1: J Allergy Clin Immunol. 2008 Sep;122(3):481-7. Epub 2008 Aug 9.
Advances in upper airway diseases and allergen immunotherapy in 2007.
Saltoun C, Avila PC.
Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
The purpose of this review is to highlight important articles on upper airway diseases and immunotherapy that appeared in 2007. Advances in rhinitis include the realization that allergic rhinitis might be caused by local nasal IgE sensitization to aeroallergens in the absence of systemic evidence of IgE sensitization. After inhalation, allergens might reach systemic circulation. Epidemiologic studies continue to show that allergic rhinitis impairs school performance and is a risk factor for future asthma. New pathways are being identified in chronic sinusitis, as well as in different types of allergic ocular diseases. New treatments for patients with allergic rhinitis include use of beta-1,3-glucan, a mushroom product that can reduce allergic symptoms by inducing T(H)1 response, and olopatadine nasal spray. Studies on immunotherapy in 2007 suggest that sublingual immunotherapy induces similar immunologic alterations as those induced by subcutaneous immunotherapy, although to a lesser degree. Among allergists in the United States, there is a sizable variation in clinical practice, particularly related to concomitant administration of immunotherapy and beta-blockers, to administration of angiotensin-converting enzyme inhibitors, and to patients with HIV or autoimmune diseases. The combination of omalizumab with allergen subcutaneous immunotherapy can enhance clinical efficacy. Recombinant technology can modify allergen structure to prevent binding to IgE (allergenicity) while enhancing immunogenicity (stimulation of T cells), which might improve the safety and efficacy of immunotherapy.
PMID: 18694591 [PubMed - indexed for MEDLINE]
2: Ann Allergy Asthma Immunol. 2008 Jun;100(6):551-7
Inhaled corticosteroids and augmented bronchodilator responsiveness in Latino and African American asthmatic patients.
Naqvi M, Tcheurekdjian H, DeBoard JA, Williams LK, Navarro D, Castro RA, Rodriguez-Santana JR, Chapela R, Watson HG, Meade K, Rodriguez-Cintron W, LeNoir M, Thyne SM, Avila PC, Choudhry S, Burchard EG.
University of California, San Francisco, California 94143-2911, USA.
BACKGROUND: National asthma guidelines recommend that patients with persistent asthma regularly use an inhaled corticosteroid (ICS) in addition to as-needed albuterol, yet recent debates question whether this combination is equally efficacious in all ethnicities. OBJECTIVE: To examine the effect of ICS use on bronchodilator responsiveness to albuterol in 3 different ethnic populations. METHODS: A cross-sectional study of 106 Mexican Americans, 246 Puerto Ricans, and 163 African Americans with physician-diagnosed persistent asthma. Asthma severity, ethnicity, and medication use were evaluated using spirometry and questionnaires. Percentage change in forced expiratory volume in 1 second (FEV) was compared in patients who used ICSs vs those who used a short-acting beta2-agonist as their only asthma medication. RESULTS: Inhaled corticosteroid use was associated with improvements in the percentage change in FEV1 after albuterol administration in Mexican Americans (21.7%, P = .01) and Puerto Ricans (18.5%, P = .02) but not in African Americans (3.0%, P = .73). CONCLUSIONS: Inhaled corticosteroid use is associated with augmented bronchodilator responsiveness to albuterol in Mexican Americans and Puerto Ricans, but not in African Americans, with persistent asthma. This underscores the need for an improved understanding of ethnic-specific drug-drug interactions, particularly in those subgroups experiencing the highest burden of asthma morbidity and mortality in the United States.
PMID: 18592818 [PubMed - indexed for MEDLINE]
3: Hum Mol Genet. 2008 Sep 1;17(17):2681-90. Epub 2008 Jun 4.
An african-specific functional polymorphism in KCNMB1 shows sex-specific association with asthma severity.
