Rapid onset of Stevens-Johnson syndrome and toxic epidermal necrolysis after ingestion of acetaminophen.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare, but life-threatening, severe cutaneous adverse reactions most frequently caused by exposure to drugs. Several reports have associated the use of acetaminophen with the risk of SJS or TEN. A typical interval from the beginning of drug therapy to the onset of an adverse reaction is 1-3 weeks. A 43-year-old woman and a 60-year-old man developed skin lesions within 3 days after administration of acetaminophen for a 3-day period. Rapid identification of the symptoms of SJS and TEN caused by ingestion of acetaminophen enabled prompt withdrawal of the culprit drug. After administration of intravenous immunoglobulin G, both patients recovered fully and were discharged. These two cases of rapidly developed SJS/TEN after ingestion of acetaminophen highlight the possibility that these complications can develop within only a few days following ingestion of over-the-counter medications such as acetaminophen.

Clusterin expression level correlates with increased oxidative stress in asthmatics.

BACKGROUND: Oxidative stress is thought to play a role in the pathogenesis of asthma. Clusterin is a sensitive cellular biosensor of oxidative stress and has antioxidant properties. The function and expression of clusterin in patients with asthma have not been fully investigated. OBJECTIVE: To investigate whether the expression of clusterin in patients with asthma is regulated by increased oxidative burden and whether clusterin expression could be used to assess the response to inhaled corticosteroids. METHODS: Clusterin levels in serum, induced sputum, and peripheral blood mononuclear cells of patients with asthma were measured by enzyme-linked immunosorbent assay and western blotting and compared with pulmonary function and levels of expression of hyperoxidized peroxiredoxins. Serum concentrations of clusterin in treatment-naive patients were compared before and after inhaled corticosteroid use. RESULTS: Serum clusterin concentration was significantly elevated in patients with severe asthma and was inversely correlated with pulmonary function. The expression of hyperoxidized peroxiredoxins was greatly increased in peripheral blood mononuclear cells of patients with asthma and was strongly correlated with clusterin expression. Serum clusterin concentrations in treatment-naive patients with asthma were decreased significantly after initial treatment with inhaled corticosteroids. CONCLUSION: Clusterin may be a biomarker of asthma severity and the burden of oxidative stress in patients with asthma. Moreover, clusterin may be useful for the prompt assessment of airway inflammation.

Influence of initial treatment modality on long-term control of chronic idiopathic urticaria.

BACKGROUND: Chronic idiopathic urticaria (CIU) is a common cutaneous disorder but the influence of initial treatment modality on long-term control is not known. The aim of this study was to evaluate clinical features, and the influence of initial treatment modality on long-term control. METHODS AND RESULTS: 641 CIU patients were enrolled from the allergy clinic in a tertiary referral hospital. Disease duration, aggravating factors and treatment modality at each visit were evaluated. Times required to reach a controlled state were analyzed according to initial treatment modality, using Kaplan-Meier survival curves, the Cox proportional-hazards model, and propensity scores. Female to male ratio was 1.7: 1; mean age at onset was 40.5 years. The most common aggravating factors were food (33.5%), stress (31.5%) and fatigue (21.6%). Most patients (82.2%) used H1-antihistamines alone as initial treatment while 17% used a combination treatment with oral corticosteroids. There was no significant difference in the time taken to reach a controlled state between patients treated with single vs multiple H1-antihistamines or between those who received H1-antihistamine monotherapy vs. a combination therapy with oral corticosteroids. CONCLUSION: The time required to control CIU is not reduced by use of multiple H1-antihistamines or oral corticosteroids in the initial treatment.

The Effectiveness of Automatic Recommending System for Premedication in Reducing Recurrent Radiocontrast Media Hypersensitivity Reactions.

BACKGROUND: Non-ionic radiocontrast media (RCM) is rarely associated with hypersensitivity reactions. Premedication of patients who reacted previously to RCM with systemic corticosteroids and/or antihistamines can help reduce recurrent hypersensitivity reactions. However, premedication is still not prescribed in many cases for various reasons. This study aimed to determine the effectiveness of our novel RCM hypersensitivity surveillance and automatic recommending system for premedication. METHODS AND RESULTS: Hospitalized patients with a history of RCM hypersensitivity were identified in an electronic medical record system that included a mandatory reporting system for past adverse drug reactions. In 2009, a novel automatic prescription system was added that classified index RCM reactions by severity and dispensed appropriate corticosteroid and/or antihistamine pretreatment prior to new RCM exposures. The data from 12 months under the previous system and 12 months under the current system were compared. The two systems had similar overall premedication rates (91% and 95%) but the current system was associated with a significantly higher corticosteroid premedication rate (65% vs. 14%), which significantly reduced the breakthrough reaction rate (6.7% vs. 15.2%). The current system was also associated with increased corticosteroid and antihistamine premedication of patients with a mild index reaction (61% vs. 7%) and a reduction in their breakthrough reaction rate (6% vs. 15%). CONCLUSIONS: Premedication with corticosteroid and/or antihistamine, which was increased by our novel automatic prescription system, significantly reduced breakthrough reactions in patients with a history of RCM hypersensitivity.

