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Archives: Medical Journal Reviews

Medical Journal Review

Posted: September 2010

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

1. The role of IgE in allergic asthma in children.
The role of IgE in allergic asthma is still a matter of debate. This may be mostly relevant in childhood, where a wide range of total serum (s) IgE levels is often detected. To evaluate whether the relationships between total or allergen-specific sIgE levels and the clinical markers of allergic inflammation and the pulmonary function values might be affected by the demographic characteristics of the patients or by the presence of multiple sensitizations to allergens, the authors included in the study 64 steroid-free children of both sexes sensitized to house dust mites (HDM), who underwent nitric oxide (NO) level analysis and spirometry with reversibility test, in addition to standard blood analysis including the evaluation of total sIgE and HDM-specific sIgE levels and eosinophil counts.The roles of age, sex and multiple sensitisations were evaluated by multiple regression model (MRM) analysis. Total and HDM-specific sIgE levels showed similar moderate-to-strong correlations with exhaled nitric oxide (FeNO) and blood eosinophilia but not with FVC, FEV1, and %FEV1 change after salbutamol. The positive associations between total sIgE levels and Log FeNO levels or Log blood eosinophilia were also detected by MRM analysis. Age brought a negative, although limited, contribution to FENO levels and blood eosinophilia. Positive similar associations were also detected between HDM-specific sIgE levels and FeNO levels or blood eosinophilia; however, however, no significant contribution of age or of other covariates was noted.
Editor's comment: These data support the role not only of allergen-specific IgE but also of total IgE in the pathogenesis of allergic inflammation in asthmatic children.
M Silvestri M, Pistorio A, Battistini E et al. IgE in childhood asthma: relevance of demographic characteristics and polysensitisation. Archives of Diseases in Childhood. [Published online before print 23 July 2010. doi: 10.1136/adc.2009.163667]

2. Wheezing phenotypes in childhood.
The authors have written an interesting review of the different phenotypes of asthma in childhood and the use of a multi-dimensional approach for their categorization and study. This approach is based on a wide range of features and methods such as multivariate cluster or latent class analysis. Phenotypes identified in this manner are arguably more complex but more objective. The authors suggested the use of cluster analysis, a group of techniques that seek to organize the subjects of a multivariate dataset into relatively homogenous groups. Such methods allow phenotypes to be identified in a data-driven manner and might therefore minimize the subjectivity involved in selecting the features. The underlying pathophysiology and aetiology will need to be understood to characterize properly the diseases causing recurrent wheeze in children.
Editor's comment: Better phenotype definitions increase the precision of research into causes and mechanisms.
Spycher BD, Silverman M, Kuehni CE. Phenotypes of childhood asthma: are they real? Clinical & Experimental Allergy 2010; 40(8): 1130-1141.

3. A probiotic may benefit children with asthma and rhinitis.
The role of probiotic administration in allergic airway diseases remains controversial. For the current study, the researchers enrolled 105 schoolchildren (6-12 y), with asthma (A) and allergic rhinitis (AR) who were assigned to receive an L. gasseri supplement (n=49) or placebo (n=56) each day for 8 weeks. All the children kept symptom diaries during the study period and underwent extensive clinical assessments at baseline and every 2 weeks, during which blood samples were also taken for analysis. The children also underwent lung function tests at baseline, at week 6, and at the end of the study period. The researchers found that mean FEV1 increased significantly from 1.21 l to 1.52 l over the study period in the probiotic group, and only from 1.37 l to 1.42 l in the placebo group. Children in the probiotic group also experienced significantly greater improvements in FVC and nighttime PEF rates over the study period. Probiotic-treated children also showed significantly greater reductions in clinical symptom scores for both A and AR at the end of the study period. Furthermore, treatment with L. gasseri was associated with significant reductions in tumor necrosis factor-α, interferon-γ, interleukin (IL)-12, and IL-13 production by peripheral blood mononuclear cells. Probiotic supplementation may provide clinical benefits for school children suffering from allergic airway diseases. However, further studies are needed to confirm their findings.
Editor's comment: The antiallergic effects of probiotics remain unclear, and their clinical effectiveness in the treatment of asthma and AR requires further investigation.
Chen YS, Lin IL, Jan RL et al. Randomized placebo-controlled trial of lactobacillus on asthmatic children with allergic rhinitis. Pediatric Pulmonology. 2010 [Article online in advance of print 23 July 2010. doi: DOI: 10.1002/ppul.21296]