Seibold MA, Wang B, Eng C, Kumar G, Beckman KB, Sen S, Choudhry S, Meade K, Lenoir M, Watson HG, Thyne S, Williams LK, Kumar R, Weiss KB, Grammer LC, Avila PC, Schleimer RP, Burchard EG, Brenner R.
Department of Medicine, University of California San Francisco, San Francisco, CA 94143-2911, USA. mseibold@medsfgh.ucsf.edu
A highly heritable and reproducible measure of asthma severity is baseline pulmonary function. Pulmonary function is largely determined by airway smooth muscle (ASM) tone and contractility. The large conductance, voltage and calcium-activated potassium (BK) channel negatively regulates smooth muscle tone and contraction in ASM. The modulatory subunit of BK channels, the beta1-subunit, is critical for proper activation of BK channels in smooth muscle and has shown sex hormone specific regulation. We hypothesized that KCNMB1 genetic variants in African Americans may underlie differences in bronchial smooth muscle tone and thus pulmonary function, possibly in a sex-specific manner. Through resequencing of the KCNMB1 gene we identified several common variants including a novel African-specific coding polymorphism (C818T, R140W). The C818T SNP and four other KCNMB1 variants were genotyped in two independent groups of African American asthmatics (n = 509) and tested for association with the pulmonary function measure--forced expiratory volume (FEV(1)) % of predicted value. The 818T allele is associated with a clinically significant decline (-13%) in FEV(1) in both cohorts of asthmatics among males but not females (P(combined) = 0.0003). Patch clamp electrophysiology studies of the BK channel expressed with the 140Trp variant of the beta1-subunit demonstrated significantly reduced channel openings, predicted by the loss of pulmonary function observed. African American male asthmatics carrying the 818T allele (10% of population) are potentially at risk for greater airway obstruction and increased asthma morbidity. Female asthmatics may be insulated from the deleterious effects of the 818T allele by estrogen-mediated upregulation in BK channel activity.
PMID: 18535015 [PubMed - indexed for MEDLINE]
4: Am J Respir Crit Care Med. 2008 Jun 1;177(11):1194-200. Epub 2008 Feb 28.
ORMDL3 gene is associated with asthma in three ethnically diverse populations.
Galanter J, Choudhry S, Eng C, Nazario S, Rodríguez-Santana JR, Casal J, Torres-Palacios A, Salas J, Chapela R, Watson HG, Meade K, LeNoir M, Rodríguez-Cintrón W, Avila PC, Burchard EG.
Lung Biology Center, Department of Medicine, Institute for Human Genetics, University of California, San Francisco, California 94143-2911, USA. joshua.galanter@ucsf.edu
RATIONALE: Independent replication of genetic associations in complex diseases, particularly in whole-genome association studies, is critical to confirm the association. OBJECTIVES: A whole-genome association study identified ORMDL3 as a promising candidate gene for asthma in white populations. Here, we attempted to confirm the role of ORMDL3 genetic variants in asthma in three ethnically diverse populations: Mexican, Puerto Rican, and African American. METHODS: We used family-based analyses to test for association between seven candidate single-nucleotide polymorphisms (SNPs) in and around the ORMDL3 gene and asthma and related phenotypes in 701 Puerto Rican and Mexican parent-child trios. We also evaluated these seven SNPs and an additional ORMDL3 SNP in 264 African American subjects with asthma and 176 healthy control subjects. MEASUREMENTS AND MAIN RESULTS: We found significant associations between two SNPs within ORMDL3 (rs4378650 and rs12603332) and asthma in Mexicans and African Americans (P = 0.028 and 0.001 for rs4378650 and P = 0.021 and 0.001 for rs12603332, respectively), and a trend toward association in Puerto Ricans (P = 0.076 and 0.080 for SNPs rs4378650 and rs12603332, respectively). These associations became stronger among Mexican and Puerto Rican subjects with asthma with IgE levels greater than 100 IU/ml. We did not find any association between ORMDL3 SNPs and baseline lung function or response to the bronchodilator albuterol. CONCLUSIONS: Our results confirm that the ORMDL3 locus is a risk factor for asthma in ethnically diverse populations. However, inconsistent SNP-level results suggest that further studies will be needed to determine the mechanism by which ORMDL3 predisposes to asthma.
