A European-Japanese study on peach allergy: IgE to Pru p 7 associates with severity.

BACKGROUND: Pru p 3 and Pru p 7 have been implicated as risk factors for severe peach allergy. This study aimed to establish sensitization patterns to five peach components across Europe and in Japan, to explore their relation to pollen and foods and to predict symptom severity. METHODS: In twelve European (EuroPrevall project) and one Japanese outpatient clinic, a standardized clinical evaluation was conducted in 1231 patients who reported symptoms to peach and/or were sensitized to peach. Specific IgE against Pru p 1, 2, 3, 4 and 7 and against Cup s 7 was measured in 474 of them. Univariable and multivariable Lasso regression was applied to identify combinations of parameters predicting severity. RESULTS: Sensitization to Pru p 3 dominated in Southern Europe but was also quite common in Northern and Central Europe. Sensitization to Pru p 7 was low and variable in the European centers but very dominant in Japan. Severity could be predicted by a model combining age of onset of peach allergy, probable mugwort, Parietaria pollen and latex allergy, and sensitization to Japanese cedar pollen, Pru p 4 and Pru p 7 which resulted in an AUC of 0.73 (95% CI 0.73-0.74). Pru p 3 tended to be a risk factor in South Europe only. CONCLUSIONS: Pru p 7 was confirmed as a significant risk factor for severe peach allergy in Europe and Japan. Combining outcomes from clinical and demographic background with serology resulted in a model that could better predict severity than CRD alone.

Identification of patterns of factors preceding severe or life-threatening asthma exacerbations in a nationwide study.

BACKGROUND: Reducing near-fatal asthma exacerbations is a critical problem in asthma management. OBJECTIVES: To determine patterns of factors preceding asthma exacerbations in a real-world setting. METHODS: In a nationwide prospective study of 190 patients who had experienced near-fatal asthma exacerbation, cluster analysis was performed using asthma symptoms over the 2-week period before admission. RESULTS: Three distinct clusters of symptoms were defined employing the self-reporting of a visual analogue scale. Cluster A (42.1%): rapid worsening within 7.4 hours from moderate attack to admission, young to middle-aged patients with low Body mass index and tendency to depression who had stopped anti-asthma medications, smoked, and hypersensitive to environmental triggers and furred pets. Cluster B (40.0%): fairly rapid worsening within 48 hours, mostly middle-aged and older, relatively good inhaled corticosteroid (ICS) or ICS/long-acting beta-agonist (LABA) compliance, and low perception of dyspnea. Cluster C (17.9%): slow worsening over 10 days before admission, high perception of dyspnea, smokers, and chronic daily mild-moderate symptoms. There were no differences in overuse of short-acting beta-agonists, baseline asthma severity, or outcomes after admission for patients in these 3 clusters. CONCLUSION: To reduce severe or life-threatening asthma exacerbation, personalized asthma management plans should be considered for each cluster. Improvement of ICS and ICS/LABA compliance and cessation of smoking are important in cluster A. To compensate for low perception of dyspnea, asthma monitoring of peak expiratory flow rate and/or exhaled nitric oxide would be useful for patients in cluster B. Avoidance of environmental triggers, increase usual therapy, or new anti-type 2 response-targeted therapies should be considered for cluster C.

Lip b 1 is a novel allergenic protein isolated from the booklouse, Liposcelis bostrychophila.

BACKGROUND: Booklice, belonging to the order Psocoptera, are small household insect pests that are distributed worldwide. Liposcelis bostrychophila, a common home-inhabiting species of booklouse, infests old books, sheets of paper, and stored food. Recent entomological and serological studies demonstrated that L. bostrychophila accounted for the majority of detectable insects in house dust and could be a potent inducer of respiratory allergy. Our recent proteomic analysis identified a potent allergenic protein from L. bostrychophila, designated Lip b 1, and determined its partial amino acid sequences. METHODS: Cloning of cDNAs for Lip b 1 was performed by large-scale transcriptome analysis (RNA-seq) and subsequent reverse transcription polymerase chain reaction. The full-length amino acid sequences deduced from Lip b 1 cDNAs were bioinformatically analyzed. The recombinant proteins of glutathione S-transferase (GST)-fused Lip b 1 were analyzed by Western blot and enzyme-linked immunosorbent assay. RESULTS: Lip b 1 cDNAs encoding two types of 254-amino acid proteins were cloned. The clones shared 87% identity, and the deduced molecular weights and isoelectric points were consistent with those determined in our previous study. The two types of Lip b 1 proteins in the GST-fused form were similarly reactive with sera from allergic patients sensitized with L. bostrychophila. CONCLUSIONS: Lip b 1 is a novel protein possibly causing booklouse allergy.

