A case of piperacillin-induced occupational anaphylaxis: detection of serum IgE to piperacillin-HSA conjugate.

This is the first reported detection of serum IgE antibody to piperacillin-human serum albumin (HSA) conjugate in a patient presenting with anaphylaxis that developed after occupational exposure. A 24-yr-old nurse, who had worked at a University Hospital for 2 yr, experienced chest tightness, dizziness, generalized urticaria, abdominal pain, and diarrhea 10 min after administering a piperacillin injection. She had previously suffered from atopic dermatitis. A skin prick test for common inhalant allergens was entirely negative; in contrast, her serum total IgE was elevated (283 IU/mL). A high level of piperacillin-specific serum IgE was detected by ELISA using piperacillin-HSA conjugate. Significant inhibition upon addition of both free piperacillin and piperacillin-HSA conjugate was detected by inhibition ELISA. These data suggest that piperacillin exposure in the workplace can induce occupational anaphylaxis and urticaria mediated by an interaction of IgE with the hapten of piperacillin.

Genetic polymorphisms of drug-metabolizing enzymes and anti-TB drug-induced hepatitis.

AIMS: Although some genetic risk factors have been reported for the development of hepatitis due to anti-TB drugs, an extensive candidate gene approach evaluating drug-metabolizing enzymes has not been attempted. This study aimed to investigate the association of genetic polymorphisms in drug-metabolizing enzymes with anti-TB drug-induced hepatitis. MATERIALS & METHODS: We compared genotype distributions of tagging SNPs in promoter, exons and haplotypes in seven drug-metabolizing enzyme genes (CYP2C9, CYP2C19, CYP2D6, CYP2E1, NAT2, UGT1A1 and UGT1A3) between 67 cases and 159 controls. RESULTS: Among four tagging SNPs of N-acetyltransferase 2 (NAT2), -9796T>A in promoter and R197Q were significantly associated (p = 0.0016 and p = 0.0007, respectively). NAT2 haplotype 2 [A-A-A-G] carrying A allele of -9796T>A and A allele of R197Q showed significant association (p = 0.0004). However, there was no significant association between genotypes of other enzyme-metabolizing genes and anti-TB drug-induced hepatitis. The constructs containing -9796A of NAT2 showed significantly lower luciferase activity (p < 0.01), suggesting decreased expression of NAT2. The variant alleles and haplotype 2 showed significantly higher peak serum levels of isoniazid, lower acetyl isoniazid:isoniazid ratio and lower isoniazid clearance compared with wild-types. CONCLUSION: These findings suggest that genetic variants in the promoter and exons of NAT2 increase the risk of anti-TB drug-induced hepatitis by modifying acetylation phenotypes and/or gene expression of NAT2, and there is no essential role for genetic mutation of the other metabolizing enzymes in the development of this adverse reaction.

Association between polymorphisms in prostanoid receptor genes and aspirin-intolerant asthma.

BACKGROUND: Genetic predisposition is linked to the pathogenesis of aspirin-intolerant asthma. Most candidate gene approaches have focused on leukotriene-related pathways, whereas there have been relatively few studies evaluating the effects of polymorphisms in prostanoid receptor genes on the development of aspirin-intolerant asthma. Therefore, we investigated the potential association between prostanoid receptor gene polymorphisms and the aspirin-intolerant asthma phenotype. METHODS: We screened for genetic variations in the prostanoid receptor genes PTGER1, PTGER2, PTGER3, PTGER4, PTGDR, PTGIR, PTGFR, and TBXA2R using direct sequencing, and selected 32 tagging single nucleotide polymorphisms among the 77 polymorphisms with frequencies >0.02 based on linkage disequilibrium for genotyping. We compared the genotype distributions and allele frequencies of three participant groups (108 patients with aspirin-intolerant asthma, 93 patients with aspirin-tolerant asthma, and 140 normal controls). RESULTS: Through association analyses studies of the 32 single nucleotide polymorphisms, the following single nucleotide polymorphisms were found to have significant associations with the aspirin-intolerant asthma phenotype: -616C>G (P=0.038) and -166G>A (P=0.023) in PTGER2; -1709T>A (P=0.043) in PTGER3; -1254A>G (P=0.018) in PTGER4; 1915T>C (P=0.015) in PTGIR; and -4684C>T (P=0.027), and 795T>C (P=0.032) in TBXA2R. In the haplotype analysis of each gene, the frequency of PTGIR ht3[G-G-C-C], which includes 1915T>C, differed significantly between the aspirin-intolerant asthma patients and aspirin-tolerant asthma patients (P=0.015). CONCLUSION: These findings suggest that genetic polymorphisms in PTGER2, PTGER3, PTGER4, PTGIR, and TBXA2R play important roles in the pathogenesis of aspirin-intolerant asthma.

