Barbara Kariuki

Fungi and allergic lower respiratory tract diseases

Asthma is a common disorder that in 2009 afflicted 8.2% of adults and children, 24.6 million persons, in the United States. In patients with moderate and severe persistent asthma, there is significantly increased morbidity, use of health care support, and health care costs. Epidemiologic studies in the United States and Europe have associated mold sensitivity, particularly to Alternaria alternata and Cladosporium herbarum, with the development, persistence, and severity of asthma. In addition, sensitivity to Aspergillus fumigatus has been associated with severe persistent asthma in adults. Allergic bronchopulmonary aspergillosis (ABPA) is caused by A fumigatus and is characterized by exacerbations of asthma, recurrent transient chest radiographic infiltrates, coughing up thick mucus plugs, peripheral and pulmonary eosinophilia, and increased total serum IgE and fungus-specific IgE levels, especially during exacerbation. The airways appear to be chronically or intermittently colonized by A fumigatus in patients with ABPA. ABPA is the most common form of allergic bronchopulmonary mycosis (ABPM); other fungi, including Candida, Penicillium, and Curvularia species, are implicated. The characteristics of ABPM include severe asthma, eosinophilia, markedly increased total IgE and specific IgE levels, bronchiectasis, and mold colonization of the airways. The term severe asthma associated with fungal sensitization (SAFS) has been coined to illustrate the high rate of fungal sensitivity in patients with persistent severe asthma and improvement with antifungal treatment. The immunopathology of ABPA, ABPM, and SAFS is incompletely understood. Genetic risks identified in patients with ABPA include HLA association and certain T(H)2-prominent and cystic fibrosis variants, but these have not been studied in patients with ABPM and SAFS. Oral corticosteroid and antifungal therapies appear to be partially successful in patients with ABPA. However, the role of antifungal and immunomodulating therapies in patients with ABPA, ABPM, and SAFS requires additional larger studies.

IL-4 alpha chain receptor (IL-4Rα) polymorphisms in allergic bronchopulmonary sspergillosis

BackgroundAllergic bronchopulmonary aspergillosis occurs in 7–10% of cystic fibrosis (CF) and 1–2% of asthmatic patients. HLA-DR restriction and increased sensitivity to IL-4 stimulation have been proposed as risk factors in these populations.ObjectiveWe examined for the presence of IL-4 receptor alpha chain (IL-4Rα) single nucleotide polymorphisms (SNPs) in ABPA and whether these accounted for increased sensitivity to IL-4 stimulation.MethodsOne extracellular (ile75val) and four cytoplasmic IL-4Rα SNPs were analyzed in 40 CF and 22 asthmatic patients and in 56 non-ABPA CF and asthmatic patients. Sensitivity to IL-4 stimulation was measured by induction of CD23 expression on B cells.ResultsIL-4Rα SNPs were observed in 95% of ABPA patients. The predominant IL-4Rα SNP was the extracellular IL-4Rα SNP, ile75val, observed in 80% of ABPA patients.ConclusionThe presence of IL-4Rα SNPs, principally ile75val, appears to be a genetic risk for the development of ABPA.

Family history as a risk factor for pelvic organ prolapse

The aim of this study was to determine whether a family history of prolapse and/or hernia is a risk factor for prolapse. A cohort of 458 women seeking gynecological care was classified as exposed (family history) or unexposed (without family history). We used χ2 to assess confounding and logistic regression to determine risk. Nearly half (47.3%) of the 458 participants reported a positive family history. Of these, 52.5% had prolapse. This was significantly higher than the 28.9% rate of prolapse in women without a family history (p < 0.001). The crude risk ratio for family history of prolapse and/or hernia and prolapse was 1.8 (95% CI 1.4–2.3). After adjusting for vaginal deliveries, incontinence, and hysterectomy, the risk of prolapse was 1.4 (95% CI 1.2–1.8) times higher in women with a family history of prolapse and/or hernia. Heredity is a risk factor for prolapse. History taking should include both male and female family members.

Mold‐sensitivity in children with moderate‐severe asthma is associated with HLA‐DR and HLA‐DQ

To cite this article: Knutsen AP, Vijay HM, Kumar V, Kariuki B, Santiago LA, Graff R, Wofford JD, Shah MR. Mold‐sensitivity in children with moderate‐severe asthma is associated with HLA‐DR and HLA‐DQ. Allergy 2010; 65: 1367–1375.

Association of IL-4RA single nucleotide polymorphisms, HLA-DR and HLA-DQ in children with Alternaria -sensitive moderate-severe asthma

BackgroundAsthma afflicts 6% to 8% of the United States population, and severe asthma represents approximately 10% of asthmatic patients. Several epidemiologic studies in the United States and Europe have linked Alternaria sensitivity to both persistence and severity of asthma. In order to begin to understand genetic risk factors underlying Alternaria sensitivity and asthma, in these studies we examined T cell responses to Alternaria antigens, HLA Class II restriction and HLA-DQ protection in children with severe asthma.MethodsSixty children with Alternaria-sensitive moderate-severe asthma were compared to 49 children with Alternaria-sensitive mild asthma. We examined HLA-DR and HLA-DQ frequencies in Alternaria-sensitive asthmatic by HLA typing. To determine ratios of Th1/Th2 Alternaria-specific T-cells, cultures were stimulated in media alone, Alternaria alternata extract and Alt a1. Sensitivity to IL-4 stimulation was measured by up-regulation of CD23 on B cells.ResultsChildren with Alternaria-sensitive moderate-severe asthma trended to have increased sensitivities to Cladosporium (46% versus 35%), to Aspergillus (43% versus 28%), and significantly increased sensitivities to trees (78% versus 57%) and to weeds (68% versus 48%). The IL-4RA ile75val polymorphism was significantly increased in Alternaria-sensitive moderate-severe asthmatics, 83% (0.627 allele frequency) compared to Alternaria-sensitive mild asthmatics, 57% (0.388 allele frequency). This was associated with increased sensitivity to IL-4 stimulation measured by significantly increased IL-4 stimulated CD23 expression on CD19+ and CD86+CD19+ B cells of Alternaria-sensitive moderate-severe asthmatics. IL-5 and IL-13 synthesis was significantly increased in Alternaria-sensitive moderate-severe asthmatics compared to mild asthmatics to Alternaria extract and Alt a1 stimulation. The frequency of HLA-DQB1*03 allele was significantly decreased in Alternaria-sensitive moderate-severe asthmatics compared to mild asthmatics, 39% versus 63%, with significantly decreased allele frequency, 0.220 versus 0.398.SummaryIn children with Alternaria-sensitive moderate severe asthma, there was an increased Th2 response to Alternaria stimulation and increased sensitivity to IL-4 stimulation. This skewing towards a Th2 response was associated with an increased frequency of the IL-4RA ile75val polymorphism. In evaluating the HLA association, there was a decreased frequency of HLA-DQB1*03 in Alternaria-sensitive moderate severe asthmatic children consistent with previous studies suggest that HLA-DQB1*03 may be protective against the development of mold-sensitive severe asthma.