Severe or life-threatening asthma exacerbation: patient heterogeneity identified by cluster analysis.

BACKGROUND: Severe or life-threatening asthma exacerbation is one of the worst outcomes of asthma because of the risk of death. To date, few studies have explored the potential heterogeneity of this condition. OBJECTIVES: To examine the clinical characteristics and heterogeneity of patients with severe or life-threatening asthma exacerbation. METHODS: This was a multicentre, prospective study of patients with severe or life-threatening asthma exacerbation and pulse oxygen saturation < 90% who were admitted to 17 institutions across Japan. Cluster analysis was performed using variables from patient- and physician-orientated structured questionnaires. RESULTS: Analysis of data from 175 patients with severe or life-threatening asthma exacerbation revealed five distinct clusters. Cluster 1 (n = 27) was younger-onset asthma with severe symptoms at baseline, including limitation of activities, a higher frequency of treatment with oral corticosteroids and short-acting beta-agonists, and a higher frequency of asthma hospitalizations in the past year. Cluster 2 (n = 35) was predominantly composed of elderly females, with the highest frequency of comorbid, chronic hyperplastic rhinosinusitis/nasal polyposis, and a long disease duration. Cluster 3 (n = 40) was allergic asthma without inhaled corticosteroid use at baseline. Patients in this cluster had a higher frequency of atopy, including allergic rhinitis and furred pet hypersensitivity, and a better prognosis during hospitalization compared with the other clusters. Cluster 4 (n = 34) was characterized by elderly males with concomitant chronic obstructive pulmonary disease (COPD). Although cluster 5 (n = 39) had very mild symptoms at baseline according to the patient questionnaires, 41% had previously been hospitalized for asthma. CONCLUSIONS & CLINICAL RELEVANCE: This study demonstrated that significant heterogeneity exists among patients with severe or life-threatening asthma exacerbation. Differences were observed in the severity of asthma symptoms and use of inhaled corticosteroids at baseline, and the presence of comorbid COPD. These findings may contribute to a deeper understanding and better management of this patient population.

Molecular-based allergy diagnosis of allergic bronchopulmonary aspergillosis in Aspergillus fumigatus-sensitized Japanese patients.

BACKGROUND: Distinguishing between patients with allergic bronchopulmonary aspergillosis (ABPA) and Aspergillus fumigatus (Af)-sensitized asthmatic patients without ABPA is sometimes difficult owing to the IgE-cross-reactivity between Af and other fungal allergens. OBJECTIVE: To establish the usefulness of molecular-based allergy diagnostics using allergen components from Af in distinguishing ABPA from Af-sensitized asthma without ABPA. METHODS: Sera from Japanese patients with ABPA (n = 53) and Af-sensitized asthma without ABPA (n = 253) were studied. The levels of IgE and IgG antibodies to allergen components from Af and IgE antibodies to different fugal allergen extracts were measured by ImmunoCAP. Comorbid atopic dermatitis (AD) was taken into consideration in the sensitization profile analysis. RESULTS: Patients with ABPA possessed significantly higher levels of IgE antibodies to Asp f 1, and Asp f 2 than asthmatic patients without ABPA. The areas under the receiver operating characteristic curves for the levels of IgE to Asp f 1 and Asp f 2 as diagnostic markers of ABPA were 0.75 and 0.78, respectively. The presence of IgE positivity to Asp f 1 and/or Asp f 2 resulted in increased sensitivity while losing little specificity. Comorbid AD was associated with higher levels of IgE to Asp f 6 (manganese superoxide dismutase from Af, a ubiquitous pan-allergen in fungi) and low but positive levels of IgE to other Af-components, which hampered the serological discrimination of ABPA. CONCLUSIONS AND CLINICAL RELEVANCE: The levels of IgE to Asp f 1 and/or Asp f 2 can effectively differentiate ABPA from Af-sensitized asthma, suggesting that the amounts of IgE specific for these molecules are markers for genuine Af-sensitization in ABPA. However, comorbid AD must be taken into consideration in the interpretation of high IgE to Asp f 6. Establishing of IgE-sensitization profiles using panel of Af-allergen components provides valuable information for distinguishing genuine vs. cross-reactive sensitization in Af-sensitized patients.

