unknown.
Objectives
This comparative prospective cohort study aimed to ascertain the roles of the IP‐10/CXCR3 axis in DRESS and SJS/TEN.
Methods
Plasma IP‐10 levels were analysed, and univariate analyses were conducted to assess the relationship between IP‐10, human herpesvirus (HHV)‐6 reactivation and the development of long‐term sequelae. We also performed immunohistochemical staining using skin specimens and flow cytometry to determine the expression of CXCR3 in peripheral blood mononuclear cells (PBMCs).
Results
Significantly higher plasma IP‐10 levels were observed in patients with DRESS with long‐term sequelae (effect size 0·81) and also in those with HHV‐6 reactivation (effect size 0·83). By immunohistochemistry, more abundant IP‐10+ and CXCR3+ cells were demonstrated in the skin lesions of patients with DRESS with HHV‐6 reactivation. The percentages of CLA+ CXCR3+ CD4+ cells and CLA+ CXCR3+ CD8+ cells were also higher in the PBMCs of HHV‐6‐reactivated patients with DRESS than in those of patients with SJS/TEN.
Conclusions
Higher plasma IP‐10 levels are associated with the development of long‐term sequelae in DRESS. Higher IP‐10/CXCR3 expression in skin and more abundant CLA+ CXCR3+ CD4+ cells and CLA+ CXCR3+ CD8+ cells were observed in patients with DRESS with HHV‐6 reactivation. The IP‐10/CXCR3 axis is associated with HHV‐6 reactivation and development of long‐term sequelae in DRESS.
What is already known about this topic?
Elevated levels of interferon‐γ‐induced protein‐10 (IP‐10) have been observed in patients with drug reaction with eosinophilia and systemic symptoms (DRESS) and Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN).
Patients with DRESS tend to develop long‐term autoimmune sequelae, including type 1 diabetes and autoimmune thyroiditis. IP‐10 has been associated with these autoimmune diseases in previous studies.
What does this study add?
The patients with DRESS with HHV‐6 reactivation exhibited higher levels of IP‐10 in the plasma and skin than the patients with DRESS without HHV‐6 reactivation and the patients with SJS/TEN.
Patients with DRESS with higher plasma IP‐10 levels tended to develop sequelae during long‐term follow‐up.
What is the translational message?
IP‐10 is a useful biomarker to predict the development of long‐term sequelae in patients with DRESS.
Linked Comment: Belloón and Kardaun. Br J Dermatol 2020; 183:804–805.
What is already known about this topic?
Elevated levels of interferon‐γ‐induced protein‐10 (IP‐10) have been observed in patients with drug reaction with eosinophilia and systemic symptoms (DRESS) and Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN).
Patients with DRESS tend to develop long‐term autoimmune sequelae, including type 1 diabetes and autoimmune thyroiditis. IP‐10 has been associated with these autoimmune diseases in previous studies.
What does this study add?
The patients with DRESS with HHV‐6 reactivation exhibited higher levels of IP‐10 in the plasma and skin than the patients with DRESS without HHV‐6 reactivation and the patients with SJS/TEN.
Patients with DRESS with higher plasma IP‐10 levels tended to develop sequelae during long‐term follow‐up.
What is the translational message?
IP‐10 is a useful biomarker to predict the development of long‐term sequelae in patients with DRESS.
Linked Comment: Belloón and Kardaun. Br J Dermatol 2020; 183:804–805.
Plain language summary available online
Background
There is increasing use of anti‐osteoporotic agents (AOA) worldwide for prevention or management of patients with osteoporosis. However, there have been reports of severe cutaneous adverse ...reactions (SCAR) induced by AOA. A recent study showed weak association between HLA and strontium ranelate (SR)‐SCAR.
Objective
To characterize patients with AOA‐SCAR and investigate the HLA association and utility of in vitro diagnostic methods.
Methods
We enrolled 16 cases with AOA‐cutaneous adverse drug reactions (cADR), including SCAR (n = 10: 8 with Stevens–Johnson syndrome SJS and 2 with drug rash with eosinophilia and systemic symptoms DRESS) and maculopapular exanthema (MPE) (n = 6) from Taiwan and Hong Kong. We analysed the clinical characteristics, outcomes, HLA alleles and in vitro testing of AOA‐SCAR, and tolerability to alternative drugs. We further performed literature review and meta‐analysis on the HLA association of AOA‐SCAR.