Characteristics of liver injury in drug-induced systemic hypersensitivity reactions.

BACKGROUND: The liver is the most commonly involved internal organ in drug-induced systemic hypersensitivity. However, data obtained from these patients have yet to be analyzed in depth with respect to liver injury. METHODS: The medical records of 136 patients who developed delayed-type drug hypersensitivity were reviewed at a tertiary referral hospital. Culprit drugs, the pattern and degree of liver injury, and the effect of systemic corticosteroids were evaluated in the group of patients with drug-induced systemic hypersensitivity and liver dysfunction (aspartate aminotransferase or alanine aminotransferase ≥80 IU/L). Clinical characteristics of patients with drug-induced systemic hypersensitivity and liver injury were analyzed. RESULTS: Among the 61 patients with drug-induced systemic hypersensitivity and liver dysfunction, the clinical phenotypes were drug reaction with eosinophilia and systemic symptoms (n = 29, 48%), Stevens-Johnson syndrome/toxic epidermal necrolysis (n = 11, 18%), and maculopapular rash (n = 17, 28%). Antibiotics (n = 27, 44%) were the most common cause of drug-induced systemic hypersensitivity with liver dysfunction. Whereas patients with Stevens-Johnson syndrome/toxic epidermal necrolysis had mild hepatocellular-type liver injury of relatively brief duration, those with drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome had more severe and prolonged hepatocellular injury in addition to moderate to severe cholestatic-type liver injury. The use of systemic corticosteroids did not significantly affect either recovery from liver injury or mortality. LIMITATIONS: This study was retrospective and the number of subjects was small. CONCLUSION: The results suggest that the severity, pattern, and duration of liver injury differ according to the drug-hypersensitivity phenotype. Further studies are needed to evaluate the role of systemic corticosteroids in drug-induced systemic hypersensitivity and liver injury.

Identification of subtypes of refractory asthma in Korean patients by cluster analysis.

BACKGROUND: Refractory asthma, a subtype of asthma with uncontrolled symptoms despite antiasthma medications, is a heterogeneous syndrome with variable clinical features, presumably different etiologies, and pathophysiological mechanisms. The heterogeneity of refractory asthma, however, is poorly understood. We aimed to characterize refractory asthma and to improve our understanding of the heterogeneity of refractory asthma patients. METHODS: We identified refractory asthma patients (n = 96) as defined by the American Thoracic Society's criteria from a cohort of Korean asthma patients (n = 2,187). Then, cluster analysis was conducted to classify subtypes of refractory asthma. RESULTS: Among the study group, 4.4 % (n = 96) of all asthma patients had refractory asthma. Cluster analysis identified four distinct groups of refractory asthma. Age at onset was younger in clusters 1 and 2 than in clusters 3 and 4. Patients in cluster 1 had the most well-preserved pulmonary function; patients in cluster 2 had a female predominance and the most severe airway obstruction; patients in cluster 3 were mostly female and had the most enhanced bronchial hyperresponsiveness; and patients in cluster 4 were most male and tended to be cigarette smokers. CONCLUSIONS: The current results suggest that refractory asthma is a heterogeneous syndrome and could be classified into four subtypes. Underlying pathogenesis and therapeutic approaches may differ for the different subtypes and further research is needed.

Clinical characteristics that distinguish eosinophilic organ infiltration from metastatic nodule development in cancer patients with eosinophilia.