Epidemiological link between wheat allergy and exposure to hydrolyzed wheat protein in facial soap.

BACKGROUND: Recent studies have highlighted the importance of extra-intestinal routes of sensitization to food-related allergens as the cause of epidemics of food allergy. Instances of Japanese women developing food allergy to wheat after exposure to hydrolyzed wheat protein (HWP) present in facial soap have been reported. However, the epidemiologic impact of these ingredients as a cause of food allergy has not been well studied. METHODS: To clarify the epidemiological relationship between food allergy to wheat and contact exposure to HWP, a case-control study of Japanese women aged 20-54 years with self-reported wheat allergy (WA) (cases, n = 157) and age-matched control subjects without WA (controls, n = 449) was performed using a large-scale Web-based research panel. Subjects answered a Web-based questionnaire regarding the use of skin and hair care products, as well as other possible risk factors. RESULTS: Current use of an HWP-containing facial soap (Cha no Shizuku; Yuka) was significantly associated with an increased risk of WA (adjusted odds ratio, 2.6; 95% confidence interval, 1.2-5.7; frequencies of current use in cases and controls; 11% and 6%, respectively). Use of Cha no Shizuku was more common in subjects with more recent-onset WA, implying that this soap may have contributed to the recent epidemic of WA. CONCLUSIONS: An epidemiological relationship between WA and contact exposure to HWP has been documented. This study implicates a possible role of contact exposure to food-derived protein hydrolysates as a risk factor for the development of food allergy manifesting itself as anaphylaxis.

Obesity and aspirin intolerance are risk factors for difficult-to-treat asthma in Japanese non-atopic women.

BACKGROUND: Asthma is a clinical syndrome characterized by variabilities in disease expression and severity. The pathophysiological mechanism underlying anti-asthma treatment resistance is also assumed to be different between disease phenotypes. OBJECTIVE: To elucidate the effect of gender and atopic phenotype on the relationship between clinical factors and the risk of treatment resistance. METHODS: We compared outpatients with difficult-to-treat asthma (DTA; n = 486) in a tertiary hospital for allergic diseases in central Japan with those with controlled severe asthma (n = 621) with respect to clinical factors including body mass index (BMI) and aspirin intolerance using multivariate logistic regression analysis stratified by gender and atopic phenotype. RESULTS: When analysis was performed on the entire study populations, obesity (BMI ≥ 30 kg/m(2); adjusted odds ratio (OR) 1.92; 95% confidence interval (95% CI: 1.07-3.43) and aspirin intolerance (OR: 2.56, 95% CI: 1.44-4.57) were found to be the significant risk factors for DTA. However, after the stratification by gender and atopic phenotype, the association between obesity and DTA was significant only in women (OR: 2.76, 95% CI: 1.31-5.78), but not in men (OR: 1.03, 95% CI: 0.38-2.81), and only in non-atopics (OR: 4.03, 95% CI: 1.15-14.08), but not in atopics (OR: 1.54, 95% CI: 0.79-3.02). The similar gender and phenotypic differences were also observed in the association between aspirin intolerance and DTA: namely, the association was significant only in women (OR: 3.96, 95% CI: 1.84-8.50), but not in men (OR: 1.19, 95% CI: 0.46-3.05); and only in non-atopics (OR: 5.49, 95% CI: 1.98-15.19), but not in atopics (OR: 1.39, 95% CI: 0.65-2.98). CONCLUSIONS AND CLINICAL RELEVANCE: Significant associations of obesity and aspirin intolerance with DTA were observed only in women and in non-atopics. These findings suggest that a phenotype-specific approach is needed to treat patients with DTA.

Sensitization to acid-hydrolyzed wheat protein by transdermal administration to BALB/c mice, and comparison with gluten.

