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Archives: Medical Journal Reviews

Medical Journal Review

Posted: February 2011

Reviewed and edited by Dr. Juan Carlos Ivancevich and Dr. Phil Lieberman

1. Inflammatory phenotypes in adults and children with acute asthma.
To investigate inflammatory phenotypes in stable adult asthma, stable childhood asthma, and acute asthma, and to examine whether infection with Chlamydophila pneumoniae is a possible cause of noneosinophilic asthma, the researchers studied 51 adults with stable (n = 29) or acute (n = 22) asthma, and 77 children with stable (n = 49) or acute (n = 28) asthma. Sputum samples were collected from all of the participants and assessed for inflammatory cell types and C. pneumoniae DNA. Patients with sputum eosinophil levels of more than 3% were classified as having eosinophilic asthma, and those with neutrophil levels of more than 61% and eosinophil levels of less than 3% were classified as having neutrophilic asthma. Patients with neutrophil levels of more than 61% and eosinophil levels of more than 3% were classified as having mixed granulocytic asthma; and those with neutrophil levels of less than 61% and eosinophil levels of less than 3% were classified as having paucigranulocytic asthma. The researchers found that eosinophilic asthma was the most common phenotype in children with acute asthma (50.0%), followed by mixed granulocytic (35.7%), and neutrophilic and paucigranulocytic asthma (both at 7.1%). In adults with acute asthma, the most common phenotype was neutrophilic asthma (81.8%), followed by mixed granulocytic asthma (18.2%). The eosinophilic and paucigranulocytic phenotypes were not found in any of the adults with acute asthma. Paucigranulocytic asthma was the most common phenotype in adults with stable asthma (51.7%), followed by neutrophilic (27.6%), eosinophilic (17.2%), and mixed granulocytic asthma (3.5%). Paucigranulocytic asthma was also the most common phenotype in children with stable asthma (49.0%), followed by eosinophilic (28.6%), neutrophilic (20.4%), and mixed granulocytic asthma (2.0%). C. pneumoniae DNA was detected in just one sputum sample, from a child with acute asthma. The authors concluded that the pattern of inflammatory phenotypes differs between adults and children, with eosinophilic inflammation being more prevalent in both acute and stable childhood asthma, and neutrophilic inflammation being the dominant pattern of acute asthma in adults. Current C. pneumoniae infection does not appear to explain the noneosinophilic phenotype in asthma nor increase respiratory acute exacerbation.
Editor's comment: This Australian study shows that inflammatory phenotypes differ between adults and children with acute or stable asthma and are rarely caused by C. pneumoniae.
Wang F, He XY, Baines KJ et al. Different inflammatory phenotypes in adults and children with acute asthma. European Respiratory Journal 2011 [Published online before print, doi: 10.1183/09031936.00170110].

2. The risk for asthma attacks may be predicted by a simple questionnaire.
To investigate if a composite measure such as the Asthma Control Questionnaire (ACQ), which assesses the adequacy of asthma control by using symptoms, activity limitation, use of rescue medications, and lung function, may capture several aspects of asthma control and prediction of risk, the authors analyzed data from 292 patients with moderate-to-severe atopic asthma. The patients were 18-65 years old (mean age 41 years), who had participated in a 12-week study of an IL-4 receptor antagonist. The participants completed the ACQ before treatment initiation and every 2 weeks for 16 weeks after treatment began. For the ACQ, patients were asked to recall their symptoms during the previous week and to respond to six questions regarding nighttime waking, symptoms on waking, activity limitation, shortness of breath, wheeze, and rescue medication use on a scale from zero (no impairment) to six (maximum impairment). The patients' lung function was also scored on a similar scale. The composite score was then calculated from these seven items, ranging from zero (totally controlled) to six (severely uncontrolled). In total, 31 patients each experienced one exacerbation over the course of the study period. After adjusting for age, race, gender, and height, the researchers found that each one-point increase in ACQ composite score was associated with a hazard ratio of 1.5 for an exacerbation during the following 2-week period. Analysis of individual components of the ACQ revealed a similar but less pronounced predictive trend, with hazard ratios ranging from 1.1 to 1.3 for each one-point increase in individual component scores. The baseline ACQ composite score was not associated with the overall exacerbation risk during the 12-week study. A significant correlation was found between measurements of the ACQ composite score over time and the risk of future asthma exacerbation. The results with the ACQ composite measure were superior to those of the individual ACQ components. These results confirm the utility of measuring the composite ACQ score in clinical trials as well as clinical practice.
Editor's comment: The composite score on the Asthma Control Questionnaire (ACQ) predicts patients' risk for asthma attacks over the following 2 weeks.
Meltzer EO, Busse WW, Wenzel SE et al. Use of the Asthma Control Questionnaire to predict future risk of asthma exacerbation. The Journal of Allergy and Clinical Immunology 127: 167-172, 2011.