Results
Our data showed strontium ranelate is the most common causality of AOA‐SCAR in Asian populations. There was no cross‐hypersensitivity of SR‐SCAR with other AOA. HLA genotyping showed that SR‐SJS was most significantly associated with HLA‐A*33:03 (Pc = 5.17 × 10−3, OR: 25.97, 95% CI: 3.08–219.33). Meta‐analysis showed that HLA‐A*33:03 was associated with SR‐SJS (P = 5.01 × 10−5; sensitivity: 85.7%) in Asians. The sensitivity of lymphocyte activation test (LAT) for identifying the culprit drug of SR‐SJS was 83.3%.
Conclusions
Strontium ranelate is identified as the most notorious AOA associated with SCAR. The HLA‐A*33:03 genetic allele and LAT testing may add benefits to the diagnosis of SR‐SCAR in patients whose reaction developed while taking multiple drugs.
Linked Commentary: T. Shiohara. J Eur Acad Dermatol Venereol 2021; 35: 567‐568. https://doi.org/10.1111/jdv.17138.
BackgroundThe goal of this study was to characterize viral loads and factors affecting viral clearance in persons with severe influenza MethodsThis was a 1-year prospective, observational study ...involving consecutive adults hospitalized with influenza. Nasal and throat swabs were collected at presentation, then daily until 1 week after symptom onset. Real-time reverse-transcriptase polymerase chain reaction to determine viral RNA concentration and virus isolation were performed. Viral RNA concentration was analyzed using multiple linear or logistic regressions or mixed-effect models ResultsOne hundred forty-seven inpatients with influenza A (H3N2) infection were studied (mean age ± standard deviation, 72±16 years). Viral RNA concentration at presentation positively correlated with symptom scores and was significantly higher than that among time-matched outpatients (control subjects). Patients with major comorbidities had high viral RNA concentration even when presenting >2 days after symptom onset (mean ± standard deviation, 5.06±1.85 vs 3.62±2.13 log10 copies/mL; P=.005; β, +0.86 95% confidence interval, +0.03 to +1.68). Viral RNA concentration demonstrated a nonlinear decrease with time; 26% of oseltamivir-treated and 57% of untreated patients had RNA detected at 1 week after symptom onset. Oseltamivir started on or before symptom day 4 was independently associated with an accelerated decrease in viral RNA concentration (mean β standard error, −1.19 0.43 and −0.68 0.33 log10 copies/mL for patients treated on day 1 and days 2–3, respectively; P<.05) and viral RNA clearance at 1 week (odds ratio, 0.10 95% confidence interval, 0.03–0.35 and 0.30 0.10–0.90 for patients treated on day 1–2 and day 3–4, respectively). Conversely, major comorbidities and systemic corticosteroid use for asthma or chronic obstructive pulmonary disease exacerbations were associated with slower viral clearance. Viral RNA clearance was associated with a shorter hospital stay (7.0 vs 13.5 days; P=.001) ConclusionPatients hospitalized with severe influenza have more active and prolonged viral replication. Weakened host defenses slow viral clearance, whereas antivirals started within the first 4 days of illness enhance viral clearance
A well-behaved spin-light emitting diode (LED) composed of InGaN/GaN multiple quantum disks (MQDs), ferromagnetic contact, and Fe3O4 nanoparticles has been designed, fabricated, and characterized. ...The degree of circular polarization of electroluminescence (EL) can reach up to a high value of 10.9% at room temperature in a low magnetic field of 0.35 T, which overcomes a very low degree of spin polarization in nitride semiconductors due to the weak spin–orbit interaction. Several underlying mechanisms play significant roles simultaneously in this newly designed device for the achievement of such a high performance. Most of all, the vacancy between nanodisks can be filled by half-metal nanoparticles with suitable energy band alignment, which enables selective transfer of spin polarized electrons and holes and leads to the enhanced output spin polarization of LED. Unlike previously reported mechanisms, this new process leads to a weak dependence of spin relaxation on temperature. Additionally, the internal strain in planar InGaN/GaN multiple quantum wells can be relaxed in the nanodisk formation process, which leads to the disappearance of Rashba Hamiltonian and enhances the spin relaxation time. Our approach therefore opens up a new route for the further research and development of semiconductor spintronics.
