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Archives: Medical Journal Reviews

Medical Journal Review

Posted: November 2010

Reviewed by Juan Carlos Ivancevich, MD, in collaboration with Phil Lieberman, MD.

1. Does the use and dose of inhaled corticosteroids increase the risk of diabetes onset and progression?
The question of the association between inhaled corticosteroid use and the induction and worsening of diabetes has been rekindled recently. This issue is particularly relevant to patients with Chronic Obstructive Pulmonary Disease (COPD), a major cause of chronic disability whose prevalence increases steadily with age, similarly to type-2 diabetes. To assess whether the use and dose of inhaled corticosteroids increases the risk of the development of diabetes and its progression, the authors formed a new-user cohort of patients treated for respiratory disease during 1990-2005. They used Quebec health insurance databases to identify the cohort and followed the subjects through 2007 or until diabetes onset. The subcohort treated with oral hypoglycemics was followed until diabetes progression. A nested case-control analysis was used to estimate the rate ratios of diabetes onset and progression associated with current inhaled corticosteroid use; adjusted for age; sex; respiratory disease severity; and co-morbidity. The cohort included 388,584 patients of whom 30,167 had diabetes onset during 5.5 years of follow-up, and 2099 subsequently progressed from oral hypoglycemic treatment to insulin. Current use of inhaled corticosteroids was associated with a 34% increase in the rate of development of diabetes. The risk increases were greatest with the highest inhaled corticosteroid doses, equivalent to fluticasone 1000 µg per day or more. The authors concluded that in patients with respiratory disease, inhaled corticosteroid use is associated with modest increases in the risk of the development of diabetes and its progression. The risks are more pronounced at the higher doses currently prescribed in the treatment of COPD.
Editor's comment: Patients instituting therapy with high doses of inhaled corticosteroids should be assessed for possible hyperglycemia.
Suissa S, Kezouh A, Ernst P. Inhaled Corticosteroids and the Risks of Diabetes Onset and Progression. The American Journal of Medicine 2010: 123(11); 1001-1006.
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2. Volatile organic compounds (VOCs) in home air linked to asthma and allergies in children.
The risk for asthma and allergies in children associated with exposure to Volatile Organic Compounds (VOCs), which are emitted by many household products including computers, televisions, synthetic building materials, carpets, composite wood, polyvinyl chloride (PVC) flooring, and foam cushions, is not known. To investigate, the researchers studied air samples collected from the bedrooms of 198 children with asthma and/or allergies and 202 healthy children without such conditions who were aged between 3 and 8 years. The air samples were analyzed for levels of eight classes of VOCs: aromatic hydrocarbons, alkanes, organic acids, aldehydes, methyl-alkanes, propylene-glycol and glycol ethers (PGEs), dimethyl-alkanes, and texanol A+B. Of these, they found that only PGEs were associated with a 1.5-fold increased risk for asthma and allergies in children. Regarding specific conditions, each natural-log unit increase in PGEs was associated with a 1.5-fold increased risk for asthma, a 2.8-fold increased risk for rhinitis, and a 1.6-fold increased risk for eczema, after accounting for confounding factors such as gender, parental allergies, and exposure to secondhand smoke, household cleaning agents, and cat and dog allergens. Among the children with asthma and allergies, each natural-log unit increase in PGEs was associated with 1.8-fold increased risk for immunoglobulin (Ig)-E sensitization. The authors concluded that the present investigation demonstrates for the first time that the bedroom concentrations of PGEs are significantly associated with elevated risks of multiple allergic symptoms, rhinitis and eczema, as well as IgE-sensitization in preschool age children.
Editor's comment: Increased levels of certain volatile organic compounds (VOCs) in household air are associated with an increased risk for asthma and allergies in children.
Choi H, Schmidbauer N, Sundell J et al. Common Household Chemicals and the Allergy Risks in Pre-School Age Children. PLoS One 2010; 5(10): e13423 [doi:10.1371/journal.pone.0013423]
Full Text, Open Access