3. Allergic disease and thrombosis risk.
Previous studies have shown that the coagulation pathway can be activated in the airways of patients with allergic asthma and allergic rhinitis, and that platelet activation can also play a role in allergic inflammation. In the current study, the authors compared the prevalence of allergic rhinitis, allergic asthma, and atopic dermatitis in 129 patients (aged 20-45 years) with venous thromboembolism (VTE) versus 144 VTE-free controls matched for age, gender, and smoking status. The overall prevalence of atopic diseases was significantly higher among the patients with VTE (38%) compared with controls (22.9%). The prevalence of allergic rhinitis was significantly higher in patients relative to controls (30.2% vs 18.8%), whereas the prevalence of asthma (5.4% vs 3.5%) and atopic dermatitis (2.3% vs 0.7%) did not differ significantly between the two groups. VTE patients with atopic diseases had a 32.0% higher plasminogen activator inhibitor (PAI)-1 level and a 21.4% longer clot lysis time than nonatopic VTE patients. The researchers remarked that the mechanism(s) underlying the association between atopic diseases and VTE remain obscure, but suggested that a PAI-1-mediated impairment of fibrinolysis could in part account for the increased prevalence of atopy among VTE patients. They concluded that their preliminary report sheds new light on the complex links between allergic inflammation/atopic diseases and blood coagulation.
Editor's comment: Patients with venous thromboembolism (VTE) are nearly twice as likely to have atopic diseases, such as allergic rhinitis, as individuals with no history of thrombosis.
Undas A, Cieśla-Dul M, Drążkiewicz T et al. Association between atopic diseases and venous thromboembolism: a case-control study in patients aged 45 years or less. Journal of Thrombosis and Haemostasis 2011 [Published online before print. doi: 10.1111/j.1538-7836.2011.04198.x]

4. Irritable larynx as a cause of chronic cough (CC).
Stimulation of sensory receptors in the upper airway can cause reflex laryngoconstriction. The authors of this investigation previously found that most patients with rhinosinusitis, postnasal drip, and pharyngolaryngitis show laryngeal hyperresponsiveness (LHR), as manifested by an increased sensitivity to histamine induced vocal cord adduction, a finding they interpreted as consistent with an irritable larynx. In this study they evaluated the role of LHR in the production of CC associated with airway disease or gastroesophageal reflux (GERD) as well as CC occurring in subjects with no known airway disease. They assessed LHR and bronchial hyperresponsiveness (BHR) to histamine in 372 patients with CC. The following groups were studied: CC and perennial rhinitis (PR)/chronic rhinosinusitis (CRS, n = 208), CC and asthma (asthma/CC+, n = 41), CC and GERD (n = 62), and CC of unexplained origin (UNEX, n = 61); 52 asthmatic subjects without cough (asthma/CC-) served as controls. LHR prevalence was 76% in patients with PR/CRS, 77% in patients with GERD, 66% in patients with UNEX, 93% in asthma/CC+ patients, and 11% in asthma/CC- patients. The high prevalence in all groups with CC meant that LHR could not discriminate between triggers of cough, although it did distinguish asthma/CC+ from asthma/CC-. In 172 patients without asthma, the challenge was repeated after treatment for the underlying cause of cough. After treatment, LHR resolved in 63% of the patients and improved in 11%, and BHR resolved in 57% and improved in 18%. The authors concluded that an irritable larynx is common in patients with CC and indicates upper airway involvement even in asthma patients.
Editor's comment: The evaluation of LHR might help in identifying irritable larynx as a cause of CC.
Bucca CB, Bugiani M, Culla B, et al. Chronic cough and irritable larynx. The Journal of Allergy and Clinical Immunology 2010; 127(2): 412-419.