PMID: 18310477 [PubMed - indexed for MEDLINE] PMCID: PMC2408437 [Available on 06/01/09]
5: J Allergy Clin Immunol. 2007 Dec;120(6):1279-84. Epub 2007 Oct 18.
Epithelium: at the interface of innate and adaptive immune responses.
Schleimer RP, Kato A, Kern R, Kuperman D, Avila PC.
Department of Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA. rpschleimer@northwestern.edu
Several diseases of the airways have a strong component of allergic inflammation in their cause, including allergic rhinitis, asthma, polypoid chronic rhinosinusitis, eosinophilic bronchitis, and others. Although the roles played by antigens and pathogens vary, these diseases have in common a pathology that includes marked activation of epithelial cells in the upper airways, the lower airways, or both. Substantial new evidence indicates an important role of epithelial cells as both mediators and regulators of innate immune responses and adaptive immune responses, as well as the transition from innate immunity to adaptive immunity. The purpose of this review is to discuss recent studies that bear on the molecular and cellular mechanisms by which epithelial cells help to shape the responses of dendritic cells, T cells, and B cells and inflammatory cell recruitment in the context of human disease. Evidence will be discussed that suggests that secreted products of epithelial cells and molecules expressed on their cell surfaces can profoundly influence both immunity and inflammation in the airways.
PMID: 17949801 [PubMed - indexed for MEDLINE]
6: J Asthma. 2007 Oct;44(8):639-48.
Ethnic-specific differences in bronchodilator responsiveness among African Americans, Puerto Ricans, and Mexicans with asthma.
Naqvi M, Thyne S, Choudhry S, Tsai HJ, Navarro D, Castro RA, Nazario S, Rodriguez-Santana JR, Casal J, Torres A, Chapela R, Watson HG, Meade K, LeNoir M, Avila PC, Rodriguez-Cintron W, Burchard EG.
University of California, San Francisco, California 94110, USA.
Socioeconomic and environmental differences do not fully explain differences in asthma prevalence, morbidity, and mortality among Puerto Ricans, African Americans, and Mexican Americans. Differences in response to albuterol may be a factor. We compared bronchodilator responsiveness between these three populations. All groups demonstrated below expected responsiveness. Puerto Ricans of all ages and African American children with moderate-to-severe asthma demonstrated the lowest responsiveness overall. Among subjects with moderate-to-severe asthma, children were even less likely than adults to show the expected bronchodilator response. We conclude that ethnic-specific differences in bronchodilator drug responsiveness exist between Mexicans, Puerto Ricans, and African Americans with asthma. This may be of importance in asthma management.
PMID: 17943575 [PubMed - indexed for MEDLINE]
7: J Infect Dis. 2007 Sep 15;196(6):817-25. Epub 2007 Aug 6.
Comment in:
· J Infect Dis. 2007 Sep 15;196(6):810-1.
Pan-viral screening of respiratory tract infections in adults with and without asthma reveals unexpected human coronavirus and human rhinovirus diversity.
Kistler A, Avila PC, Rouskin S, Wang D, Ward T, Yagi S, Schnurr D, Ganem D, DeRisi JL, Boushey HA.
