December 2006 World Medical Journal Review
Reviewed by Shyam S. Mohapatra, Ph.D., WAO Guest Editor
1. Abnormalities of the bronchial arteries in asthma.
This study compares the structure of the bronchial arteries, which supply systemic blood to the airways, tracheobronchial lymph nodes and nerves, in post-mortem lungs of three groups of subjects (n=12): one group with fatal asthma and death due to asthma, one group with fatal asthma and death not due to asthma, and one non-asthmatic group. In the two asthmatic groups, the intimal area was significantly larger than in the control group. Gender, age, smoking and duration of asthma were found to have significant effects on the intimal area in asthmatics. The increase in intimal area was associated with smooth muscle proliferation and reduplication and calcification of elastica but not with inflammatory cell infiltration. Editor’s Comments: This paper is interesting because quantitative analysis of bronchial arteries has not been done before. However, although the differences are statistically significant, the number of subjects in each group is small and the clinical significance of these findings in the context of severe or fatal asthma is unclear. Green F.H.Y et al. Chest 2006;130 1025.
2. Safety of trivalent inactivated influenza vaccine in children 6 to 23 months old.
This paper reports on the screening for medically attended events in the clinic, emergency department or hospital after administration of trivalent inactivated influenza vaccine to children 6-23 months old between 1991 and 2003 (45,356 children with 69,359 vaccinations). This is a retrospective cohort study using self-control analysis with chart review of vaccine data from significant medically attended events at eight managed care organizations in the United States. The primary endpoint was any medically attended event associated with administration of trivalent vaccine within the risk windows of 0-3 days and 1-14 days. All individual ICD-9 codes and predefined aggregate codes were examined. The results showed that 13 of 14 medical conditions including acute upper respiratory tract infection, asthma, bronchiolitis and otitis media were less likely to occur after vaccination. Only one condition, gastritis/duodenitis was more likely to occur after 14 days of vaccination; however, it was not significant after chart review. Editor’s Comments: This report is the largest study of the safety of vaccines in infants with a variety of medical conditions suspected of reacting adversely to vaccination. It clearly establishes that flu vaccination of infants in the presence of certain diseases, including upper respiratory tract infections, allergies and asthma, is safe. It should be pointed out, however, that this is a retrospective study based on medical records and not an actual trial. In addition, the results showed that the vaccine may cause gastritis, the reason for which is unclear. Hambidge SJ et al. JAMA 2006; 296:16: 1990-7.
3. Role of small airways in asthma: Investigation using high-resolution computed tomography.
Small airways may have an important role in asthma but their pathophysiological relevance remains unclear. Their condition is assumed to reflect air trapping and may be a useful noninvasive indicator of airway disease. The objective of this study was to use high-resolution computed tomography for evaluating lung density and to determine correlations with clinical and physiologic variables in 29 patients with stable asthma. Both lungs were scanned at full-inspiration and full-expiration to measure the percentage of lung occupied by low attenuation areas (LAA%;<-960 Hounsfield units) and the mean lung density. Asthma severity, pulmonary function, methacholine airway sensitivity and reactivity, and sputum eosinophil counts were also evaluated. The results showed that the mean lung density increased and LAA% decreased in all patients during the expiratory phase compared to the inspiratory phase. In conclusion, expiratory/inspiratory high-resolution computed tomography is useful for assessing small airway involvement in airflow obstruction, airway hypersensitivity and more severe diseases such as asthma. Editor’s Comments: HRCT can be very useful in diagnosing small airway disease. Tetsuya Ueda, MD J Allergy Clin Immounol 2006; 118:1019-25.
4. Successful management of mite-allergic asthma with modified extracts of Dermatophagoides pteronyssinus and Dermatophagoides farinae.