5. Mechanisms of resistance to oral theophylline treatment of hyposmia.
Theophylline regulates the concentrations of cyclic nucleotides such as cAMP and cGMP, which stimulate the maturation of olfactory epithelial cells. A trial of theophylline to treat patients with hyposmia (n = 312) resulted in improved sense of smell in more than half, but not all, of the subjects. To understand why some subjects did not respond, the authors examined a subset of 31 subjects for whom data on serum theophylline and nasal mucus cAMP and cGMP were available both before and after treatment. These subjects were divided into 2 groups, responders (n = 20) and nonresponders (n = 11), based on whether treatment had improved the sense of smell. In both groups, serum theophylline concentration increased as dose increased, but it increased significantly more in responders. At baseline, cAMP and cGMP concentrations were equally low in both groups, but treatment only increased the concentrations in responders. Thus, some patients with hyposmia with initially low nasal mucus cAMP and cGMP levels may be relatively resistant to oral theophylline treatment.
Editor's comment: Nasal levels of cAMP and cGMP may play a crucial role in both the homeostasis of olfaction and the pathogenesis of hyposmia. Thus, manipulation of their synthesis may be an effective therapy for disorders of olfaction.
Henkin R, Velicu I, Schmidt L. Relative Resistance to Oral Theophylline Treatment in Patients With Hyposmia Manifested by Decreased Secretion of Nasal Mucus Cyclic Nucleotides. The American Journal of the Medical Sciences 2011; 341(1): 17-22.

6. Different contributions of biologic factors to asthma severity in blacks and whites.
Rates of morbidity and mortality due to asthma are higher in black patients than in white patients, but the relative roles of biologic and environmental factors in contributing to this observation remains unclear. Clinical, immunologic, and physiologic data from 916 participants (71% white, 29% black) in the Severe Asthma Research Program were examined to determine whether immunoinflammatory predictors of asthma severity would differ by race. About 40% of subjects in each group had severe asthma by American Thoracic Society criteria. Although several factors (age, baseline FEV1, gastroesophageal reflux disease) increased the odds of severe asthma in both races, others factors differed by race. Immunoglobulin (Ig) E levels were significantly associated with asthma severity in black, but not white, subjects. Having two or more family members with asthma more than doubled the likelihood of severe asthma in black patients, whereas it almost halved the likelihood in white patients. Atopy was negatively associated with severe asthma in both races in a univariate analysis, but in a multivariate analysis remained marginally negatively associated with severe asthma only in blacks. In contrast, the presence of comorbidities was associated with severe asthma only in whites. The authors conclude that a comprehensive analysis of biologic and genetic factors associated with asthma might lead to the development of therapies that target specific biologic risk factors in black subjects.
Editor's comment: Asthma severity in black patients, but not white patients, is linked to family history and IgE levels.
Gamble C, Talbott E, Youk A et al. Racial differences in biologic predictors of severe asthma: Data from the Severe Asthma Research Program. The Journal of Allergy and Clinical Immunology 2010; 126: 1149-1156.
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7. Tobacco smoke, asthma, and wheeze in teenagers.
The link between environmental tobacco smoke (ETS) and asthma is less well studied in adolescents than in children and adults. To investigate the effects of exposure to ETS and personal smoking on the prevalence of asthma and wheeze among teenagers, the authors studied data from a longitudinal study of 3,430 Swedish schoolchildren that started in 1996 when the children were aged 7-8 years. The children completed annual questionnaires on asthma and allergies, parental smoking habits, and personal histories of smoking. At the age of 16-17 years, 13.6% of boys and 13.0% of girls had doctor-diagnosed asthma; 21.9% and 26.1%, respectively, reported having wheezed at some point in their lives (ever wheeze); and 16.5% and 24.8%, respectively, had current wheeze. The researchers found that the prevalence of doctor-diagnosed asthma, ever wheeze, and current wheeze was significantly higher among those exposed to maternal ETS and daily smokers. Indeed, after accounting for confounding factors, such as a family history of asthma and allergies, the 538 participants exposed to maternal ETS were 1.3 times more likely to have doctor-diagnosed asthma and 1.5 times more likely to have suffered from wheezing than unexposed individuals. Daily smokers at the age of 16-17 years (n = 123) were 2.0 times more likely to have current wheeze than nonsmokers. Daily smokers who were also exposed to maternal ETS (n = 111) had the greatest risk for asthma and wheeze. The authors concluded that exposure to maternal ETS and personal smoking were independently related to asthma and wheeze among teenagers.
Editor's comment: Effective smoking prevention programs among teenagers are necessary and would be expected to reduce the number of smokers and thereby the prevalence of asthma.
Hedman L, Bjerg A, Sundberg S et al. Both environmental tobacco smoke and personal smoking is related to asthma and wheeze in teenagers. Thorax 2011; 66: 20-25.