BACKGROUND: When new space-occupying lesions are observed together with peripheral blood eosinophilia in patients diagnosed with cancer, the possibility of eosinophilic organ involvement should be differentiated from metastasis of primary cancer, since a misdiagnosis could lead to unnecessary chemotherapy. The aim of this study is to identify the clinical characteristics of eosinophilic organ involvement that distinguish it from distant metastasis in patients with primary cancer. METHODS: The medical records of 43 cancer patients who developed hepatic or pulmonary nodules with peripheral blood eosinophilia between January 2005 and February 2010 in the Asan Medical Center (Seoul) were reviewed. Eosinophilic infiltration and distant metastasis were identified on the basis of pathological findings and radiological features. Fisher's exact test, χ² test or Mann-Whitney test were used for statistical analysis. RESULTS: In total, 33 patients (76%) were diagnosed with eosinophilic infiltration, 5 (12%) with cancer metastasis and 5 (12%) had undetermined diagnoses. Compared to the patients with metastases, the patients with eosinophilic infiltration were significantly more likely to have serology indicating a parasitic infection, a history of eating raw food, high serum levels of total IgE, normal liver function, normal C-reactive protein levels, a normal erythrocyte sedimentation rate, and fewer and smaller nodules. The most common underlying malignancy in the eosinophilic organ infiltration group was stomach cancer. Physicians tended to neglect the eosinophilia in patients with a history of cancer. CONCLUSIONS: Several clinical characteristics of eosinophilic organ infiltration distinguish it from cancer metastasis. Physicians should make greater efforts to determine the causes of organ involvement with peripheral blood eosinophilia, especially in cancer patients.

The role of nitrosative stress in the pathogenesis of unexplained chronic cough with cough hypersensitivity.

BACKGROUND: Unexplained chronic cough is a common condition without specific causes. A hyperreactivity of the cough reflex has been suggested as a mechanism for inducing chronic cough. We hypothesized that nitrosative stress in the upper airway might play a role in cough hypersensitivity by causing neurochemical abnormalities. METHODS: Fifty-one patients with unexplained chronic cough and 27 controls were enrolled. A capsaicin cough provocation test was performed to determine cough sensitivity. Nitrosative stress in the upper airway was assessed by quantifying 3-nitrotyrosine (3-NT) immunostaining in nasal epithelial cells (NECs) and measuring nasal nitric oxide (nNO). The effect of NO on airway epithelium was investigated by measuring the levels of substance P (SP) in nasal lavage fluid and evaluating SP expression in airway epithelial cells. RESULTS: Based on the results of the capsaicin test, patients were divided into two groups: a cough hypersensitivity (CHS) group and a normal cough sensitivity (NCS) group. The levels of 3-NT immunoreactivity in NECs were significantly higher in CHS (49 ± 2.9%) than in NCS (27 ± 3.3%) and controls (12 ± 1.6%), a pattern that was also reflected in the values of nNO (350 ± 43, 215 ± 23, and 138 ± 23 ppb in CHS, NCS, and controls, respectively). SP concentration was also elevated in nasal lavage fluids from CHS (746 ± 28 pg/mL) compared with that from NCS (624 ± 40 pg/mL) and controls (526 ± 41 pg/mL). SP expression in airway epithelial cells was greatly enhanced by exposure to NO donor, which was attenuated by pretreatment with either NO scavenger or NO synthase inhibitor. CONCLUSION: Increased nitrosative stress in the upper airway may play a role in the pathogenesis of unexplained chronic cough with CHS through enhanced secretion of SP.

Hyperoxidized peroxiredoxins in peripheral blood mononuclear cells of asthma patients is associated with asthma severity.

AIMS: Oxidative stress is involved in the pathogenesis of asthma, and peroxiredoxins (PRDX) may be critical in controlling intracellular oxidative stress. The aim of this study was to evaluate expressions of PRDX and their hyperoxidized forms in asthmatic individuals. MAIN METHODS: The levels of expression of PRDX1, PRDX2, PRDX3, and PRDX6 and their hyperoxidized forms (PRDX-SO(3)) were measured in PBMCs from asthma patients and control subjects. In addition, cells from these subjects were treated with hydrogen peroxide (H(2)O(2)) and their intracellular concentrations of reactive oxygen species (ROS) were measured. KEY FINDINGS: The ratios of hyperoxidized to total PRDX (PRDX-SO(3/)PRDX) in PBMCs were significantly higher in asthma patients than in normal subjects and were correlated with disease severity, with the highest ratio seen in patients with severe asthma. Furthermore, H(2)O(2) treatment of PBMCs, particularly lymphocytes, increased intracellular ROS concentrations with greater and more persistent increases observed in cells from asthmatic than from control subjects. SIGNIFICANCE: Hyperoxidation of PRDX may serve as a biomarker of asthma severity and may predict enhanced susceptibility to oxidative stress load in PBMCs of asthmatics.