3. Agents that bind bitter taste receptors cause marked bronchodilation of intact airways which is greater than that produced by β-agonists.
The authors found expression of bitter taste receptors (TAS2Rs) on human airway smooth muscle (ASM) and considered these to be avoidance receptors for inhalants that, when activated, lead to ASM contraction and bronchospasm. TAS2R agonists such as saccharin, chloroquine and denatonium evoked increased intracellular calcium ([Ca2+]i) in ASM in a Gβγ-, phospholipase Cβ (PLCβ)- and inositol trisphosphate (IP3) receptor-dependent manner, an activity which would be expected to evoke contraction. Paradoxically, bitter tastants caused relaxation of isolated ASM resulting in dilation of airways that was threefold greater than that elicited by β-adrenergic receptor agonists. The relaxation induced by TAS2Rs was associated with a localized [Ca2+]i response at the cell membrane, which opens large-conductance Ca2+-activated K+(BKCa) channels, leading to ASM membrane hyperpolarization. Inhaled bitter tastants decreased airway obstruction in a mouse model of asthma.
Editor's comment: Given the need for efficacious bronchodilators for treating obstructive lung diseases, this pathway can be exploited for therapy with the thousands of known synthetic and naturally occurring bitter tastants.
Deshpande DA, Wang WCH, McIlmoyle EL et al. Bitter taste receptors on airway smooth muscle bronchodilate by localized calcium signaling and reverse obstruction. Nature Medicine 2010: 16(11); 1299-1304.

4. Daily physical activity in children with asthma and the impact of the level of asthma control.
To investigate the effects of treatment-induced changes in asthma control on daily physical activity, cardiovascular fitness, and body composition, the authors evaluated 55 children, aged 6-14 years, with recently diagnosed, untreated asthma and 154 healthy, age- and gender-matched children without the condition. Among the children with asthma, treatment with inhaled corticosteroids was initiated after a baseline period of 4 weeks. All of the children were assessed for physical activity levels, cardiovascular fitness, and body composition during the baseline period and after 1 year. At 1 year, children with asthma aged less than 13 years were assessed for disease control using the Childhood Asthma Control Test (C-ACT) and older asthmatic children were assessed using the Asthma Control Test (ACT). Most of the children with asthma experienced a significant improvement in asthma control between baseline and 1 year. The mean number of minutes spent per day in light to vigorous physical activity increased significantly among children in the asthma group, from 170.1 min/day at baseline to 195.4 min/day at 1 year. In contrast, the mean number of minutes spent per day in light to vigorous physical activity did not increase significantly among children in the control group. Cardiovascular fitness, measured using an ergometer cycle test, also increased significantly during the study period in asthmatic children and improved to a lesser extent in the control group. There were no statistically significant differences in changes in body fat, bone mineral density, or lean tissue levels between the two groups over the study period.
Editor's comment: Treatment-induced improvements in asthma control are associated with a clinically relevant increase in daily physical activity and cardiovascular fitness.
Vahlkvist S, Inman MD, Pedersen S. Effect of asthma treatment on fitness, daily activity and body composition in children with asthma. Allergy 2010; 65(11): 1464-1471.

5. In utero smoke exposure reduces asthma treatment response in children.
To address the effects of in utero exposure to tobacco smoke (IUS) on lung function and the impact of IUS on treatment outcomes in children with asthma, the researchers studied data on 1,041 asthmatic children, age 5-12 years, from the Childhood Asthma Management Program - a 4-year, multicenter, randomized, placebo-controlled trial evaluating the comparative long-term efficacy of inhaled anti-inflammatory medications. All of the children underwent lung function tests twice a year and methacholine challenge tests once a year after bronchodilation, in which the concentration of methacholine needed to provoke a 20% fall in FEV1 (PC20) was assessed. Interviews conducted with the children's mothers revealed that 150 (14%) children had IUS. The researchers found that although airway responsiveness improved in most of the children over the study period, those with IUS experienced around 26% less improvement than those without such exposure. Children without IUS who received ICSs experienced a substantial 1.25-fold improvement in PC20 over the study period compared with untreated children. In contrast, those with IUS who were treated with ICSs experienced only a 1.04-fold improvement in PC20 compared with untreated children. The authors concluded that his study demonstrates for the first time that IUS has the potential to attenuate the beneficial effect of inhaled corticosteroids on airways responsiveness in children with asthma.
Editor's comment: These results provide further reasons for physicians to emphasize the importance of preventing this exposure through smoking cessation counseling efforts with pregnant women.
Cohen RT, Raby BA, Van Steen K et al. In utero smoke exposure and impaired response to inhaled corticosteroids in children with asthma. Journal of Allergy and Clinical Immunology 2010; 126(3): 491-497.

