Background
Proton pump inhibitors (PPIs) have been known to induce type I hypersensitivity reactions. However, severe delayed‐type hypersensitivity reactions (DHR) induced by PPI, such as ...Stevens‐Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), or drug rash with eosinophilia and systemic symptoms (DRESS), are rarely reported. We conducted a study of a large series of PPI‐related DHR, followed up their tolerability to alternative anti‐ulcer agents, and investigated the T‐cell reactivity to PPI in PPI‐related DHR patients.
Methods
We retrospectively analyzed patients with PPI‐related DHR from multiple medical centers in Taiwan during the study period January 2003 to April 2016. We analyzed the causative PPI, clinical manifestations, organ involvement, treatment, and complications. We also followed up the potential risk of cross‐hypersensitivity or tolerability to other PPI after their hypersensitivity episodes. Drug lymphocyte activation test (LAT) was conducted by measuring granulysin and interferon‐γ to confirm the causalities.
Results
There were 69 cases of PPI‐related DHR, including SJS/TEN (n=27) and DRESS (n=10). The LAT by measuring granulysin showed a sensitivity of 59.3% and specificity of 96.4%. Esomeprazole was the most commonly involved in PPI‐related DHR (51%). Thirteen patients allergic to one kind of PPI could tolerate other structurally different PPI without cross‐hypersensitivity reactions, whereas three patients developed cross‐hypersensitivity reactions to alternative structurally similar PPI. The cross‐reactivity to structurally similar PPI was also observed in LAT assay.
Conclusions
PPIs have the potential to induce life‐threatening DHR. In patients when PPI is necessary for treatment, switching to structurally different alternatives should be considered.
Background. Better understanding of complications and outcomes of adults hospitalized with respiratory syncytial virus (RSV) infection is necessary. Methods. A retrospective cohort study was ...conducted on all adults (≥18 years) admitted to 3 acute care general hospitals in Hong Kong with virologically confirmed RSV infection during 2009–2011 (N = 607). Adults hospitalized for seasonal influenza during the period were used for comparison (n = 547). Both infections were prospectively diagnosed following a standard protocol. Independent reviews of chest radiographs were performed by radiologists. Main outcome measures were all-cause death, respiratory failure requiring ventilatory support, and hospitalization duration. Cox proportional hazards models were used for analyses. Results. The mean age of RSV patients was 75 (SD, 16) years; 87% had underlying conditions. Lower respiratory and cardiovascular complications were diagnosed in 71.9% (pneumonia, 42.3%; acute bronchitis, 21.9%; chronic obstructive pulmonary disease/asthma exacerbation, 27.3%) and 14.3% of patients, respectively; 12.5% had bacterial superinfections. Supplemental oxygen and ventilatory support were required in 67.9% and 11.1%, respectively. Crude all-cause mortality was 9.1% and 11.9% within 30 days and 60 days, respectively; mean length of stay of survivors was 12 (SD, 13) days. Advanced age, radiographic pneumonia, requirement for ventilation, bacterial superinfection, and elevated urea level and white blood cell count were independently associated with poorer survival. Systemic corticosteroid use was associated with longer hospitalization and secondary infections. The overall outcomes of survival and length of stay were not significantly different from those in influenza. Conclusions. RSV can cause severe lower respiratory complications in older adults, resulting in respiratory failure, prolonged hospitalization, and high mortality similar to seasonal influenza. Corticosteroids did not seem to improve outcomes. The unmet need for antiviral therapy and vaccination against RSV in adults should be promptly addressed.
Summary
Background
Indigo naturalis and its refined formulation, Lindioil, are effective in treating psoriatic symptoms topically. Indirubin is the active ingredient in indigo naturalis.
Objectives
...To determine the efficacy and safety of different concentrations of indirubin in Lindioil ointment for treating psoriasis.
Methods
In this randomized, double‐blind trial, adult patients presenting with chronic plaque psoriasis for > 1 year and with < 20% of the body surface area (BSA) affected were randomized to apply Lindioil ointment containing 200, 100, 50 or 10 μg g−1 of indirubin twice daily for 8 weeks followed by an additional 12‐week safety/extension period. The primary end point was the mean percentage change in Psoriasis Area and Severity Index (PASI) score along with the proportion of participants achieving 75% and 90% reductions in PASI scores (PASI 75 and PASI 90, respectively) from baseline to week 8.
Results
The results from week 8 revealed that the 200 μg g−1 group had the greatest reduction in PASI score 69·2%, 95% confidence interval (CI) 55·5–82·8, followed by the 100 μg g−1 group (63·1%, 95% CI 52·8–73·5), the 10 μg g−1 group (53·4%, 95% CI 42·8–64·0) and the 50 μg g−1 group (50·3%, 95% CI 37·4–63·2), with a between‐group comparison of P = 0·0445. The group with the highest proportion of the patients achieving PASI 75 (57%, P = 0·0474) and PASI 90 (30%, P = 0·0098) was the 200 μg g−1 group. No severe treatment‐related adverse events were reported during the 20‐week evaluation.