Background
Sequential human herpes virus (HHV) reactivation is well known in drug reaction with eosinophilia and systemic symptom (DRESS), but such a phenomenon has seldom studied in other types of ...cutaneous adverse drug reactions (cADRs). Moreover, the association between viral reactivations and cytokine or chemokine changes is largely unknown. We aimed to evaluate the viral reactivation rates of HHV‐6, HHV‐7, Epstein–Barr virus (EBV), and cytomegalovirus (CMV) in different cADRs and their impacts on clinical prognosis. Cytokine and chemokine changes with viral reactivations were also examined.
Methods
A prospective study was conducted to monitor the viral statuses of patients with different cADRs by polymerase chain reaction and serum‐specific antibody titers. Changes in plasma cytokine and chemokine levels were also evaluated by sequential blood samples.
Results
Among the various cADRs, HHV‐6 reactivation was only observed in DRESS, but EBV and CMV could be detected in other cADRs. Many proinflammatory cytokines and chemokines, including interleukin (IL)‐1β, IL‐2, IL‐6, interferon‐γ, tumor necrosis factor‐α, were significantly lower in DRESS patients with HHV‐6 reactivation when compared to those without HHV‐6 reactivation. In addition, these mediators were significantly lower before and during HHV‐6 reactivation, compared to cytokine levels after HHV‐6 reactivation in the same patient.
Conclusion
HHV‐6 reactivation was only observed in DRESS patients, not in any other cADR. In DRESS patients, some proinflammatory cytokines were significantly lower before or during HHV‐6 reactivation.
Background
Only few studies had investigated the histopathological presentations of drug reaction with eosinophilia with systemic symptoms (DRESS). The results of these studies were diverse and not ...conclusive. A characteristic histopathological feature is still lacking.
Objective
We tempted to identify characteristic histopathological features in DRESS and to correlate them with clinical presentations.
Methods
We retrospectively collected data from patients treated from 1998 through 2015. Available skin specimens from probable or definite cases according to the RegiSCAR criteria were analysed for histopathological patterns, which were then compared with the patients' clinical presentations. Chi‐squared test was used for comparisons, while Bonferroni correction was applied if multiple comparison tests were encountered.
Results
Fifty‐six patients with an average age of 52 years were identified, including 22 definite cases. The single most common histopathological pattern was interface dermatitis (75%). The co‐existence of two or more patterns in a skin specimen was common (62.5%). In such cases, the co‐existence of three patterns (the eczematous pattern, the interface dermatitis pattern and the vascular damage pattern) was most frequently encountered. It exhibited a significantly higher likelihood of being definite cases (P = 0.004) and was significantly associated with high grades of cutaneous abnormalities (P < 0.001). It showed a trend towards having higher grades of haematological abnormalities in patients with co‐existence of three patterns (P = 0.04). In addition, patients with the co‐existence of three patterns tended to have a higher rate of reactivation of human herpesvirus‐6 than those with other patterns but not statistically significant (P = 0.052).
Conclusion
The co‐existence of three histopathological patterns in a skin specimen is characteristic in DRESS and shows a significant association with clinical severity.
We identified seasonal human coronaviruses, influenza viruses and rhinoviruses in exhaled breath and coughs of children and adults with acute respiratory illness. Surgical face masks significantly ...reduced detection of influenza virus RNA in respiratory droplets and coronavirus RNA in aerosols, with a trend toward reduced detection of coronavirus RNA in respiratory droplets. Our results indicate that surgical face masks could prevent transmission of human coronaviruses and influenza viruses from symptomatic individuals.
Summary
Background
Acral melanoma (AM) is the most common histopathological subtype of malignant melanoma in Asians. However, differences in the mutational profiles underlying AM and nonacral ...cutaneous melanoma (NAM) in Asians are not well understood.
Objectives
To augment the understanding of the prevalence, patterns and associations of various mutations between different subtypes of melanoma.
Methods
We performed comprehensive genomic profiling of 409 cancer‐associated genes, using next‐generation sequencing, in 66 primary melanomas comprised of 45 AMs and 21 NAMs.
