Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening adverse reactions, which could be induced by a variety of drugs. It was proposed that human leukocyte antigen (HLA)-restricted presentation of antigens (drugs or their metabolites) to T lymphocytes initiates the immune reactions of SJS/TEN. However, the genetic susceptibility and the exact pathogenesis were not clear until the recent studies. We first identified that HLA-B^*1502 is strongly associated with carbamazepine (CBZ)-induced SJS/TEN and HLA-B^*5801 with allopurinol-SJS/TEN in Han Chinese. The same associations had been validated across different human populations. For the downstream danger signals, Fas-Fas ligand (FasL) and perforin/granzyme B had been advocated as cytotoxic mediators for keratinocyte death in SJS/TEN. However, expression levels of these cytotoxic proteins from the skin lesions were too low to explain the distinct and extensive epidermal necrosis. Our recent study identified that the granulysin, a cytotoxic protein released from cytotoxic T cells or natural killer (NK) cells, is a key mediator for disseminated keratinocyte death in SJS/TEN. This article aims to provide an overview of both of the genomic and immunologic perspectives of SJS/TEN. These studies give us a better understanding of the immune mechanisms, biomarkers for disease prevention and early diagnosis, as well as providing the therapeutic targets for the treatments of SJS/TEN.

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The immune reconstitution syndrome (IRS) is an increasingly recognized disease concept and is observed with a broad-spectrum of immunosuppressive therapy-related opportunistic infectious diseases and severe drug eruptions complicated by viral reactivations. Clinical illness consistent with IRS includes tuberculosis, herpes zoster, herpes simples, cytomegalovirus infections and sarcoidosis: thus, the manifestations of this syndrome and diverse and depend on the tissue burden of the preexisting infectious agents during the immunosuppressive state, the nature of the immune system being restored, and underlying diseases of the hosts. Although IRS has originally been reported to occur in the setting of HIV infection, it has become clear that the development of IRS can also be in HIV-negative hosts receiving immunosuppressive agents, such as prednisolone and tumor necrosis factor α inhibitors, upon their reduction and withdrawal. Drug-induced hypersensitivity syndrome, a life-threatening multiorgan system reaction, is another manifestation of the newly observed IRS. Clinical recognition of the IRS is especially important in improving the outcome for diseases with an otherwise life-threatening progenosis. Clinicians should be aware of the implications of IRS and recognize that relieving the symptoms and signs of immune recovery by anti-inflammatory therapies needs to be balanced with anti-microbial therapies aiming at reducing the amplitude and duration of tissue burden of preexisting microbes.

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Background: The impairment that pruritic skin diseases have on patient productivity at work, in the classroom, and in daily activities is substantial and needs to be characterized. The objective of this study was to determine how pruritic skin diseases impact patient productivity and quality of life (QOL), in order to improve the measurement of these endpoints to allow the influence of treatment options including sedative and non-sedative antihistamines to be analyzed.
Methods: The impact of pruritic skin diseases and the effect of antihistamine therapy on work, classroom, and daily productivity were evaluated using the Work Productivity Assessment Index-Allergy Specific Questionnaire. The intensity of itch and patient QOL were assessed using a visual analogue scale and Skindex-16, respectively.
Results: Pruritic skin diseases resulted in significant impairment of work, classroom, and daily productivity. The severity of overall work impairment in atopic dermatitis (AD), urticaria, and prurigo was higher than for other diseases analyzed. However, classroom activity was more adversely affected in patients with urticaria relative to other diseases. All pruritic diseases in this study negatively impacted daily activity to a similar degree. Impaired productivity was significantly improved in patients taking non-sedative antihistamines for 1 month, and the improvements correlated with the alleviation of itch and improved QOL.
Conclusions: These results indicate that pruritic skin diseases reduce patient productivity at work, in the classroom, and during daily activities, and that non-sedative antihistamines may offer an advantage over sedative antihistamines for alleviating certain negative consequences of these skin diseases.