Role of staphylococcal superantigen-specific IgE antibodies in aspirin-intolerant asthma.

IgE antibodies specific for staphylococcal superantigens (SAg) have been implicated in the pathology of several allergic diseases such as rhinosinusitis, nasal polyposis, asthma, and aspirin intolerance. We sought to determine whether SAg-specific IgE levels associate with clinical parameters in patients with aspirin-intolerant asthma (AIA), as compared with patients with aspirin-tolerant asthma (ATA) and nonatopic controls. Eighty patients with AIA, 62 patients with ATA, and 52 normal controls were enrolled in this study. Total serum IgE and IgE specific for staphylococcal enterotoxin A, staphylococcal enterotoxin B, and staphylococcal toxic shock syndrome toxin 1 (TSST-1) were measured using the CAP system (Pharmacia, Uppsala, Sweden). The prevalence of staphylococcal enterotoxin B-specific IgE and TSST-1-specific IgE was significantly higher in the asthma patients than in the healthy controls. The prevalence of SEB-specific IgE was slightly higher in patients with AIA than in those with ATA (22.5% versus 14.5%), although this difference was not statistically significant. No significant difference in staphylococcal enterotoxin A-specific or TSST-1-specific IgE was found between AIA and ATA subjects. Total serum IgE levels were higher in asthma patients with detectable SAg-specific serum IgE than in those without. Airway hyperresponsiveness, as measured by PC20 methacholine, was significantly increased in asthma patients with detectable SAg-specific IgE than in asthma patients without (p = 0.038). There were no significant differences in other clinical parameters between AIA and ATA patients with and without detectable SAg-specific antibody responses. These findings suggest that the staphylococcal SAg may contribute to airway inflammation and the development of airway hyperresponsiveness in asthma.

A case of pulmonary cryptococcosis by capsule-deficient Cryptococcus neoformans.

Pulmonary infection by capsule-deficient Cryptococcus neoformans (CDCN) is a very rare form of pneumonia and it is seldom seen in the immunocompetent host. The authors experienced a case of pulmonary cryptococcosis by CDCN in 25-year-old woman who was without any significant underlying disease. The diagnosis was made from the percutaneous lung biopsy and special tissue staining, including Fontana-Masson silver (FMS) staining. Fungal culture confirmed the diagnosis afterward. Her clinical and radiologic features improved under treatment with fluconazol. It's known that CDCN is not so readily confirmed because fungal culture does not always result in growth of the organism and the empirical fungal stain is not helpful for the differentiation between CDCN and the other infections that are caused by the nonencapsulated yeast-like organisms. In this report, we emphasize the diagnostic value of performing FMS staining for differentiating a CDCN infection from the other confusing nonencapsulated yeast-like organisms.

Association between genetic variations of vascular endothelial growth factor receptor 2 and atopy in the Korean population.