Results
Most of the AMs (n = 27/45; 60%), but only five of 21 (24%) NAMs, were triple wild‐type (triple‐WT) tumours. Compared with AMs, NAMs exhibited a significantly higher frequency of BRAF mutations. The frequencies of NRAS/KRAS mutations, cell‐cycle aberrations, copy number gains in BIRC2, BIRC3 and BIRC5, and gains of receptor tyrosine kinase genes were significantly higher in AMs. Ulceration was found at significantly higher rates in the AMs and NAMs with cell‐cycle aberrations and gains of receptor tyrosine kinase genes. Notably, cell‐cycle aberrations and copy number gains in BIRC2, BIRC3 and BIRC5 were significantly associated with poor melanoma‐specific survival in the 66 patients with melanoma and especially in the 45 patients with AM. Multivariate analysis showed that lymph node metastasis and cell‐cycle aberrations were independent prognostic factors of melanoma‐specific survival.
Conclusions
This study strengthens our understanding of the patterns and clinical associations of oncogenic mutations in AMs and NAMs in Asians.
What's already known about this topic?
Mutation frequencies of driver genes vary between melanoma subtypes.
Acral melanoma is the most common subtype of melanoma in Asians.
KIT mutations and copy number variations occur more frequently in the acral subtype of melanoma than in the nonacral subtype
What does this study add?
NRAS/KRAS mutations, cell‐cycle aberrations, copy number gains in BIRC2, BIRC3 and BIRC5, and amplifications of receptor tyrosine kinase genes were significantly enriched in acral melanoma and could be potential targets for treatment.
Melanomas with cell‐cycle aberrations and gains in receptor tyrosine kinase genes were significantly more likely to contain ulceration.
What is the translational message?
Cell‐cycle aberrations and copy number gains in BIRC2, BIRC3 and BIRC5 were significantly associated with poor melanoma‐specific survival.
These observations should be explored further for future drug development.
Linked Comment: Johansson. Br J Dermatol 2020; 182:1085.
Plain language summary available online
With the aim of gathering temporal trends on bacterial epidemiology and resistance from multiple laboratories in China, the CHINET surveillance system was organized in 2005. Antimicrobial ...susceptibility testing was carried out according to a unified protocol using the Kirby-Bauer method or automated systems. Results were analyzed according to Clinical and Laboratory Standards Institute (CLSI) 2014 definitions. Between 2005 and 2014, the number of bacterial isolates ranged between 22 774 and 84 572 annually. Rates of extended-spectrum β-lactamase production among Escherichia coli isolates were stable, between 51.7 and 55.8%. Resistance of E. coli and Klebsiella pneumoniae to amikacin, ciprofloxacin, piperacillin/tazobactam and cefoperazone/sulbactam decreased with time. Carbapenem resistance among K. pneumoniae isolates increased from 2.4 to 13.4%. Resistance of Pseudomonas aeruginosa strains against all of antimicrobial agents tested including imipenem and meropenem decreased with time. On the contrary, resistance of Acinetobacter baumannii strains to carbapenems increased from 31 to 66.7%. A marked decrease of methicillin resistance from 69% in 2005 to 44.6% in 2014 was observed for Staphylococcus aureus. Carbapenem resistance rates in K. pneumoniae and A. baumannii in China are high. Our results indicate the importance of bacterial surveillance studies.
Growing evidence indicates that resistin-an obesity-related cytokine-is upregulated in breast cancer patients, yet its impact on breast cancer behavior remains to be ascertained. Similarly, Toll-like ...receptor 4 (TLR4) has been implicated in breast cancer progression, however, its clinically relevant endogenous ligand remains elusive. In this study, we observed that high serum resistin levels in breast cancer patients positively correlated with tumor stage, size and lymph node metastasis. These findings were replicated in animal models of breast cancer tumorigenesis and metastasis. Resistin was found to promote epithelial-mesenchymal transition and stemness in breast cancer cells-mechanisms critical to tumorigenesis and metastasis-through a TLR4/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)/signal transducer and activator of transcription 3 (STAT3) signaling pathway and negated by TLR4-specific antibody and antagonist. These findings provide clear evidence that resistin is a clinically relevant endogenous ligand for TLR4, which promotes tumor progression via TLR4/NF-κB/STAT3 signaling, providing insights into a novel therapeutic target in breast cancer.
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