Conclusions
An amount of 200 μg g−1 of indirubin in Lindioil ointment is the most effective concentration studied so far for treating psoriasis topically, and is safe.
What's already known about this topic?
As a result of safety concerns about the long‐term use of corticosteroids and other standard treatments, there is a growing demand for herbal treatments for psoriasis.
Indigo naturalis, a herb used in Chinese medicine, is effective for the topical treatment of psoriasis when used as a crude ointment or in its refined form, Lindioil.
What does this study add?
Indirubin is the active ingredient in indigo naturalis, and different concentrations of indirubin in indigo naturalis ointment yield different results in treating psoriasis.
This study provides evidence that 200 μg g−1 of indirubin, the highest concentration studied so far, is the most effective concentration and is safe.
Linked Comment: Sekhon and Koo. Br J Dermatol 2018; 178:21.
Plain language summary available online
Respond to this article
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.
The aim of this study was to investigate factors affecting clinical outcomes of adults hospitalised with severe seasonal influenza.
A prospective, observational cohort study was conducted over 24 ...months (2007-2008) in two acute, general hospitals. Consecutive, hospitalised adult patients were recruited and followed once their laboratory diagnosis of influenza A/B was established (based on viral antigen detection and virus isolation from nasopharyngeal aspirates collected per protocol). Outcomes studied included in-hospital death, length of stay and duration of oxygen therapy. Factors affecting outcomes were analysed using multivariate Cox proportional hazards models. Sequencing analysis on the neuraminidase gene was performed for available H1N1 isolates.
754 patients were studied (influenza A, n=539; >75% H3N2). Their mean age was 70+/-18 years; co-morbidities and serious complications were common (61-77%). Supplemental oxygen and ventilatory support was required in 401 (53.2%) and 41 (5.4%) patients, respectively. 39 (5.2%) patients died; pneumonia, respiratory failure and sepsis were the causes. 395 (52%) patients received antiviral (oseltamivir) treatment. Omission of antiviral treatment was associated with delayed presentation or negative antigen detection results. The mortality rate was 4.56 and 7.42 per 1000 patient-days in the treated and untreated patients, respectively; among those with co-morbidities, it was 5.62 and 11.64 per 1000 patient-days, respectively. In multivariate analysis, antiviral use was associated with reduced risk of death (adjusted HR (aHR) 0.27 (95% CI 0.13 to 0.55); p<0.001). Improved survival was observed with treatment started within 4 days from onset. Earlier hospital discharge (aHR 1.28 (95% CI 1.04 to 1.57); p=0.019) and faster discontinuation of oxygen therapy (aHR 1.30 (95% CI 1.01 to 1.69); p=0.043) was associated with early treatment within 2 days. Few (n=15) H1N1 isolates in this cohort had the H275Y mutation.
Antiviral treatment for severe influenza is associated with reduced mortality and improved clinical outcomes.
Abstract
KAGRA is a newly built gravitational wave observatory, a laser interferometer with a 3 km arm length, located at Kamioka, Gifu, Japan. In this series of articles we present an overview of ...the baseline KAGRA, for which we finished installing the designed configuration in 2019. This article describes the method of calibration (CAL) used for reconstructing gravitational wave signals from the detector outputs, as well as the characterization of the detector (DET). We also review the physical environmental monitoring (PEM) system and the geophysics interferometer (GIF). Both are used for characterizing and evaluating the data quality of the gravitational wave channel. They play important roles in utilizing the detector output for gravitational wave searches. These characterization investigations will be even more important in the near future, once gravitational wave detection has been achieved, and in using KAGRA in the gravitational wave astronomy era.
Background. It is unclear whether pandemic 2009 influenza A (pH1N1) infection caused more significant disease among hospitalized adults than seasonal influenza. Methods. A prospective, observational ...study was conducted in adults hospitalized with polymerase chain reactionconfirmed pH1N1 infection in 2 acute-care general hospitals from June 2009 to May 2010 (n=382). Complications and outcomes were described and compared with those in a seasonal influenza cohort (2007-2008, same hospitals; n=754). Results. Hospitalized patients with pH1N1 influenza were younger than those with seasonal influenza (mean age ± standard deviation, 47 ± 20 vs 70 ± 19 years) and fewer had comorbid conditions (48% vs 64%). The rate of positive immunofluorescence assay results was low (54% vs 84%), and antiviral use was frequent (96% vs 52%). Most patients in both cohorts developed complicated illnesses (67.8% vs 77.1%), but patients with pH1N1 influenza had higher rates of extrapulmonary complications (23% vs 16%;P = .004) and intensive care unit admission and/or death (patient age <35 years, 2.3% vs 0%; 35-65 years, 12.4% vs 3.2%; >65 years, 13.5% vs 8.5%; adjusted odds ratio OR 2.13; 95% confidence interval CI, 1.25-3.62; P = .005). Patients who received antiviral treatment within 96 h after onset had better survival (log-rank test, P < .001). However, without timely treatment, the mortality risk was higher with pH1N1 infection (9.0% vs 5.8% for seasonal influenza; adjusted OR, 6.85; 95% CI, 1.64-28.65; P = .008. Bacterial superinfection worsened outcomes. Conclusions. Adults hospitalized for pH1N1 influenza had significant complications and mortality despite being younger than patients with seasonal influenza. Antiviral treatment within 96 h may improve survival.