6. Mode of delivery and wheezing.
There is evidence from two meta-analyses that children born through cesarean section may have an increased risk of developing asthma in comparison with those born through vaginal delivery. However, most studies were carried out in high-income countries, thus limiting the extrapolation of the findings to low- and middle-income societies. To address this, the researchers assessed associations between mode of delivery and wheezing in two birth cohorts from the Brazilian city of Pelotas. They evaluated two cohorts, one comprised of 5,429 infants born in 1993 and another consisting of 4,288 infants born in 2004. The team noted that Brazil has a high percentage of cesarean section deliveries, and the prevalence of asthma symptoms is as high as that reported in high-prevalence countries such as Australia, New Zealand, and the United Kingdom. The mothers of children in both cohorts completed questionnaires on wheezing in their infants at the age of 4 years, and the mothers of children in the 1993 cohort also completed these questionnaires when their children were aged 11 and 15 years. The authors found that, at the age of 4 years, prevalence of current wheezing in the 1993 and 2004 cohorts was 20% and 28%, respectively. In the 1993 cohort, the prevalence of current wheezing had fallen to 14% at the age of 11 years and to 12% at the age of 15 years. In both cohorts, there was no significant difference in the prevalence of current wheezing at the age of 4 years between children delivered by cesarean section and those with a vaginal delivery. Furthermore, there was no significant difference in wheezing rates regarding mode of delivery among children at the ages of 11 and 15 years. The authors concluded that despite the increase in the proportion of cesarean section in two cohorts in Southern Brazil, they found no evidence of an association between mode of delivery and the subsequent risk of wheezing.
Editor's comment: Results from this study do not support previous findings of a link between cesarean section delivery and an increased risk for wheezing in children.
Menezes AMB, Hallal PC, Matijasevich AM et al. Caesarean sections and risk of wheezing in childhood and adolescence: data from two birth cohort studies in Brazil. Clinical & Experimental Allergy 2010 [Published online ahead of print. doi: 10.1111/j.1365-2222.2010.03611.x]

7. Can clarithromycin improve asthma control?
To investigate whether treatment with clarithromycin in patients with persistent asthma and evidence of infection or colonization with Mycoplasma pneumonia and/or Chlamydophila pneumonia can improve asthma control, the authors studied 92 patients with asthma that remained poorly controlled despite 4 weeks of treatment with fluticasone propionate. Airway biopsies were collected from the participants and analyzed using polymerase chain reaction (PCR), which revealed evidence of Mycoplasma pneumonia and/or Chlamydophila pneumonia infection in 12 (13%) patients. Patients with and without evidence of infection were then randomly assigned to receive 16 weeks of treatment with either clarithromycin or placebo in addition to fluticasone propionate. The Asthma Control Questionnaire (ACQ) was completed by the participants at randomization and at the end of the study period. The researchers found that in PCR-positive participants, those assigned to take clarithromycin showed a 0.4-unit improvement in ACQ scores over the study period compared with a 0.1-unit improvement in those assigned to placebo - a non-significant between-group difference. In participants who were PCR-negative, those assigned to take clarithromycin also showed a 0.4-unit improvement in ACQ score compared with a 0.2-unit improvement in those assigned to take placebo. Again, this between-group difference was nonsignificant. Treatment with clarithromycin was not associated with improvements in lung function or airway inflammation, but was associated with improvement in airway hyper-responsiveness. The authors concluded that adding clarithromycin to fluticasone in adults with mild-to-moderate persistent asthma that was suboptimally controlled by low-dose inhaled corticosteroids alone did not further improve asthma control.
Editor's comment: Antibiotic treatment does not improve disease control in adults with mild-to-moderate asthma.
Sutherland ER, King TS, Icitovic N et al. A trial of clarithromycin for the treatment of suboptimally controlled asthma. Journal of Allergy and Clinical Immunology 2010; 126(4): 747-753.