BACKGROUND: An increasing number of studies have shown that hydrolyzed wheat protein (HWP) can induce IgE-mediated hypersensitivity by skin contact and/or food ingestion. However, there has been no study of the sensitizing potential of HWP. In this study, the possibility of transdermal pathway for sensitization to acid-HWP (HWP1) was investigated using BALB/c mice, and compared with that of gluten. METHODS: HWP1 or gluten (500 µg/mouse) was transdermally administered using patches. After three or four cycles of sensitization for 3 days/week, active systemic anaphylaxis (ASA) was induced by intraperitoneal injection of the antigen, and rectal temperatures, scores of anaphylactic responses, and plasma histamine levels were determined. Because HWP1 was included in facial soap in Japan, the effect of detergent on the sensitizing potential was also investigated. RESULTS: Transdermal administration of HWP1 induced dose-dependent production of IgE and IgG1. After sensitization for 3 or 4 weeks, intraperitoneal injection of HWP1 caused ASA, leading to decreased rectal temperatures, increased anaphylaxis scores, and increased plasma histamine levels. In addition, splenocytes harvested after ASA produced IL-4, IL-5, and IL-10 by re-stimulation with HWP1. Transdermal exposure to gluten also induced IgE and IgG1 production, and intraperitoneal injection of gluten also induced ASA only in mice sensitized in the presence of sodium dodecyl sulfate. CONCLUSIONS: Transdermal exposure to HWP1 is sufficient to activate key immune pathways necessary for sensitizing mice for immediate hypersensitivity reactions. This study shows that HWP has a sensitizing potential as well as gluten, whereas its allergenicity may be different from that of gluten.

The prevalence of rhinitis and its association with smoking and obesity in a nationwide survey of Japanese adults.

BACKGROUND: Rhinitis is a common disease, and its prevalence is increasing worldwide. Several studies have provided evidence of a strong association between asthma and rhinitis. Although smoking and obesity have been extensively analyzed as risk factors of asthma, associations with rhinitis are less clear. OBJECTIVE: The aims of our study were (i) to evaluate the prevalence of rhinitis using the European Community Respiratory Health Survey (ECRHS) questionnaire in Japanese adults and (ii) to evaluate the associations of smoking and body mass index (BMI) with rhinitis. METHODS: Following our study conducted in 2006-2007 to determine the prevalence of asthma using the ECRHS questionnaire, our present analysis evaluates the prevalence of rhinitis and its association with smoking and BMI in Japanese adults 20-79 years of age (N = 22819). We classified the subjects (20-44 or 45-79 years) into four groups as having (i) neither rhinitis nor asthma; (ii) rhinitis without asthma; (iii) asthma without rhinitis; or (iv) rhinitis with asthma. We then evaluated associations with smoking and BMI in each group. RESULTS: The overall age-adjusted prevalence of rhinitis was 35.1% in men and 39.3% in women. A higher prevalence was observed in the younger population than in the older population. Active smoking and obesity were positively associated with asthma without rhinitis. In contrast, particularly in the 20- to 44-year age-group, active smoking and obesity were negatively associated with rhinitis without asthma. CONCLUSION: The results of the present study suggest that smoking and obesity may have different effects on the development of rhinitis and asthma.

Increased production of cysteinyl leukotrienes and prostaglandin D2 during human anaphylaxis.

BACKGROUND: Anaphylaxis is a life-threatening syndrome resulting from the sudden release of mast cell- and basophil-derived mediators into the circulation. However, pathological evidence of the association between inflammatory mediators and human anaphylaxis is insufficient. OBJECTIVE: The aim of this study was to better understand the relationship between in vivo production of inflammatory mediators and the pathogenesis of anaphylaxis. We also sought to evaluate mast cell activation in anaphylaxis. METHODS: We measured the concentrations of various inflammatory mediators in urine samples, which were collected from 32 anaphylactic patients during the onset of anaphylaxis and during clinical remission, 21 patients with asthma on acute exacerbation and 15 healthy control subjects. Blood and urine specimens were collected from the patients after provocation test. Urinary leukotriene E4 (LTE4), 9alpha, 11beta-prostaglandin F2 (9alpha, 11beta-PGF2), eosinophil-derived neurotoxin (EDN) and leukotriene B4 glucuronide (LTBG) concentrations were determined by enzyme immunoassay, and the activity of plasma platelet-activating factor acetylhydrolase and serum tryptase concentration were measured using commercially available kits. RESULTS: Significantly higher concentrations of urinary LTE4 and 9alpha, 11beta-PGF2, which immediately decreased during clinical remission, were observed in the anaphylactic patients than in asthmatic patients on acute exacerbation and healthy control subjects. Concentrations of EDN and LTBG were not significantly different among the anaphylactic patients, asthmatic patients on acute exacerbation and healthy subjects. There was a significant correlation between urinary LTE4 and 9alpha, 11beta-PGF2 concentrations in the anaphylactic patients (r=0.672, P=0.005, n=32). In addition, LTE4 concentration in patients with anaphylactic shock is significantly elevated compared with that in patients without anaphylactic shock. CONCLUSIONS: This is a report on the significant increase in urinary LTE4 and 9alpha, 11beta-PGF2 concentrations during anaphylaxis. Urinary LTE4 and 9alpha, 11beta-PGF2 concentrations may be a reliable marker of endogenous production of inflammatory mediators associated with anaphylaxis.