BACKGROUND: Vascular endothelial growth factor (VEGF) has been suggested to be a key mediator in the development of atopy and T(H)2 inflammation. OBJECTIVE: We sought to evaluate the effects of variations in the gene coding VEGF receptor (VEGFR) 2 on intermediate phenotypes of asthma in the Korean population. METHODS: A cohort of 2055 children and adolescents responded to a questionnaire concerning asthma symptoms and risk factors and underwent methacholine bronchial challenge and skin tests. The VEGFR2 gene, including the promoter area, was sequenced on 24 healthy subjects to discover informative single nucleotide polymorphisms (SNPs; minor allele frequency >2%). After haplotype reconstruction, 4 tagging SNPs (IVS6+54A>G, +889G>A, +1416T>A, and IVS25-92G>A) were scored. These SNPs were also scored in 480 adult asthmatic patients to verify the above genetic association study. RESULTS: The prevalence of atopy was associated with a single SNP (+889G>A) of VEGFR2 with borderline significance (P = .048; relative risk, 1.13; 95% CI, 1.00-1.28). However, haplotype analysis showed that the atopy prevalence was strongly associated with a haplotype (AGAG) of VEGFR2 (P = .002; relative risk, 1.25; 95% CI, 1.09-1.42). As for airway hyperresponsiveness, neither individual SNPs nor haplotypes were found to be associated. Interestingly, the significant association was also found between atopy and the AGAG haplotype among adult asthmatic patients (P = .008; odds ratio, 1.66; 95% CI, 1.14-2.44). CONCLUSIONS: The present study demonstrated that genetic variations of VEGFR2 are significantly associated with atopy in the Korean population.

Comparison of asthma phenotypes using different sensitizing protocols in mice.

BACKGROUND: Several methods have been reported to induce asthmatic reactions in mice but few studies have compared their efficiency. We evaluated the efficiency of the protocols frequently used in the literature. METHODS: BALB/c mice were sensitized to ovalbumin (OVA) by intraperitoneal injection; 1] Once a week for two weeks using OVA with alum (IPOA-2) or without (IPO-2), and provocation on days 28-30 by 1% OVA inhalation; 2] seven times for two weeks by OVA with alum (IPOA-7) or without (IPO-7) and provocation by 1% OVA inhalation on days 42-44. 3] Sensitization by 1% OVA inhalation for ten days (IHO-10) and provocation by 1% OVA inhalation on days 28-30. After the last challenge, airway hyperresponsiveness was measured with single chamber plethysmography 24 hours later and mice were sacrificed 48 hours later. RESULTS: Airway hyperresponsiveness, BALF eosinophilia, airway inflammation, and OVA-specific IgE and IgG1 production were effectively induced in IPOA-2, IPOA-7, and IPO-7. However, these phenotypes were not induced in IPO-2 (except for increased BALF eosinophils) or IHO-10 (except for an increased OVA-specific IgG1 level). CONCLUSION: The intraperitoneal injections of OVA with alum once a week for two weeks proved to be the most efficient sensitization method of inducing an asthmatic reaction in mice.

Airway inflammation and allergen specific IgE production may persist longer than airway hyperresponsiveness in mice.

During the preclinical study of new therapeutic modality, we evaluate whether the treatment can reverse the established asthma phenotypes in animal model. However, few have reported on the long term persistence of asthma phenotypes upon re-challenge with allergen (secondary challenge) in animal model. We evaluated the persistence of asthma phenotypes by secondary challenge at different times in previously challenged murine asthma model. BALB/c mice sensitized by intraperitoneal injections of 20 micro g of ovalbumin and 1 mg of alum on days 1 and 14 were challenged initially by the inhalation of 1% ovalbumin for 30 min on days 21, 22, and 23. Each group of mice was rechallenged at 5, 7, 9, or 12 weeks after the initial challenge. Airway hyperresponsiveness, BAL fluid, airway histology and serum ovalbumin-specific IgE level were evaluated. Airway eosinophilia, airway inflammation and serum ovalbumin-specific IgE production persisted upon secondary allergen challenges at least 12 weeks after the initial challenge. However, airway hyperresponsiveness persisted only until mice were rechallenged 7 weeks after the initial challenge. Airway inflammation and allergen specific IgE production may persist longer than airway hyperresponsiveness in a mouse asthma model of secondary allergen challenge.