The objective of this prospective, double-blind, placebo-controlled study of 64 subjects was to evaluate the clinical efficacy and safety of a vaccine containing depigmented, polymerized allergens of Dermatophagoides pteronyssinus and D. farinae (equal amounts) in individuals diagnosed with mild to moderate asthma and rhinoconjunctivitis. The bronchial provocation test (BPT) was used to determine clinical efficacy. Among 54 patients who completed the study, the allergen-treated group experienced a significant improvement in BPT (p < 0.001), while the placebo group did not (p = 0.648). At the end of the study, allergen (n=20) vs. placebo (n=9) group (p=.013; odds ratio, 5.71[1.76, 18.51]) needed more than twice the amount of allergen to obtain a positive BPT. The active group showed median improvement of 53.76% in total symptom and 58.09% in medication scores over placebo. Thus, immunotherapy with a mixture of modified allergen extracts of D. pteronyssinus and D. farinae is safe and efficacious to treat mite-allergic asthma. Editor’s Comments: Although polymerized allergens have been tested in other allergies, there have been few reports on their use in dust mite therapy in mild/moderate asthmatics. This study demonstrates that polymerized allergen immunotherapy is safe and effective. Jose-Carlos Garcia-Robaina, MD, PhD J Allergy Clin Immounol 2006;118:1026-32
5. FceRI-mediated signal strength plays a key role in regulating basophil signaling and deactivation.
This study characterized the mechanisms for the control of FceRI-triggered basophil activation, which is a critical mediator of the symptoms of allergic disease and its underlying TH2-type response. Human basophils were purified by Ficoll density centrifugation and negative selection with immunomagnetic beads. Levels of various intracellular signal proteins were measured by Western blotting, and mediator release was analyzed either spectrofluorometrically (histamine) or by ELISA (IL-4 and IL-13). Supraoptimal anti-IgE concentrations led to lower mediator release than optimal concentrations but simultaneously to greater histamine release. In parallel, basophil signaling proteins (syk, p38 mitogen-activated protein kinase, and extracellular signal-regulated kinases 1 and 2) were more rapidly phosphorylated at higher anti-IgE concentrations but more transiently activated in the supraoptimal range. This regulation involved the inositol 5’ phosphatase, SHIP, which was phosphorylated with supraoptimal anti-IgE but not with lower concentrations. Basophils stimulated with N-formyl-methionylleucyl-phenylalanine failed to phosphorylate SHIP in the supraoptimal concentration range. Editor’s Comments: It appears that the kinetics of IgE-mediated signaling and mediator release in primary human FceRI+ cells varies substantially. This paper shows that the magnitude of stimulation and the phosphatase SHIP play an important role in terminating these events. Bernhard F. Gibbs, PhD. J Allergy Clin Immounol 2006; 118:1060-7.
6. Sequence, haplotype, and association analysis of ADRB2 in multiethnic asthma.
This study identified ADRB2 polymorphisms and haplotypes in White and African American subjects and correlated them with asthma phenotypes. A 5.3 kb region of ADRB2 was sequenced in 669 individuals --429 Whites and 240 African Americans. Twelve polymorphisms, representing an optimal haplotype tagging set, were genotyped in Whites (338 patients and 326 control subjects) and African Americans (222 patients and 299 control subjects). The study identified 49 polymorphisms, 21 of which were novel. Thirty-one polymorphisms (frequency > 0.03) were used to identify 24 haplotypes (frequency > 0.01) and assess linkage disequilibrium. An association of genotype with the ratio FEV1/FVC was observed in African Americans. This report demonstrates that additional genetic variants besides +46 (Gly16Arg) are important in determining asthma phenotypes. For example, the length of a poly-C repeat (+1269) in the 3’ untranslated region of ADRb2 may influence lung function and may account for variation in b-agonist responses, especially in African Americans. Editor’s Comments: A comprehensive evaluation of gene variation, haplotype structure, and linkage disequilibrium is important in understanding the influence of the b2-adrenergic receptor gene ADRB2 on disease susceptibility, pulmonary function, and therapeutic response in different ethnic groups with asthma. This study demonstrates that there are additional ADRB2 genetic variants besides +46 (Gly 16 Arg) and +79 (Gln 27 Glu) that are important in determining asthma phenotype. Gregory A Hawkins AM J Respir Crit Care Med Vol 174 20061101-1109, 2006.