4. Children with asthma and allergic rhinitis (AR) have altered oxidative state.
Oxidative stress may be defined as a disruption of the balance between the level of oxidants and reductants (antioxidants), and the oxidative state in children may influence the risk of asthma and allergic disease. To investigate oxidative stress levels in children with asthma and AR, the researchers recruited 50 children with and 52 without asthma (7-12 y). All the children underwent skin prick allergy tests, spirometry, and fractional exhaled nitric oxide (FeNO) measurements. Blood samples were collected and analyzed for levels of the antioxidants selenium, vitamin E, bilirubin, albumin, uric acid and transferrin and the oxidant ferritin. In total, 23 children were found to have AR - 19 with asthma and four without the condition. 48 children with neither asthma nor AR made up the control group. The children with asthma alone had significantly lower levels of albumin than controls, after accounting for age and gender. Furthermore, children with asthma alone who had a FeNO level of 20 ppb or higher had even lower levels of albumin than those with a FeNO level of less than 20 ppb. Children with asthma and AR also had lower levels of albumin, but higher levels of ferritin. Partly controlled or uncontrolled asthma was associated with lower vitamin E levels, lower transferrin levels, and higher albumin levels compared with controlled asthma. The authors concluded that children with asthma had reduced levels of the major serum antioxidant albumin, and reduced albumin was associated with increased FeNO, a marker of allergic inflammation in asthma. Poorly controlled asthma was associated with further imbalance in oxidative state.
Editor's comment: The complex associations between oxidative state and inflammation in asthma and allergic disease need further investigation.
Bakkeheim E, Mowinckel P, Carlsen KH et al. Altered oxidative state in schoolchildren with asthma and allergic rhinitis. Pediatric Allergy and Immunology 2010 [Article online in advance of print 13 July 2010. DOI: 10.1111/j.1399-3038.2010.01092.x]

5. Confirmation of asthma diagnosis.
It was recently shown that 30% of adults with a physician diagnosis of asthma (A) did not have A when objectively assessed using an algorithm involving spirometry, bronchial challenge testing, and subsequent tapering of asthma medications. To investigate how many steps of an A diagnostic algorithm are realistically required to confirm or exclude A in previously-diagnosed patients, the authors studied 540 randomly selected community patients (older than 15 y) with the condition. Patients taking long-term oral corticosteroids or with a smoking history of more than 10 pack-years were excluded. The protocol involved one to four visits. In the first visit, the patient underwent pre- and post-bronchodilator spirometry, and if they showed an improvement in FEV1 of at least 200 ml or 15% after the bronchodilator, then A was confirmed. If spirometry was negative, the patient returned for a bronchial challenge test with methacholine, and if this was positive ( < 8 mg/ml methacholine causing a 20% fall in FEV1), then A was confirmed. If this test proved negative, A was excluded in subjects not taking any controller medications on a regular basis. Those subjects who were taking such medications and gave negative test results at visits 1 and 2 were required to taper their asthma medications and undergo repeat bronchial challenge testing at further visits. The researchers found that of the 499 patients who completed the diagnostic algorithm, 69% had A confirmed and 30% had A excluded. Overall, 95% of patients with confirmed A, including those using regular asthma controller medications, had it confirmed at the first or second visit. Only 9% required tapering of A medications and repeated bronchial challenge tests.The main factors associated with earlier confirmation were lower FEV1 and younger age.
Editor's comment: In most patients with previously diagnosed asthma, pre- and post-bronchodilator spirometry and a single methacholine challenge test performed during two visits are enough to confirm the diagnosis.
Luks VP, Vandemheen KL, Aaron SD. Confirmation of asthma in an era of overdiagnosis. European Respiratory Journal 2010; 36(2): 255-260.