Smoking, longer disease duration and absence of rhinosinusitis are related to fixed airway obstruction in Koreans with severe asthma: findings from the COREA study.

BACKGROUND: The clinical manifestations of severe asthma are heterogeneous. Some individuals with severe asthma develop irreversible fixed airway obstruction, which is associated with poor outcomes. We therefore investigated the factors associated with fixed airway obstruction in Korean patients with severe asthma. METHODS: Severe asthma patients from a Korean adult asthma cohort were divided into two groups according to the results of serial pulmonary function tests. One group had fixed airway obstruction (FAO) [forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) ratio < 0.7, n = 119] and the other had reversible airway obstruction (RAO) [FEV1/FVC ratio ≥ 0.7, n = 116]. Clinical and demographic parameters were compared between the two groups. RESULTS: Multivariate analysis showed that longer duration of disease, greater amount of cigarette smoking and absence of rhinosinusitis were significantly related to the development of FAO in severe asthmatics. Other parameters, including atopic status, pattern of airway inflammatory cells in induced sputum, and frequency of asthma exacerbations did not differ between the FAO and RAO groups. CONCLUSION: Severe asthma patients with longer disease duration and the absence of rhinosinusitis are more likely to develop FAO. This study also demonstrates the importance of quitting smoking in order to prevent irreversible airway obstruction. Further investigation is required to determine the mechanism by which these factors can modify the disease course in Korean patients with severe asthma.

Severe pneumonia caused by combined infection with Pneumocystis jiroveci, parainfluenza virus type 3, cytomegalovirus, and Aspergillus fumigatus in a patient with Stevens-Johnson syndrome/toxic epidermal necrolysis.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe adverse cutaneous reactions to drugs. We report here the first case of severe pneumonia caused by an unusual combined infection with Pneumocystis carinii (jiroveci), parainfluenza virus type 3, cytomegalovirus and Aspergillus fumigatus in a 63-year-old female patient with allopurinol-induced SJS/TEN overlap syndrome. Following treatment with high-dose systemic corticosteroids and intravenous immunoglobulin for SJS/TEN, her mucocutaneous lesions improved and she was due to be discharged. However, 15 days after cessation of corticosteroids, she developed pneumonia. Broncho-alveolar lavage revealed that the cause of infection was Pneumocystis carinii (jiroveci), parainfluenza virus type 3, cytomegalovirus and Aspergillus. These findings indicate that patients with SJS/TEN, particularly those treated with systemic corticosteroids, may be susceptible to infection with combinations of pathological agents resulting from damage to the bronchial epithelia.

A case of anaphylaxis to oral minocycline.

Minocycline is a semisynthetic tetracycline derivative that is often used in the treatment of acne vulgaris. To date, there has been only one case report of anaphylaxis to minocycline. We report here a case of anaphylaxis to oral minocycline. A 56-yr-old woman visited our hospital after three episodes of recurrent anaphylaxis. We performed an oral challenge test, the standard method for diagnosing drug allergies, with minocycline, one of the drugs she had taken previously. She developed urticaria, angioedema, nausea, vomiting, hypotension, and dyspnea within 4 min and was treated with intramuscular epinephrine, intravenous antihistamine and systemic corticosteroid. However, she presented similar symptoms at 50 min and at 110 min. In prescribing oral minocycline, physicians should consider the possibility of serious adverse reactions, such as anaphylaxis.

Chlamydophila pneumoniae enhances secretion of VEGF, TGF-beta and TIMP-1 from human bronchial epithelial cells under Th2 dominant microenvironment.

PURPOSE: Chlamydophila pneumoniae infection in the airways is thought to be associated with the pathogenesis of asthma, especially in non-atopic severe asthma with irreversible airway obstruction that may be related to airway remodeling. Here, we investigated whether C. pneumoniae infection enhances the secretion of critical chemical mediators for airway remodeling, such as VEGF, TGF-beta, and TIMP-1, in human bronchial epithelial cells (BECs) in a Th2-dominant microenvironment. METHODS: Human bronchial epithelial cells (BEAS-2B cells) were infected with C. pneumoniae strain TW183 and cultured in both a Th1-dominant microenvironment with INF-gamma and a Th2-dominant microenvironment with IL-4 or IL-13 added to the culture medium. The VEGF, TGF-beta, and TIMP-1 levels in the culture supernatants were measured using enzyme-linked immunosorbent assays (ELISA). The activation of NF-kappaB in each experimental condition was determined using an electrophoretic mobility shift assay. RESULTS: Chlamydophila pneumoniae-infected BECs showed enhanced secretion of VEGF, TGF-beta, and TIMP-1 compared with non-infected BECs. The levels of cytokines secreted from BECs were increased more when IL-13 was added to the culture medium. C. pneumoniae-infected BECs also showed increased NF-kappaB activation. CONCLUSIONS: These results suggest that C. pneumoniae plays a role in the pathogenesis of airway remodeling in asthma, revealing a Th2-dominant immune response. Further studies are required to clarify the precise mechanism of C. pneumoniae infection in airway remodeling.