Howard Hughes Medical Institute, Department of Medicine, University of California, San Francisco, CA 94158, USA. amy@derisilab.ucsf.edu
BACKGROUND: Between 50% and 80% of asthma exacerbations are associated with viral respiratory tract infections (RTIs), yet the influence of viral pathogen diversity on asthma outcomes is poorly understood because of the limited scope and throughput of conventional viral detection methods. METHODS: We investigated the capability of the Virochip, a DNA microarray-based viral detection platform, to characterize viral diversity in RTIs in adults with and without asthma. RESULTS: The Virochip detected viruses in a higher proportion of samples (65%) than did culture isolation (17%) while exhibiting high concordance (98%) with and comparable sensitivity (97%) and specificity (98%) to pathogen-specific polymerase chain reaction. A similar spectrum of viruses was identified in the RTIs of each patient subgroup; however, unexpected diversity among human coronaviruses (HCoVs) and human rhinoviruses (HRVs) was revealed. All but one of the HCoVs corresponded to the newly recognized HCoV-NL63 and HCoV-HKU1 viruses, and >20 different serotypes of HRVs were detected, including a set of 5 divergent isolates that formed a distinct genetic subgroup. CONCLUSIONS: The Virochip can detect both known and novel variants of viral pathogens present in RTIs. Given the diversity detected here, larger-scale studies will be necessary to determine whether particular substrains of viruses confer an elevated risk of asthma exacerbation.
PMID: 17703411 [PubMed - indexed for MEDLINE]
8: Proc Am Thorac Soc. 2007 Jul;4(3):226-33.
Dissecting complex diseases in complex populations: asthma in latino americans.
Choudhry S, Seibold MA, Borrell LN, Tang H, Serebrisky D, Chapela R, Rodriguez-Santana JR, Avila PC, Ziv E, Rodriguez-Cintron W, Risch NJ, Burchard EG.
Department of Medicine, University of California, San Francisco, San Francisco, CA 94143-2911, USA.
Asthma is a common but complex respiratory ailment; current data indicate that interaction of genetic and environmental factors lead to its clinical expression. In the United States, asthma prevalence, morbidity, and mortality vary widely among different Latino ethnic groups. The prevalence of asthma is highest in Puerto Ricans, intermediate in Dominicans and Cubans, and lowest in Mexicans and Central Americans. Independently, known socioeconomic, environmental, and genetic differences do not fully account for this observation. One potential explanation is that there may be unique and ethnic-specific gene-environment interactions that can differentially modify risk for asthma in Latino ethnic groups. These gene-environment interactions can be tested using genetic ancestry as a surrogate for genetic risk factors. Latinos are admixed and share varying proportions of African, Native American, and European ancestry. Most Latinos are unaware of their precise ancestry and report their ancestry based on the national origin of their family and their physical appearance. The unavailability of precise ancestry and the genetic complexity among Latinos may complicate asthma research studies in this population. On the other hand, precisely because of this rich mixture of ancestry, Latinos present a unique opportunity to disentangle the clinical, social, environmental, and genetic underpinnings of population differences in asthma prevalence, severity, and bronchodilator drug responsiveness.
PMID: 17607004 [PubMed - indexed for MEDLINE]
9: Annu Rev Med. 2007;58:185-203.
Does anti-IgE therapy help in asthma? Efficacy and controversies.
Avila PC.
Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA. pa@northwestern.edu
Omalizumab, a humanized monoclonal antibody against IgE, is clinically efficacious when it neutralizes almost all free IgE and reduces IgE receptors on basophils and mast cells. Asthmatic subjects on inhaled corticosteroids who are treated with omalizumab as an add-on therapy experience only modest benefits in symptoms and perhaps in quality of life, but the most significant effects are reductions in airway inflammation and in exacerbation rate. Airway obstruction and hyperresponsiveness do not change significantly. Although the magnitude of the beneficial effects is small, they are observed even in the most severe cases, particularly the reduction in exacerbation rate. The safety profile of omalizumab is very encouraging, although phase IV studies are ongoing to clarify the incidence of neoplasias. Because of its cost, omalizumab therapy may be most cost-effective in patients with severe and refractory asthma, particularly those with frequent exacerbations requiring hospital care. Further clinical studies are now evaluating the best place for omalizumab in the algorithm of asthma management.
PMID: 17059361 [PubMed - indexed for MEDLINE] |