6. Different citokine profile and eosinophil activation in rhinovirus (RV) and respiratory syncytial (RSV)-induced wheezing.
In order to detect respiratory viruses and measure eosinophil cationic protein (ECP), and 27 types of cytokines/chemokines in both serum and nasal secretions from wheezing children, the authors performed an observational, case-control study on 267 subjects, who were visited and/or hospitalized with acute respiratory symptoms (with wheezing: males, 115; females, 59; mean/median age, 3.6/3.0 y) or who were visited for regular physical examination and treatment (non-symptomatic: males, 48; females, 31; mean/median age, 5.0/4.7 y), and 14 control subjects (controls: males, 9; females 5; mean/median age, 3.6/3.7 y). Viruses were detected in nasal secretions from 174 patients with acute wheezing exacerbations. They measured peripheral eosinophil counts, serum and nasal concentrations of ECP and 27 cytokines/chemokines. Of 174 samples from wheezing exacerbations, rhinovirus (RV) was detected in 59; Respiratory syncytial virus (RSV) in 44; enterovirus in 17; other viruses in 19; and no viruses in 35. Serum concentrations of ECP, IL-5, IL-6, IL-1ra, and interferon-γ-induced protein (IP-10) were significantly elevated in RV-induced wheezing compared with asymptomatic wheezing. Similarly, serum ECP, IL-5, and IP-10 were significantly higher in RV-induced wheezing than in controls. On the other hand, IL-1ra and IP-10, but not ECP and IL-5 were significantly higher in RSV-induced wheezing than in controls. Furthermore, only IL-5 was significantly elevated in the RV group compared with the RSV group in both serum and nasal secretions.
Editor's comment: These observations and previous reports clearly indicate that different cytokine profiles and eosinophil activation patterns are found in in RV and RSV-induced wheezing/asthma exacerbations.
Kato M, Tsukagoshi H, Yoshizumi M et al. Different cytokine profile and eosinophil activation are involved in rhinovirus- and RS virus-induced acute exacerbation of childhood wheezing. Pediatric Allergy and Immunology. 2010 [Article online in advance of print 28 June 2010. DOI: 10.1111/j.1399-3038.2010.01026.x]

7. Association between socio-economic status and childhood food allergy and anaphylaxis in Australia.
The objective of this study was to examine the association between socio-economic status (SES), geographic remoteness and childhood food allergy (FA) and anaphylaxis in Australia. Sales of infant hypoallergenic formulae (IHF) and EpiPens in children aged 0-4 years and hospital anaphylaxis admission rates in age groups 0-4, 5-14, 15-24, 25-64 and 65+ years were used as proxy markers of FA and anaphylaxis. Annual IHF sales rates were higher in those with the greatest compared with the least socio-economic advantage. EpiPen sales trends were also higher in those with the greatest socio-economic advantage in all age groups, most marked in those aged 0-4 and 5-14 years. Formula sales rates were higher in major cities than remote/very remote regions with similar EpiPen sales trends, particularly in ages 0-4 and 5-14 years. Socio-economic advantage and geographic remoteness remained statistically significant in multivariable analysis of prescription rates and were unchanged by adjustment for health services access. While anaphylaxis admission rates were higher in those with the greatest compared with the least socio-economic advantage in children aged 0-4 years, this relationship did not hold for older groups. There was no association between geographic remoteness and anaphylaxis admissions.
Editor's comment: The 'westernized lifestyle' appeared to be a risk factor for FA/anaphylaxis development.
Mullins RJ, Clark S, Camargo CA. Socio-economic status, geographic remoteness and childhood food allergy and anaphylaxis in Australia. Clinical and Experimental Allergy. 2010 [Article online in advance of print 16 July 2010. DOI: 10.1111/j.1365-2222.2010.03573.x]