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Background: To reduce deaths from asthma, further use of inhaled corticosteroids (ICS) in accordance with the guidelines is required. The present study was conducted because specialists are responsible for increasing the use of guidelines, but the current state of asthma care provided by specialists in primary clinical settings has not been clarified.
Methods: In collaboration with five primary medical facilities throughout Japan, severity of asthma, contents of asthma therapy, and the implementation rate of pulmonary function testing and peak flow measurements were analyzed for 1007 outpatients ≥40 years old with stable bronchial asthma. In all patients, peak inspiratory flow (PIF) was measured during examination.
Results: Either ICS or ICS/long-acting beta 2 agonist (LABA) was used in almost all patients with at least mild persistent asthma. Although treatments adhered to the guidelines, therapeutic steps did not match asthma severity in many patients with mild intermittent asthma. Large gaps existed between facilities that measure pulmonary function and PEF in daily clinical practice and those that do not. While mean PIF value for all subjects was well maintained at 102.0 ± 29.1L/min, some patients may not have been able to inhale efficiently in terms of PIF (5.1% of Turbuhaler^® users and 5.7% of Diskhaler^® users).
Conclusions: When stepping down asthma therapy, some confusion in policy may exist, leading to guideline mismatches. Differences in the implementation of pulmonary function and PEF measurements, as indicators for long-term management, need to be minimized among specialists. For maintaining effective inhalation, inspiratory flow should be periodically checked.

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Background: The measurement of the exhaled nitric oxide fraction (FE_NO) is proposed as a useful marker of airway inflammation. In healthy adults, there have been a few studies of the reference ranges for FE_NO in Caucasians. A community study in other regions may reveal any possible ethnic differences in the FE_NO levels.
Methods: A total of 240 healthy adults aged between 18 to 74 years were recruited from four medical centers in Japan. Current smokers and subjects having a history of atopic disease were not included. FE_NO was measured using an online electrochemical nitric oxide analyzer according to the current guidelines. The reference ranges for FE_NO were estimated using two different statistical methods recommended by International Federation of Clinical Chemistry and Laboratory Medicine.
Results: The mean FE_NO was 16.9 ppb (parts per billion) with a 95% prediction interval (2.5 to 97.5 percentiles) of 6.5 to 35.0 ppb in healthy Japanese adults. Normality assumptions were met for the logarithm-transformed FE_NO. The geometric mean FE_NO was 15.4 ppb with a mean ± two standard deviations of 6.5 to 36.8 ppb. Age, gender, height, and past smoking history were not associated with the FE_NO levels.
Conclusions: The reference ranges for FE_NO in healthy Japanese adults were similar to those of Caucasians. It seems reasonable that the upper limit of FE_NO for healthy adults should be set at approximately 36.0 ppb irrespective of ethnic differences.

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Background: The influence of food avoidance due to allergic symptoms in infancy on the growth of children at school age has not been well evaluated.
Methods: To determine the growth of schoolchildren who avoided eggs, milk, or wheat due to immediate allergic symptoms in infancy (food avoiders in infancy) (FAI), a questionnaire on the presence of allergic diseases, as well as present height and weight, was administered to the parents of 14,669 schoolchildren. 11,473 subjects had available data. The height and weight standard deviation scores (HtSDS and WtSDS) and body mass index percentile (BMI percentile) of each subject were calculated.
Results: FAI had significantly lower WtSDS than non-FAI (P = 0.01). Among those with avoidance at age 3 years, those who avoided two or more foods and those who avoided milk had significantly lower HtSDS than their counterparts (P = 0.02 and 0.04, respectively). FAI had a significantly lower prevalence of obesity (P = 0.01) and overweight (P = 0.002), while there was no difference in the prevalence of underweight (P = 0.58), resulting in a significantly higher prevalence of appropriate weight (P = 0.01) compared to non-FAI. Significantly lower prevalence of obesity and overweight was observed even among those who terminated the avoidance by age 3 years.
Conclusions: FAI were less likely to be obese or overweight, resulting in a higher prevalence of appropriate weight at school age. Further investigation should contribute to better management of food allergy and obesity.

