Medical Journal Review
Posted: November 2009
Reviewed by Juan Carlos Ivancevich, MD, in collaboration with Phil Lieberman, MD.
1. Acetaminophen use and the risk of asthma in children and adults: a systematic review and metaanalysis.
The authors searched databases including MEDLINE (1966-2008) and EMBASE (1980-2008) to identify studies of acetaminophen use and its relation to a diagnosis of asthma. Thirteen cross-sectional, four cohort and two case-control studies of 425,140 subjects were included. The pooled odds ratio (OR) for asthma among acetaminophen users was 1.63 (95% CI, 1.46-1.77). The risk of asthma in children among acetaminophen users in the year prior to a diagnosis of asthma and in the first year of life was elevated (1.60 [95% CI, 1.48-1.74], 1.47 [95% CI, 1.36-1.56] respectively). Only one study reported the association between high acetaminophen dose and asthma in children (3.23 [95%CI, 2.9-3.6]). There was an increased risk of asthma and wheezing with prenatal use of acetaminophen by mothers (1.28 [95% CI, 1.16-41], 1.50 [95% CI, 1.10-2.05] respectively).
Editor's comment: The results are consistent with an increase in the risk of asthma and wheezing in both children and adults exposed to acetaminophen.
Etminan M et al. Acetaminophen use and the risk of asthma in children and adults: a systematic review and metaanalysis, Chest 2009;136(5):1316-1323, November 2009.
2. GA²LEN skin test study III: Minimum battery of test inhalent allergens needed in epidemiological studies in patients.
The authors defined the minimal number and the necessary allergens required to identify a sensitized patient in the Pan-European GA²LEN skin prick test study (17 centers in 14 countries). A standardized panel of 18 allergens was employed to evaluate 3034 subjects. 1996 (68.2%) were sensitized to at least one allergen. Overall, eight allergens (grass pollen, D. pteronyssinus, birch pollen, cat dander, Artemisia, olive pollen, Blatella and Alternaria) identified more than 95% of sensitized subjects. Depending on the country, up to 13 allergens were needed to identify all sensitized subjects. The authors concluded that a panel of eight to ten allergens was sufficient to identify the majority of sensitized subjects. For clinical care, the whole battery of 18 allergens is needed.
Editor's comment: Knowing the number of allergens necessary to identify a sensitized patient is important for a cost-effective approach in epidemiological studies.
Bousquet P et al. GA²LEN skin test study III: Minimum battery of test inhalent allergens needed in epidemiological studies in patients. Allergy 2009;64(11):1656-1662.
3. Adrenergic β2-receptor(ADRB2) genotype predisposes to exacerbations in steroid-treated asthmatic patients taking frequent albuterol or salmeterol.
The researchers studied the role of the Arg16 allele on asthma exacerbations requiring the use of albuterol and salmeterol. Arg/Gly status at position 16 of ADRB2 was assessed in 1182 young asthmatic patients (age, 3-22 years). An increased risk of exacerbations per copy of the Arg16 allele was observed, regardless of treatment regimen (OR, 1.30; 95% CI, 1.09-1.55; P = .003). The risk of exacerbations in patients with the Arg16 allele was only observed in those receiving daily inhaled long- or short-acting β2-agonists (OR, 1.64; 95% CI, 1.22-2.20; P = .001). There was no genotypic risk in patients using inhaled β2-agonists less than once a day (OR, 1.08; 95% CI, 0.85-1.36; P = .525). The Arg16 genotype-associated risk for exacerbations was significantly different in those exposed to β2-agonists daily versus those that were not (test for interaction, P = .022)
Editor's comment: The Arg16 genotype of ADRB2 is associated with exacerbations in asthmatic children and young adults exposed daily to β2-agonists.
Basu K et al. Adrenergic β2-receptor(ADRB2) genotype predisposes to exacerbations in steroid-treated asthmatic patients taking frequent albuterol or salmeterol, J Clin Allergy Immun 2009: Article in press, published online 05 October 2009.