8. Is there association between asthma or asthma medications with prostate cancer risk?
The researchers used data for 16,934 men from the Melbourne Collaborative Cohort Study to investigate whether a history of asthma or the use of asthma medications is associated with prostate cancer risk. A total of 1179 participants were diagnosed with prostate cancer during an average follow-up period of 13.4 years, with 11% of the whole cohort reporting a history of physician-diagnosed asthma at baseline. Two-thirds (67%) of the asthmatic men reported using medication to control their asthma including antihistamines, bronchodilators, inhaled glucocorticoids, and systemic glucocorticoids. Overall, a history of asthma was associated with a small but significant 1.25-fold increased risk for prostate cancer, and the risk for men who used medications was statistically similar to those who did not use medications, at a respective 1.29- versus 1.12-fold increased risk. Hazard ratios (HRs) for the risk for prostate cancer by type of asthma medication were: 1.71 for systemic glucocorticoids, 1.39 for inhaled glucocorticoids, 1.36 for bronchodilators, and 0.78 for antihistamines. After adjusting the results for the presence of asthma, the HRs changed only slightly, at 1.30, 1.64, 1.29, and 0.76, respectively, for each medication group. In light of the higher risks observed among men who took medications for asthma versus those who did not, the authors suggest that more severe asthma and inflammation could be more strongly associated with prostate cancer than mild asthma. However, they concede that it is difficult to disentangle the effects of asthma itself with the effects of medication. Further studies are needed to clarify the possible mechanisms underlying these associations.
Editor's comment: The study suggests that men with asthma and those who have used asthma medications, particularly systemic glucocorticoids, are at increased risk for developing prostate cancer.
Severi G, Baglietto L, Muller DC et al. Asthma, asthma medications, and prostate cancer risk. Cancer Epidemiology Biomarkers and Prevention. 2010 [Article online in advance of print 29 July 2010. doi: 10.1158/1055-9965.EPI-10-0381]

9. Intermittent allergic rhinitis (IAR): A pathway-based approach to find novel markers of local glucocorticoid (GC) treatment.
In this study, the authors aimed to identify pathways affected by local GC treatment and examine if those pathways could be used to find novel markers of local GC treatment in nasal fluids from patients with IAR. The researchers performed gene expression microarray- and iTRAQ-based proteomic analyses of nasal fluids, nasal fluid cells and nasal mucosa from patients with IAR to find pathways enriched for differentially expressed genes and proteins. The proteins representing those pathways were analyzed with ELISA in an independent material of nasal fluids from 23 patients with IAR before and after treatment with a local GC. Transcriptional and proteomic high-throughput analyses of nasal fluids, nasal fluid cells and nasal mucosal showed that local GC treatment affected a wide variety of pathways in IAR such as the glucocorticoid receptor pathway and the acute phase response pathway. The analysis of extracellular proteins encoded by genes in those pathways showed that proteins that changed significantly in expression included known biomarkers such as eosinophil cationic protein but also proteins that had not been previously described in IAR, namely CCL2, M-CSF, CXCL6 and apoH. The authors concluded that pathway-based analyses of genomic and proteomic high-throughput data can be used as a complementary approach to identify novel potential markers of GC treatment in IAR.
Editor's comment: A novel approach to find biomarkers in IAR that may be useful in other allergic diseases.
Wang H, Chavali S, Mobini R et al . A pathway-based approach to find novel markers of local glucocorticoid treatment in intermittent allergic rhinitis. Allergy. 2010 [Article online in advance of print 23 July 2010. doi: 10.1111/j.1398-9995.2010.02444.x]

10. Diabetes may affect lungs.
A recent study shows that patients with diabetes may have impaired lung function, similar to the impairment found in smokers. The researchers conducted a literature review of 40 studies describing the pulmonary function data of 3,182 patients with diabetes and 27,080 control subjects. The metaanalysis showed that, in the absence of overt pulmonary disease, diabetes was associated with a modest but statistically significant impairment in lung function in a restrictive pattern. A subanalysis revealed that the association seemed more pronounced in type 2 diabetes compared with type 1 diabetes. Researchers explain that the degree of lung function impairment found in their study closely resembles that of smoking. They further speculate that diabetes may accelerate lung function decline in those with chronic lung conditions, including chronic obstructive pulmonary disease.
Editor's comment: Both type 1 and type 2 diabetes are associated with a modestly impaired pulmonary function in a restrictive pattern.
van den Borst B, Gosker HR, Zeegers MP et al. Pulmonary Function in Diabetes: A Metaanalysis. Chest. 2010; 138(2): 393-406.

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