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Background: Creola bodies (CrBs) in the sputum are an indicator of respiratory epithelial damage and appear specifically in bronchial asthma. We studied the presence and clinical significance of CrBs in infants with respiratory syncytial virus (RSV) bronchiolitis contributing to the development of asthma.
Methods: Aspirated sputum samples were collected from 33 infants admitted with acute RSV bronchiolitis. The samples were then examined for the presence (or absence) of CrBs and classified into the RSV-CrB group and RSV-non-CrB group. Eosinophil cationic protein (ECP) and neutrophil elastase (NE) concentrations in the sputum were compared between the two groups. History of wheeze and asthma was collected at 2 years and 5 years after their discharge from hospital.
Results: CrBs were detected in 23 of the 33 subjects (69.7%). No significant difference in the ECP and the NE concentration were observed between the RSV-CrB group and RSV-non-CrB group. A significant relationship was observed between CrBs detected with RSV bronchiolitis and the development of recurrent wheezing and asthma (after 2 years: relative risk [RR], 3.09; p = 0.002; after 5 years: RR 7.00; p = 0.019).
Conclusions: These findings suggest that a high rate of CrBs in the sputum is present in infants with RSV bronchiolitis, and notably the CrBs are associated with the progression to recurrent wheezing and asthma.

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Background: House dust extract is used in conventional immunotherapy for house dust-mite (HDM) allergic rhinitis in Japan. However, an alternative administration route is desired. The aims of the present double blind, placebo-controlled trial were to evaluate the therapeutic efficacy and safety of sublingual immunotherapy (SLIT) with house dust extract in pediatric patients with HDM allergic rhinitis.
Methods: The study population comprised 31 subjects (21 males and 10 females) aged from 7 to 15 years old. Twenty patients (the active group) received house dust extract and 11 received placebo via sublingual administration. Extract or placebo (1ml) was administered at 10-fold dilution once weekly for 40 weeks. During the study period, the subjects recorded their daily nasal symptoms and use (dose and frequency) of other medications in a nasal allergy diary.
Results: The symptom scores in the active group began to decrease about 24 weeks after initiation of treatment and significant differences between the active and placebo groups were observed after 30 weeks. The average scores for the last four weeks of the study were significantly lower than those for the first four weeks in the active group but not in the placebo group. The only local adverse effect was a bitter taste reported by one patient. There were no other local or systemic adverse effects associated with SLIT.
Conclusions: Our results suggest that SLIT with house dust extract for more than 30 weeks is safe and effective treatment for HDM allergic rhinitis in children.

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Background: In previous studies, several strains of mice were used as chemical-induced skin irritation models to identify immunological hazards and elucidate the molecular and cellular mechanisms by which irritant dermatitis disease occur. BALB/c and C57BL/6 mice have been used for most of these experiments. Although there are some differences in the immune response to chemical allergens between these strains, few studies have been conducted to determine what regulatory factors contribute to these variations.
Methods: To investigate the cause of high responses to skin irritation in C57BL/6 mice that are widely used to study atopic dermatitis, changes in various immune-related factors such as ear thickness, myeloperoxidase activity, lymph node weight, IgE concentration and cytokine concentration were measured in C57BL/6 and BALB/c mice following phthalic anhydride (PA) treatment.
Results: Based on analysis of the skin irritation, C57BL/6 mice showed a greater skin irritation to PA than BALB/c mice, although the IgE concentration and auricular lymph node weight did not contribute to this difference in the response. However, the concentration of several cytokines and chemokines (interleukin [IL]-6 and vascular endothelial growth factor [VEGF], keratinocyte-derived chemokine [KC] and regulated on activation normal T cell expressed and secreted [RANTES]) were significantly higher in C57BL/6 mice than BALB/c mice following treatment with PA.
Conclusions: Our results suggest that several of the cytokines and chemokines secreted from irritant site could contribute to the regulation mechanism responsible for the difference in the skin irritation among various strains of mice following exposure to PA.

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Background: IL-25, which is a member of the IL-17 family, induces Th2 cell differentiation and Th2 cytokine production, contributing to induction of Th2-type immune responses and diseases, as a result of which it suppresses Th1- and Th17-type immune responses.
Methods: To elucidate the role of IL-25 in the pathogenesis of IL-17-mediated delayed-type hypersensitivity (DTH), IL-25-deficient mice were sensitized with methylated BSA (mBSA), and then a DTH reaction was induced by mBSA challenge. mBSA-specific T-cell induction was assessed on the basis of cell proliferation and cytokine production. The DTH reaction was evaluated on the basis of tissue swelling, histology and inflammatory mediator expression.
Results: IL-25 expression was markedly reduced in local DTH lesions. However, mBSA-specific Th1, Th2 and Th17 cell induction, and the mBSA-induced DTH reaction were comparable in IL-25-deficient and wild-type mice.
Conclusions: IL-25 is not essential for differentiation of Th1, Th2 and Th17 cells in the sensitization phase or induction of local inflammation in the elicitation phase of the mBSA-induced DTH reaction.