4. Multicentre trial evaluating alveolar NO fraction as a marker of asthma control and severity.
In this multicentre prospective study, the authors wanted to determine whether alveolar NO fraction was associated with the level of asthma control and severity when measured at baseline and during subsequent 3-month follow-up. 200 asthmatics older than 10 years (165 receiving inhaled corticosteroids), nonsmokers, without recent exacerbation and under regular treatment were included. They underwent exhaled NO measurement at multiple constant flows and were followed up for 12 weeks. Alveolar NO and FENO did not correlate with asthma control at baseline or during subsequent follow-up, as assessed by scores on asthma questionnaires. There was no difference in severity assessed by the GINA scores across different exhaled NO values at baseline. In a post hoc analysis, alveolar NO was negatively correlated to maximal expiratory flow 25-75%, suggesting that alveolar NO is a marker of peripheral airway dysfunction.
Editor's comment: These data question the value of NO and FENO in asthma assessment with the possible exception of a relation between alveolar NO and small airways obstruction.
Mahut B et al. Multicentre trial evaluating alveolar NO fraction as a marker of asthma control and severity, Allergy, 20 October 2009 [Epub ahead of print].
5. BCG vaccination and protection against development of childhood asthma - epi studies review and meta analysis.
The researchers identified eligible studies using a search strategy that included a computerized literature search and a manual search of each article's reference list, up to June 2008. A total of 23 studies were included (10 cohort, 5 case-control and 8 cross-sectional). Each study was summarized and rated for methodological quality. They considered three indicators of BCG exposure: BCG vaccination, tuberculin response and scar diameter. The pooled estimate of association for 23 studies reporting on any of the three indicators suggested a protective effect of BCG exposure on childhood asthma. The studies were heterogeneous, especially when tuberculin response was considered. Restriction to a subgroup of 16 studies that considered BCG vaccination indicated a protective effect with no evidence of heterogeneity. The overall pooled OR was 0.86.
Editor's comment: These results support the hypothesis that exposure to the BCG vaccine in early life prevents asthma.
El-Zein M et al. Does BCG vaccination protect against the development of childhood asthma? A systematic review and meta-analysis of epidemiological studies, Int J Epidemiol. 2009 Oct 12 [Epub ahead of print].
6. Phenotypic determinants of uncontrolled asthma.
The researchers estimated the distribution and the phenotypic characteristics of asthma control in two groups of patients defined by the use of inhaled corticosteroids (ICS) on 501 asthmatics participating in a large epidemiologic study on the genetics of asthma. The authors found that uncontrolled asthma was more frequent in ICS users when compared with non-ICS users. Among those taking ICS, only 25% had controlled asthma, whereas 60% of non-ICS users had their asthma under control. In ICS users, female sex and chronic cough or phlegm were associated with a greater risk for uncontrolled asthma. The risk for uncontrolled asthma was four-fold greater among patients who reported chronic cough or phlegm. In non-ICS users, a high total immunoglobulin E and sensitization to molds were associated with uncontrolled asthma.
Editor's comment: Understanding determinants of uncontrolled asthma may help in the identification of patients at increased risk.
Siroux V et al. Phenotypic determinants of uncontrolled asthma, J Allergy Clin Immunol, 2009;124(4):681-687, October 2009.
7. Critical Role of IL-17RA in immunopathology of Influenza Infection.
Acute respiratory distress syndrome is a highly fatal complication of influenza infection. Following infection, IL-17 uses a signaling receptor called IL-17RA to activate and attract large numbers of neutrophils that play a key role in the development of acute lung injury. The research team used an influenza infected IL-17RA knockout mouse model to see if the absence of IL-17 signalling would reduce lung injury.They found decreased levels of illness and death among the IL-17RA knockout mice, despite a higher viral load. The researchers found that the knockout mice had fewer neutrophils in the lung, thus lower levels of inflammation and less lung injury. Comparing their results to studies of IL-17RA knockout mice in other models of viral infection, the researchers conclude that therapeutic regulation of IL-17 signaling may be beneficial not only in acute lung injury, but also in treating viral infections of other organs.
Editor's comment: IL-17RA may be a new target to prevent fatal influenza lung complication.
Crowe CR et al. Critical Role of IL-17RA in immunopathology of Influenza Infection, J Immunol, 2009;183:5301-5310.