7. Polymorphisms in the muscarinic receptor 1 gene confer susceptibility to asthma.
Here the authors investigated the role in asthma of the human cholinergic receptor muscarinic-1 (CHRM1) gene located on chromosome 11q13. The receptor is widely distributed in the lungs and may be involved in airway constriction, epithelial cell proliferation and inflammation. In a case-controlled study using 326 Japanese patients with asthma and 333 healthy control subjects, 9 single-nucleotide polymorphisms in the CHRM1 gene were examined. The functional consequences of the -9697C > T and -4953A > G polymorphisms at the regulatory region were also determined using an mRNA reporter assay, which suggested associations with asthma. Haplotype analysis showed that the -9697T/9695T/-4953A haplotype was associated with a lower risk of asthma (p= 0.00055) and the 9697C/-6965T/-4953G haplotype was associated with an increased risk of asthma (p=0.020). The -9697T/-4953A haplotype was also associated with lower luciferase activity in vitro compared with the 9697C/-4953G haplotype. Taken together, these results suggest that the CHRM1 gene on chromosome 11q13 is an important determinant for susceptibility to asthma. Editor’s Comments: Since the beginning of asthma genetic studies, several candidate genes linked to asthma phenotypes have been found at the 11q13 locus. This study demonstrates that CHRM1, which is also at 11q13, is an important susceptibility gene for asthma. Yukiko Maeda Am J Respir Crit Care Med Vol 174 2006 1119-1124.
8. A3 adenosine receptor signaling contributes to airway mucin secretion after allergen challenge.
Mucus hypersecretion is characteristic of asthma, but the cellular and molecular mechanisms that regulate mucin production and secretion are poorly understood. This study uses genetics to investigate the contribution of the A3 adenosine receptor, A3AR, to mucus production and secretion in a mouse model of allergen-induced pulmonary disease. A3AR is part of a signaling pathway that is upregulated in the mucin-producing goblet cells of the airway, but mucin production in response to allergen is similar in wild-type and A3AR-deficient mice. Overexpression of this receptor in Clara cells neither induces mucin production itself nor enhances mucin production in response to allergen challenge, and A3AR is not required for mucus cell metaplasia. In contrast to the lack of effect on mucin production, agonist-induced mucin secretion was reduced in A3AR-deficent mice. Thus, mucin secretion induced by allergen treatment is stimulated via A3AR. In pulmonary disorders in which adenosine levels are elevated, signaling through this receptor may contribute to airway obstruction by mucus. Editor’s Comments: Mucus production and secretion in the airway is a complex phenomenon, and this study shows that the two processes are distinct. A3AR signaling does not affect mucus production but does promote mucus secretion. This is important since adenosine levels in the lung are increased as a result of inflammation and damage. Hays W. J. Young Am J Respir Cell Mol Biol Vol 35 2006 549-558.
9. Respiratory syncytial virus infection reduces B2-adrenergic responses in human airway smooth muscle.
This study addresses the hypothesis that respiratory syncytial virus (RSV) has direct effects on cAMP formation and B2-adrenergic receptor (ADRβ2) density and that the ADRβ2 haplotype influences this response. A recombinant RSV expressing green-fluorescent protein (rgRSV) was first used to determine whether RSV could infect cultured human airway smooth muscle cells (HASM). Then, the influence of RSV infection on β2-adrenergic responsiveness was determined by measuring differences in isoproterenol (ISO)-induced cyclic AMP (cAMP) formation, ADRβ2 density and Gi expression in HASM cells infected with RSV, with ultraviolet-inactivated RSV, or with vehicle. The cultured HASM cells were efficiently infected by RSV, and ISO-induced cAMP formation was significantly reduced in RSV-infected cells, compared to cells infected with ultraviolet-inactivated RSV or mock-infected, in a time- and concentration-dependent manner. Forskolin-induced cAMP formation and Gi expression were not altered in cells infected with RSV, suggesting that the influence of RSV on β2-adrenergic relaxation was upstream of cAMP formation. ADRβ2 density was reduced in cells infected with RSV and the Arg16Gln27 ADRβ2 haplotype was associated with decreased ISO-induced cAMP formation (p<0.05) and with decreased ADRβ2 density at baseline (p<0.05). Editor’s Comments: The use of b2-agonists in the treatment of airway obstruction associated with RSV infection has been controversial. The results of this study show that β2-agonist effects may be related to direct effects of RSV on HASM, and that the ADRβ2 genotype may predict bβ-adrenergic responses. Paul E. Moore Am J Respir Cell Mol Biol Vol 35 2006 559-564.