8. Interactions between fetal trophoblast and maternal uterine NK (uNK) cells influence placentation in human pregnancy.
Many common disorders of pregnancy are attributed to insufficient invasion of the uterine lining by trophoblast, fetal cells that are the major cell type of the placenta. Interactions between fetal trophoblast and maternal uterine NK (uNK) cells - specifically interactions between HLA-C molecules expressed by the fetal trophoblast cells and killer Ig-like receptors (KIRs) on the maternal uNK cells. Consistent with this, pregnancies are at increased risk of preeclampsia in mothers homozygous for KIR haplotype A (KIR AA). The authors proposed that placentation is regulated as a result of interactions between maternal killer immunoglobulin-like receptors (KIRs) expressed by uNK cells and their cognate ligands, HLA-C molecules, displayed by invading fetal trophoblast cells. In this study, the authors demonstrated that trophoblasts express both paternally and maternally inherited HLA-C surface proteins and that maternal KIR AA frequencies are increased in affected pregnancies only when the fetus has more group 2 HLA-C genes (C2) than the mother. These data raise the possibility that there is a deleterious allogeneic effect stemming from paternal C2. They found that this effect also occurred in other pregnancy disorders (fetal growth restriction and recurrent miscarriage), indicating a role early in gestation for these receptor/ligand pairs in the pathogenesis of reproductive failure. Notably, pregnancy disorders were less frequent in mothers that possessed the telomeric end of the KIR B haplotype, which contains activating KIR2DS1. In addition, uNK cells expressed KIR2DS1, which bound specifically to C2+ trophoblast cells.
Editor's comment: These findings highlight the complexity and central importance of specific combinations of activating KIR and HLA-C in maternal-fetal immune interactions.
Hiby SE, Apps R, Sharkey AM et al. Maternal activating KIRs protect against human reproductive failure mediated by fetal HLA-C2. Journal of Clinical Investigation 2010; 120(11): 4102-4110.
Full Text, Open Access

9. Tiotropium in asthma treatment?
In a double-blind, three-way, crossover trial the authors tested two hypotheses. The primary hypothesis stated that in patients with asthma that is inadequately controlled by an inhaled glucocorticoid alone, the addition of tiotropium bromide would be superior to doubling the dose of an inhaled glucocorticoid. The secondary hypothesis stated that in such patients, the addition of tiotropium would not be inferior to the addition of a LABA. The primary outcome evaluated was the morning peak expiratory flow (PEF). Secondary outcomes included evening PEF, the proportion of asthma control days, the forced expiratory volume in 1 second (FEV1) before bronchodilation, and daily symptom scores.210 patients with asthma inadequately controlled by a low dose of an inhaled glucocorticoid were evaluated. The use of tiotropium resulted in a superior primary outcome, compared with doubling the dose of an inhaled glucocorticoid, as assessed by morning peak PEF, with a mean difference of 25.8 liters per minute. Superiority was noted in most secondary outcomes, including evening PEF, the proportion of asthma control days, the forced expiratory volume in 1 second (FEV1) before bronchodilation, and daily symptom scores. The addition of tiotropium was also noninferior to the addition of salmeterol for all assessed outcomes and increased the prebronchodilator FEV1 more than did salmeterol. The study showed that the use of tiotropium was superior to a doubling of the dose of an inhaled glucocorticoid, and among patients in the study tiotropium was noninferior to salmeterol as a bronchodilator.
Editor's comment: Anticholinergic agents may be useful for asthma management.
Peters SP, Kunselman SJ, Icitovic N et al. Tiotropium Bromide Step-Up Therapy for Adults with Uncontrolled Asthma. New England Journal of Medicine 2010; 363(18): 1715-1726.

10. Remodelling of nasal mucosa in allergic rhinitis.
The authors determined the expression level and the distribution pattern of small leucine-rich repeat proteoglycans (decorin, biglycan, and lumican), collagen, metalloproteinases and the presence of lymphangiogenesis in the nasal mucosa of healthy controls, and subjects with mild as well as severe persistent allergic rhinitis. The researchers found in subjects with mild and severe persistent allergic rhinitis the nasal mucosa, compared with healthy nasal mucosa, demonstrated more intense collagen deposition in the superficial and submucosal layer. The deposition of decorin did not differ between healthy controls and patients with rhinitis. However, lumican and biglycan showed strong immunoreactivity in mild and severe persistent allergic nasal mucosa.This observation was confirmed by Western blotting. The number and endothelial length density of lymphatic vessels were increased in mild and severe persistent allergic nasal mucosa compared with healthy nasal mucosa. The expression of matrix metalloproteinase 9 (MMP 9) was increased in severe persistent allergic rhinitis. These results suggest that remodeling of the nasal mucosa occurs in patients with allergic rhinitis and consists of the increased expression and altered distribution of collagen, proteoglycans, and lymphatic vessels.
Editor's comment: These findings provide the basis for further studies on the role of collagen and proteoglycan deposition, and lymphangiogenesis on nasal stuffiness of patients with allergic rhinitis, and implies that remodeling similar to that seen in asthma occurs in the nasal mucosa of patients with allergic rhinitis.
Kim TH, Lee JY, Lee HM et al. Remodelling of nasal mucosa in mild and severe persistent allergic rhinitis with special reference to the distribution of collagen, proteoglycans, and lymphatic vessels. Clinical & Experimental Allergy 2010; 40(12): 1742-1754.

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