8. Inhaled house dust mite induces pulmonary T helper 2 cytokine production.
It is well known that the inhalation of house dust mite (HDM) results in a TH2 response in unsensitized mice, with airway hyperreactivity and airway remodelling. The authors performed a study of the molecular mediators and cellular influx in bronchoalveolar lavage (BAL) and lung to define the pulmonary inflammatory response to inhaled HDM extract. Mice were exposed five times a week to soluble HDM extract for 3 weeks. Lung function was measured in groups of mice at intervals following the final HDM challenge. Recruitment of inflammatory cells and inflammatory mediator production was then assessed in BAL and lungs of individual mice. They found that Th2 cytokines were significantly increased in BAL and lung after HDM challenge. The cytokines and chemokines levels correlated with the influx of eosinophils and Th2 cells. The production of IL-4, IL-5 and IL-13 preceded the increase in airways resistance.
Editor's comment: These data are important for studies determining the efficacy of novel treatments for allergic airways diseases.
Gregory LG et al. Inhaled house dust mite induces pulmonary T helper 2 cytokine production. Clin Exp Allergy, 2009;39(10):1597-1610.
9. Leukotriene E4-induced pulmonary inflammation is mediated by the P2Y12 (purinergic) receptor.
LTE4 is stable and abundant in vivo although shows negligible activity at the type 1 and 2 receptors for cys-LTs, it´s a powerful inducer of mucosal eosinophilia and airway hyperresponsiveness in humans with asthma. The authors showed that P2Y12 receptor expression permits LTE4-induced activation of extracellular signal-regulated kinase in Chinese hamster ovary cells and induces chemokine and prostaglandin D2 production by LAD2 cells, a human mast cell line. P2Y12 receptor expression by LAD2 cells is required for competition between radiolabeled ADP and unlabeled LTE4 but not for direct binding of LTE4, suggesting that P2Y12 complexes with another receptor to recognize LTE4. Administration of LTE4 to the airways of sensitized mice potentiates eosinophilia, goblet cell metaplasia, and expression of interleukin-13 in response to low-dose aerosolized allergen. These responses don´t persist in mice lacking P2Y12 receptors. The effects of LTE4 on P2Y12 in the airway were abrogated by platelet depletion. Thus, the P2Y12 receptor is required for proinflammatory actions of LTE4.
Editor's comment: P2Y12 receptor may be a novel potential therapeutic target for asthma.
Paruchuri S et al. Leukotriene E4-induced pulmonary inflammation is mediated by the P2Y12 (purinergic) receptor. J. Exp. Med, 2009;26(11):2543-2555.
10. Effect of natural seasonal pollen exposure and repeated nasal allergen provocations on elevation of exhaled nitric oxide (FENO).
Studies have shown that FENO is elevated during the pollen season in subjects with allergic rhinitis. The investigators studied only patients with intermittent allergic rhinitis, to determine if natural or artificial pollen exposure led to elevations of FENO. First, the researchers compared FENO of seven nonatopic controls with 13 nonasthmatic individuals with mild intermittent rhinitis to tree and/or grass pollen. In a second experiment, 16 atopic individuals and 12 controls had nasal allergen provocations on 4 consecutive days in the pollen season, with daily measurements of FENO before and after provocation. Natural pollen exposure caused a significant increase in FENO in allergic individuals. Nasal allergen provocations, however, did not result in a statistically significant increase in FENO or blood eosinophils between baseline and day 5. As no response was seen in nonallergic individuals, the data support an allergen and immunoglobulin E (IgE)-dependent rise of FENO in sensitized and symptomatic patients.
Editor's comment: Exposure to natural pollen increases exhaled nitric oxide (FENO) in individuals with allergic rhinitis.
Bergmann-Hug K et al. Effect of natural seasonal pollen exposure and repeated nasal allergen provocations on elevation of exhaled nitric oxide (FENO). Allergy, 2009;64(11):1629-1634.