Increased urinary leukotriene E4 concentration in patients with eosinophilic pneumonia.

Although eosinophils produce cysteinyl leukotrienes (CysLTs) in large quantities, information on the relationship between CysLTs and eosinophilic pneumonia (EP) is lacking. Inflammatory mediator concentrations in urine were quantified to clarify the relationship between CysLT concentrations and EP severity. Leukotriene (LT)E(4), eosinophil-derived neurotoxin (EDN), 9alpha,11beta-prostaglandin F2 and LTB(4) glucuronide concentrations were quantified in the urine of: EP patients during acute exacerbation and clinical remission; asthmatic patients during acute exacerbation and under stable conditions; and healthy control subjects. The urinary LTE(4) and EDN concentrations of EP patients during acute exacerbation were significantly higher than those of asthmatic patients and healthy subjects, and decreased immediately during clinical remission. The urinary LTE(4) concentration was associated with the urinary EDN concentration of EP patients during acute exacerbation. The urinary LTE(4) concentration significantly correlated with the diffusing capacity of the lung for carbon monoxide in EP patients during acute exacerbation. The increased urinary concentrations of leukotriene and eosinophil-derived neurotoxin were associated with acute exacerbation in eosinophilic pneumonia patients. The increased leukotriene concentration significantly correlated with diffusing capacity of the lung for carbon monoxide, suggesting that the monitoring of leukotriene concentration may aid in the management of eosinophilic pneumonia patients.

Polymorphism of the 5' flanking region of the IL-12 receptor beta2 gene partially determines the clinical types of leprosy through impaired transcriptional activity.

BACKGROUND: Individual differences in T cell responsiveness to interleukin 12 (IL-12), resulting from inherited factors, may be responsible for differences in the intensity of cell mediated immune (CMI) responses in patients with leprosy, a disease with a wide clinical spectrum. AIM: Polymorphisms in the 5' flanking region of the IL12RB2 gene were analysed to determine potential immunogenetic factors affecting CMI responses, using leprosy as a model. METHODS: Polymorphisms in the 5' flanking region of IL12RB2 were examined using direct sequencing techniques, and allele frequencies between patients with lepromatous leprosy and patients with tuberculoid leprosy were compared. The effect of these single nucleotide polymorphisms (SNPs) on IL12RB2 expression was estimated using the dual luciferase reporter gene assay in Jurkat T cells. RESULTS: Several SNPs, including -1035A>G, -1023A>G, -650delG, and -465A>G, were detected within the 5' flanking region of IL12RB2. The frequency of haplotype 1 (-1035A, -1023A, -650G, -464A) was high in the general Japanese population, but was significantly lower in lepromatous patients compared with tuberculoid patients and healthy controls. Reporter gene assays using Jurkat T cells revealed that all haplotypes carrying one or more SNP exhibited a lower transcriptional activity compared with haplotype 1. CONCLUSION: SNPs within the 5' flanking region of IL12RB2 affect the degree of expression of this gene and may be implicated in individual differences in CMI responsiveness to mycobacterial antigens, leading to lepromatous or tuberculoid leprosy.

Extrarenal Wilms' tumor in the adult patient. A case report and review of the world literature.

A case of an extrarenal Wilms' tumor arising in the retroperitoneal region of a 49-year-old male is reported. A review of the world literature indicates that the incidence of the tumor arising in the extrarenal region is extremely rare. A total of 14 cases have previously been reported, but the number of cases that occurred in adult patients is only 2. The clinical and pathologic features are briefly discussed.