The tyrosine phosphatase, SHP-1, is involved in bronchial mucin production during oxidative stress.

Mucus hypersecretion is a clinically important manifestation of chronic inflammatory airway diseases, such as asthma and Chronic obstructive pulmonary disease (COPD). Mucin production in airway epithelia is increased under conditions of oxidative stress. Src homology 2 domain-containing protein tyrosine phosphatase (SHP)-1 suppression is related to the development of airway inflammation and increased ROS levels. In this study, we investigated the role of SHP-1 in mucin secretion triggered by oxidative stress. Human lung mucoepidermoid H292 carcinoma cells were transfected with specific siRNA to eliminate SHP-1 gene expression. Cultured cells were treated with hydrogen peroxide (H(2)O(2)), and Mucin 5AC(MUC5AC) gene expression and mucin production were determined. Activation of p38 mitogen activated protein kinase (MAPK) in association with MUC5AC production was evaluated. N-acetylcysteine (NAC) was employed to determine whether antioxidants could block MUC5AC production. To establish the precise role of p38, mucin expression was observed after pre-treatment of SHP-1-depleted H292 cells with the p38 chemical blocker. We investigated the in vivo effects of oxidative stress on airway mucus production in SHP-1-deficient heterozygous (mev/+) mice. MUC5AC expression was enhanced in SHP-1 knockdown H292 cells exposed to H(2)O(2), compared to that in control cells. The ratio between phosphorylated and total p38 was significantly increased in SHP-1-deficient cells under oxidative stress. Pre-treatment with NAC suppressed both MUC5AC production and p38 activation. Blockage of p38 MAPK led to suppression of MUC5AC mRNA expression. Notably, mucin production was enhanced in the airway epithelia of mev/+ mice exposed to oxidative stress. Our results clearly indicate that SHP-1 plays an important role in airway mucin production through regulating oxidative stress.

Increased oxidative stress in the airway and development of allergic inflammation in a mouse model of asthma.

BACKGROUND: The exact pathogenic role of oxidative stress in the development of allergic airway inflammation is still largely unknown. OBJECTIVE: To investigate a possible link between increased pulmonary oxidative stress and the pivotal features of asthma during the mounting of an allergic inflammatory response. METHODS: To determine the relationship between oxidative stress and allergic inflammatory responses, we evaluated the sequential kinetics of oxidative stress in the lung, the development of airway inflammation, mucin hypersecretion, and airway hyperresponsiveness (AHR) in an ovalbumin (OVA)-sensitized and challenged mouse with and without antioxidant. Parameters were measured at 9 points for more than 28 days, starting from the first day of OVA challenge with or without antioxidant treatment. The ratio of reduced to oxidized glutathione in the lungs and levels of intracellular reactive oxygen species (ROS) in the bronchial epithelium were serially measured. Bronchoalveolar lavage fluid cells, histopathologic features, and AHR were analyzed at the same time points. RESULTS: The reduced to oxidized glutathione ratio was reduced from immediately after OVA challenge to day 1, remained at this level until day 1, and rapidly recovered to the normal level after more than 2 days. Intracellular ROS levels in the bronchial epithelium followed similar kinetics. The inflammatory cells in bronchoalveolar lavage fluid reached a maximum of 3 days and decreased progressively thereafter. Histopathologic examination revealed that substantial airway inflammation persisted through day 28. The proportion of mucin-producing epithelial cells significantly increased after day 1, reached a maximum at day 3, and remained at this level until day 5. The AHR peaked on day 1 and normalized within 5 days. The pretreatment of antioxidant significantly reduced not only the increased ROS levels but also development of other phenotypes of asthma. CONCLUSION: These results indicate that increased oxidative stress in the lung precedes other pivotal phenotypes of allergic airway disease, suggesting a critical role for increased oxidative stress in the induction of allergic airway inflammation.