11. The prevalence of food hypersensitivity (FHS) in young adults.
The researchers investigated a cohort of 1272 young adults by questionnaire, skin prick test (SPT) and histamine release (HR) followed by oral challenge (OCh) to the most common allergenic foods to estimate the prevalence of FHS. FHS was divided into primary (independent of pollen sensitization) and secondary (reactions to pollen related fruits and vegetables in pollen allergic patients). Primary FHS was reported by 19.6% and secondary FHS by 16.7%. Primary FHS was confirmed by OCh in 1.7% [1.1% - 2.95%]. In primary FHS, the most common allergenic food was peanut (0.6%) followed by additives (0.5%), shrimp (0.2%), codfish (0.1%), cow's milk (0.1%), octopus (0.1%) and soy (0.1%). In secondary FHS, kiwi allergy was reported by 7.8% of the participants followed by hazelnut (6.6%), pineapple (4.4%), apple (4.3%), orange (4.2%), tomato (3.8%), peach (3.0%) and brazil nut (2.7%).
Editor's comment: This study confirms the difference between perception and actual food allergy.
Osterballe M et al. The prevalence of food hypersensitivity (FHS) in young adults. Pediatr Allergy Immunol. 2009;20(7):686-692.
12. The Longest Wheal Diameter Is the Optimal Measurement for the Evaluation of Skin Prick Tests (SPT).
The authors compared mean or longest diameter with the surface area of the wheal skin response in 1,554 SPTs in 74 patients suspected of having an allergic reaction against inhalant allergens using the Pan-European GA²LEN SPT panel. In 264 SPTs, a macroscopically evident wheal and flare response was observed. Both mean and longest diameters correlated significantly with the wheal surface area. However, Plongest was statistically significantly larger than Pmean when the surface of the wheal was >17 mm² (Plongest > 0.860 vs. Pmean < 0.660; p < 0.05). Such a surface area involvement corresponds to a maximum diameter of approximately 7 mm and a mean diameter of approximately 6 mm. The longest wheal diameter alone seemed to be a better surrogate marker of the wheal surface area in comparison with the mean diameter.
Editor's comment: To evaluate SPTs the longest wheal diameter alone seems to be accurate, easier and faster.
Konstantinou GN et al. Int Arch Allergy Immunol, 2010;151(4):343-345.
13. Quadrupling the dose of inhaled corticosteroid to prevent asthma exacerbations: a randomized, double-blind, placebo-controlled, parallel-group clinical trial.
The researchers investigated whether a policy of quadrupling the dose of inhaled corticosteroid when asthma control starts to deteriorate reduces asthma exacerbations requiring treatment with oral corticosteroid. A total of 403 people with asthma were given a self-management plan and randomized to take an active or placebo corticosteroid inhaler in addition to their usual asthma treatment when their PEF fell by 15% on 2 consecutive days or by 30% on 1 day. The study inhalers provided a quadrupling or no change in corticosteroid dose. Eighteen of 197 (9%) and 29 of 203 (14%) participants had an exacerbation of asthma requiring treatment with oral corticosteroids in the active and placebo groups, respectively, giving a risk ratio of 0.64 (95% confidence interval, 0.37-1.11, P = 0.11). Of the 94 participants who started the study inhaler far fewer required treatment with oral corticosteroids in the active compared with the placebo group: 12 of 56 (21%) in the active group and 19 of 38 (50%) in the placebo group, giving a risk ratio of 0.43 (95% confidence interval, 0.24-0.78, P = 0.004).
Editor's comment: Quadrupling the dose of inhaled corticosteroid when asthma control starts to deteriorate appears to reduce acute exacerbations requiring oral corticosteroids and deserves further investigation.
Oborne J et al. Quadrupling the dose of inhaled corticosteroid to prevent asthma exacerbations: a randomized, double-blind, placebo-controlled, parallel-group clinical trial. Am J Respir Crit Care Med, 2009:180(7):598-602.
14. Oral Allergy Syndrome.
In this review the authors define oral allergy syndrome (OAS) symptoms of IgE-mediated immediate allergy localized in the oral mucosa. Another term used for this syndrome is pollen-food allergy syndrome (PFS); the patient is sensitized with pollen via the airways and exhibits an allergic reaction to food antigens shared with or cross reacting with pollen allergens. In addition to PFS, latex-fruit syndrome is also well-known. In many cases, antigens become edible after heating, but some are resistant to heat. Immunotherapy against the cross-reacting pollen has also been attempted in PFS.
Editor's comment: Interesting and detailed review on oral allergy syndrome.
Kondo Y and Urisu A. Oral Allergy Syndrome. Allergol Intl. 2009 Oct 25;58(4) [Epub ahead of print]
Full text, free article