Background The usefulness of the drug patch testing for Stevens–Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) is still controversial. Recent studies have shown that HLA‐B*1502 is ...strongly associated with CBZ‐SJS/TEN in Chinese and Southeast Asian populations.
Objective To evaluate the usefulness of patch tests for patients with carbamazepine (CBZ)‐induced SJS, TEN and drug reaction with eosinophilia and systemic symptoms (DRESS) and the cross‐reactivity in patch tests among the aromatic antiepileptic drugs.
Methods We measure the frequency of positive patch test reactions and cross‐sensitivity to structure‐related aromatic anti‐epileptic drugs (AEDs) for patients after SJS/TEN or DRESS episodes caused by CBZ. CBZ and other structure‐related AEDs used for patch testing were prepared in 10% and 30% petrolatum. Secondary measures included the association of HLA‐B*1502 genotype and frequency of possible side effects from the patch tests.
Results Positive patch test reactions to 30% CBZ in the CBZ‐SJS/TEN were 62.5% (10/16), and 70% (7/10) in the CBZ‐DRESS. None of the 10 healthy controls displayed a positive reaction to tested agents. Cross‐sensitivity to other aromatic AEDs was observed in both the CBZ‐SJS/TEN and the CBZ‐DRESS. Only the HLA‐B*1502 genotype was present and strongly associated with the CBZ‐SJS/TEN, but not with the CBZ‐DRESS.
Conclusion Drug patch testing is a safe and useful method for the identification of CBZ as the culprit drug of SJS/TEN as well as DRESS. Testing of chemically or pharmacologically related AEDs may provide information on cross‐reactivity for these patients.
Recent evidence suggests that a subpopulation of cancer cells, cancer stem cells (CSCs), is responsible for tumor growth in colorectal cancer. However, the role of CSCs in colorectal cancer ...metastasis is unclear. Here, we identified a subpopulation of CD26
+ cells uniformly present in both the primary and metastatic tumors in colorectal cancer patients with liver metastasis. Furthermore, in patients without distant metastasis at the time of presentation, the presence of CD26
+ cells in their primary tumors predicted distant metastasis on follow-up. Isolated CD26
+ cells, but not CD26
− cells, led to development of distant metastasis when injected into the mouse cecal wall. CD26
+ cells were also associated with enhanced invasiveness and chemoresistance. Our findings have uncovered a critical role of CSCs in metastatic progression of cancer. Furthermore, the ability to predict metastasis based on analysis of CSC subsets in the primary tumor may have important clinical implication as a selection criterion for adjuvant therapy.
► Metastatic colorectal cancers contain a subset of CD26
+ cancer stem cells ► Nonmetastatic tumors with CD26
+ CSCs frequently proceed to metastasis ► Isolated CD26
+ CSCs can initiate distant metastasis in a mouse model ► CD26
+ CSCs show enhanced invasiveness and migratory potential
Purpose This multinational study evaluated the antitumor activity of nivolumab in nasopharyngeal carcinoma (NPC). Tumor and plasma-based biomarkers were investigated in an exploratory analysis. ...Patients and Methods Patients with multiply pretreated recurrent or metastatic NPC were treated with nivolumab until disease progression. The primary end point was objective response rate (ORR) and secondary end points included survival and toxicity. The expression of programmed death-ligand 1 (PD-L1) and human leukocyte antigens A and B in archived tumors and plasma clearance of Epstein-Barr virus DNA were correlated with ORR and survival. Results A total of 44 patients were evaluated and the overall ORR was 20.5% (complete response, n = 1; partial response, n = 8). Nine patients received nivolumab for > 12 months (20%). The 1-year overall survival rate was 59% (95% CI, 44.3% to 78.5%) and 1-year progression-free survival (PFS) rate was 19.3% (95% CI, 10.1% to 37.2%). There was no statistical correlation between ORR and the biomarkers; however, a descriptive analysis showed that the proportion of patients who responded was higher among those with PD-L1 positive tumors (> 1% expression) than those with PD-L1-negative tumors. The loss of expression of one or both human leukocyte antigen class 1 proteins was associated with better PFS than when both proteins were expressed (1-year PFS, 30.9% v 5.6%; log-rank P = .01). There was no association between survival and PD-L1 expression or plasma Epstein-Barr virus DNA clearance. There was no unexpected toxicity to nivolumab. Conclusion Nivolumab has promising activity in NPC and the 1-year overall survival rate compares favorably with historic data in similar populations. Additional evaluation in a randomized setting is warranted. The biomarker results were hypothesis generating and validation in larger cohorts is needed.
PDF