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Background: Interstitial lung disease (ILD) is the major cause of mortality in collagen vascular diseases. However, its pathogenesis still needs to be elucidated.
Methods: To evaluate the alteration of certain proteins in bronchoalveolar lavage fluid (BALF) and clarify the causative role in the processes of ILD in systemic sclerosis (SSc), we compared a BALF protein profile between 5 patients with systemic sclerosis with pulmonary fibrosis (SSc-fib+) and 4 patients with systemic sclerosis without pulmonary fibrosis (SSc-fib-) using two-dimensional gel electrophoresis (2-DE), and matrix assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS).
Results: We analyzed spots over the range of 10.1kDa to 207.4kDa. SSc-fib+ patients showed increased 3 proteins compared to SSc-fib- including α2-macroglobulin, α1-antitrypsin, and pulmonary surfactant protein A and decreased 2 proteins including α2 heat shock protein (HSP) and glutathione S-transferase (GST) compared to SSc-fib- patients.
Conclusions: In conclusion, we identified several interesting proteins that might have roles in ILD of SSc patients. Further studies are warranted to clarify the role of these proteins in the processes of pulmonary fibrosis in SSc.

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Background: Matsutake mushroom is not recognized as a common food allergen. However, several case reports have suggested that this mushroom can induce anaphylaxis on rare occasions.
Case Summary: We report a woman with bronchial asthma, who experienced two episodes of Matsutake-induced anaphylaxis. Both the prick-to-prick test and basophil histamine release test showed positive reactions to this mushroom in this patient, but not in control subjects.
Discussion: Matsutake mushroom can, on rare occasions, cause anaphylaxis in sensitized people, a reaction so far observed only in Japan. Not ony the in vivo prick-to-prick test but also the in vitro basophil activation test utilizing the patient's blood represent useful methods for allergen identification and also for identification of sensitized subjects.

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Acute eosinophilic pneumonia (AEP) is characterized by febrile illness, diffuse pulmonary infiltrates with eosinophilia. The pathogenesis is not well understood. We report a case of 22-year-old men who never smoke presented with AEP 2 days after acute passive smoke exposure. He developed acute respiratory failure despite having no history of the disease. Computed tomography of the lung revealed diffuse bilateral pulmonary infiltrates. Lung biopsy specimens revealed marked eosinophil infiltration in the alveolar septa without signs of vasculitis.
Two days prior to the disease, he was exposed to cigarette smoke for 2 hours in a closed area. In the absence of other causes, passive smoking may cause lung inflammatory responses.
The level of urinary cotinine, which is a biomarker of smoke exposure, was considerably higher (0.198μg/ml [201ng/mg Creatinine]) than that in nonsmokers, but never detected following period. This case suggests that short-term passive smoking may cause AEP.

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Background: Juvenile dermatomyositis is potentially life threatening rare autoimmune illness that mainly affects muscle and skin. Cutaneous features are useful in establishing the diagnosis of this disease.
Case Summary: We report an 8-year-old male juvenile dermatomyositis who presented epidermal nevus like-lesions on the back of the right thigh. Characteristic cutaneous changes such as Gottron's papules of the hand, heliotrope rash of the eyelids, and poikiloderma-like lesions on the back were observed. Diagnosis of juvenile dermatomyositis was made by positive muscle biopsy and magnetic resonance imaging findings and typical cutaneous manifestations. However, epidermal nevus-like skin lesions, an acquired inflammatory dermatosis that follows Blaschko lines, seen in this case have been rarely reported in the literatures.
Discussion: We would like to report this case and discuss about the significance and pathogenesis of this rare cutaneous manifestation like Blaschkitis in juvenile dermatomyositis.

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