10. Airway hyperreactivity in exacerbation of chronic asthma is independent of eosinophilic inflammation.
The authors of this report have developed an animal model to investigate the mechanisms underlying an acute exacerbation of chronic asthma. Ovalbumin (OVA)-sensitized BALB/c mice were exposed to aerosolized OVA, either as a chronic low-level challenge for four weeks, a single moderate-level challenge, or chronic low-level followed by single moderate-level challenge (the acute exacerbation group). Compared with animals receiving chronic challenge alone, mice in the acute exacerbation group exhibited more marked inflammation, with involvement of intrapulmonary airways and lung parenchyma, and increased numbers of lymphocytes and eosinophils in bronchoalveolar lavage fluid. They also developed airway hyperreactivity (AHR) to methacholine, demonstrable as increased transpulmonary resistance and decreased compliance. This pattern of AHR was absent in chronically challenged animals but was present in animals given a single moderate-level challenge. However, compared with animals receiving a single moderate-level challenge, inflammation and AHR were induced more rapidly in the acute exacerbation group. Eosinophil-deficient GATA1 dbl mice exhibited undiminished AHR in the acute exacerbation model. Thus, mice with pre-existing airway lesions resembling mild chronic asthma, when exposed to a moderately high concentration of inhaled antigen, experience the symptoms of an acute exacerbation. The inflammatory response involves distal airways and is associated with a distinct pattern of AHR, which develops independently of the enhanced eosinophilia. Editor’s Comments: Eosinophilia has been considered the hallmark of allergic asthma. This study shows that the extent of airway hyperreactivity and eosinophilia actually depends upon the magnitude of antigen exposure in a specific state of the disease. Thus, chronic asthma can be devoid of eosinophilia. Jessica S. Siegle Am J Respir Cell Mol Biol Vol 35 2006 565-570.
11. Role of epithelial damage and angiogenesis in childhood asthma.
Airway remodeling and inflammation are characteristic features of adult asthma that have been little studied in childhood asthma. This study examines epithelial and vascular changes as well as the inflammatory response in airways of asthmatic children. The study analyzed bronchial biopsies obtained from 44 children undergoing bronchoscopy for clinical indications other than asthma: 17 had mild to moderate asthma (aged 2-25 yr), 12 had atopy without asthma (1-11 yr), and 15 were controls without atopy or asthma (1-14 yr). Epithelial cell loss, basement membrane thickness, number of vessels and inflammatory cells were quantified in sub epithelium by histochemisty and immunohisto-chemisty. The results showed increased epithelial loss and basement membrane thickening in children with asthma compared to controls (p = 0.005 and 0.0002, respectively) and atopic children (p = 0.002 and 0.005, respectively). The number of vessels and eosinophils was increased in asthmatic children (p = 0.03 and p = 0.0002, respectively) and in atopic children without asthma (p = 0.03 and p = 0.008, respectively) compared to controls. When the results were stratified according to age, the children younger than six years with asthma had increased epithelial loss, basement membrane thickening, and eosinophilia compared to controls of the same age. In conclusion, epithelial damage and basement membrane thickening, which are characteristic pathologic features of adult asthma, are present even in childhood asthma. Other changes, such as airway eosinophilia and angiogenesis were also observed in atopic subjects suggesting that they may represent early events in the natural history of asthma. Editor’s Comments: This is an excellent study essentially showing that childhood asthma is not significantly different from adult asthma. Angelo Barbato Am J Respir Crit Care Med Vol 174 2006 975 -981.
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