Type II citrullinemia in an elderly patient treated with living related partial liver transplantation.

A 60-year-old woman was admitted to our hospital for repeated consciousness disturbance. Blood examination showed hyperammonemia, and plasma amino acid analysis revealed a marked increase in the citrulline level. To establish a diagnosis, a percutaneous needle biopsy of the liver was performed. The determination of the urea cycle enzyme activities revealed a selective marked decrease in argininosuccinate synthetase activity, indicating the final diagnosis of type II citrullinemia. The mean survival period of this disease after the appearance of symptoms has been reported as 26.4 months, and most conservative treatments are not effective. We performed a living related partial liver transplantation. Over the subsequent 13-month follow-up, the patient's condition has remained fairly good.

[Multiple myeloma presenting as massive ascites].

Ascites is a rare complication of multiple myeloma. We report a case of multiple myeloma with peritoneal involvement. An 80-year-old woman was admitted to our hospital because of massive ascites. Laboratory findings included an Hb of 7.8 g/dl, IgA of 2,160 mg/dl, and CA125 of 942 IU/ml. Immunoelectropheresis analysis detected a monoclonal component of IgA lambda in serum, and of BJP lambda in urine. Bone marrow aspirtion revealed normal cellularity with 32.7% atypical plasma cells. The ascites was characterized by an exudate with numerous atypical plasma cells and elevated IgA and CA125 levels. The IL-6 level was 22 pg/ml and 79 pg/ml in serum and ascites, respectively. A diagnosis of IgA lambda multiple myeloma with peritoneal involvement was made. Chemotherapy consisting of melphalan and prednisolone reduced the serum IgA and CA125 levels markedly, and alleviated the patient's ascites.

[Non-Hodgkin's lymphoma with Toxoplasma encephalitis].

A 62-year-old man was admitted to our hospital due to fever and systemic lymph-node swelling on June 9, 1998. He was given a diagnosis of non-Hodgkin's lymphoma (diffuse mixed T cell lymphoma) with involvement of mediastinum and para-aortic lymph nodes, pleura, peritoneum, and bone marrow. After diagnosis, combined chemotherapy (CHOP regimen) was started. On day 11, the patient's consciusness level suddenly deteriorated. A brain computed tomographic scan showed no abnormal findings. A cytospin smear of cerebrospinal fluid disclosed tachyzoides (Toxoplasmic bodies), thus yielding a diagnosis of Toxoplasma encephalitis. Oral sulfadoxine pyrimethamine rapidly alleviated the patient's consciousness disturbance. One month later, a cytospin smear and RT-PCR analysis of cerebrospinal fluid detected no tachyzoides. Complete remission of lymphoma was achieved after 2 courses of CHOP therapy. Toxoplasma encephalitis should be considered a potential cause of consciousness disturbance in immunocompromised hosts, such as patients with malignant lymphoma. Cytospin smears of cerebrospinal fluid are a useful tool for the early diagnosis of Toxoplasma encephalitis.

[A high risk group of hepatocellular carcinoma in man, with special reference to its clinical significance for the screening of early liver cancer. Gifu Study Group for Early Liver Cancer].

A high risk group of hepatocellular carcinoma (HCC) was statistically established using multiple regression analysis of 331 cases with liver cirrhosis (LC), in which 78 cases later developed HCC. Highly contributing factors to hepatocarcinogenesis were found to be positive HBsAg, age, drinking history, sex (male), history of blood transfusion, history of acute hepatitis (or jaundice) and elevated plasma levels of alpha-fetoprotein. A prospective study was initiated in April, 1985 employing another 122 LC patients to clinically evaluate the significance of the high risk group of HCC. 28 cases with small HCC (less than 3 cm in diameter) were newly found: 4 with chronic hepatitis and 24 with LC, among whom 22 developed from the high risk group (sensitivity 92%, specificity 44%). Three year survival rate of 28 cases thus found was 56%, and causes of death of 9 fatal patients were 4 cancer death, 4 hepatic failure and 1 gastrointestinal bleeding. In conclusion, the high risk group is valuable for the screening of early liver cancers, and treatments of hepatic failure as well as of HCC itself are important to improve the prognosis of HCC patients thus diagnosed.