8. Tear neuropeptides and specific allergen challenge in allergic conjunctivitis.
The authors measured substance P (SP), calcitonin gene related peptide (CGRP), neuropeptide Y (NPY), and vasoactive intestinal peptide (VIP) in the tears of 15 subjects with allergic conjunctivitis (6 female, 9 male, mean age 30 8 years) without current symptoms and 10 age-matched healthy subjects. The conjunctival provocation test (CPT) with allergen was performed in the right eyes of all allergic patients and 5 healthy subjects; the left eyes received diluent. Tear samples were collected from both eyes before and after CPT, and the tear content of VIP, NPY, CGRP, and SP was measured by ELISA. Similar levels of neuropeptides were present in healthy and allergic patients at baseline. CPT induced conjunctival hyperemia and itching in all allergic patients, whereas no reaction was observed in the control eyes or in healthy subjects. In allergic patients SP (3.9 1.3 versus 5.8 1.1 ng/mL, P = 0.011, Wilcoxon rank test), CGRP (5.5 2.3 versus 7.3 2.7 ng/mL, P = 0.002), and VIP (4 0.9 versus 5.1 1.5 ng/mL, P = 0.007), but not NPY (2.7 0.4 versus 3.3 1.3 ng/mL) were significantly higher after CPT than at baseline. No significant changes were observed in the control eyes of allergic patients challenged with diluent or in healthy subjects after allergen provocation.
Editor's comment: Neuropeptides are present in tears of both healthy and allergic individuals and may modulate the normal and allergic responses of the conjunctiva.
Sacchetti M, Micera A, Lambiase A et al. Tear levels of neuropeptides increase after specific allergen challenge in allergic conjunctivitis. Molecular Vision 2011; 17: 47-52.
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9. Biomarkers as diagnostic tools for food allergy.
Diagnostic tests currently used to identify food allergies in general and peanut allergy in particular, such as skin prick tests and determination of specific immunoglobulin E (IgE), have limited sensitivity and specificity. "Metabolic fingerprinting" using nuclear magnetic resonance (NMR) spectroscopy or mass spectrometry may identify biomarkers (metabolites) that differ between those with and without allergies. The authors performed a pilot study of metabolites in plasma and saliva of 12 subjects with peanut allergy and 11 peanut-tolerant subjects by using NMR spectroscopy in combination with multivariate statistics, both before and after a challenge with peanut. The NMR spectra of plasma differed between peanut-allergic and peanut-tolerant subjects both before and after peanut ingestion. Thus, peanut allergy could be detected even before the onset of allergic reactions. The spectra of saliva differed only after peanut ingestion. A few specific metabolites were identified, including elevated lactate, creatinine, and glutamine and decreased lipids and nicotinic acid, but larger, more detailed studies will be needed to elucidate the full range of metabolites and their possible relationship to the pathogenesis of allergy. However, this pilot study shows that aberrant metabolite levels may serve as novel biomarkers for food allergy.
Editor's comment: New tools may improve the accuracy of the diagnostic work-up of food-allergic patients.
Peeters K, Lamers RA, Penninks AH et al. A Search for Biomarkers as Diagnostic Tools for Food Allergy: A Pilot Study in Peanut-Allergic Patients. International Archives of Allergy and Immunology 2011; 155: 23-30.

10. DNA vaccines.
This excellent review article covers many aspects of the development, mechanisms, and applications of plasmid DNA vaccines. DNA vaccines were developed as a way to overcome many of the limitations of current vaccine systems. In practical terms, they can be made easily and quickly, thereby speeding the production of novel vaccines. Because the antigen DNA can be synthesized, there is no need to handle a pathogenic organism, and the resulting vaccine will not contain additional, potentially deleterious antigens or vector antigens that may interfere with the desired response. In addition, there is no need for a cold chain, increasing the usefulness of these vaccines in low-income regions. Immunologically, DNA vaccines stimulate multiple components of the immune system (antibody production, helper T cells and cytotoxic T lymphocytes). They may stimulate responses to epitopes that are not displayed on the cell surface; by choosing appropriate targets, these vaccines can therefore be used to provide broad cross-strain protection, even against pathogens that mutate readily. In addition, because the T-helper response to DNA vaccines is biased to a Th1 phenotype, this technology is being investigated as a way to treat allergies, and has shown promising results in preclinical models of allergic disease.
Editor's comment: This article examines the various mechanisms whereby immune responses are induced and modulated by DNA vaccines, and explores the implications of these mechanisms for the clinical use of DNA vaccines.
Liu MA. DNA vaccines: an historical perspective and view to the future. Immunological Reviews 2011; 239(1): 62-84.
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11. Filaggrin gene defects and the risk of allergy.
This is an excellent review of filaggrin, a protein that facilitates the terminal differentiation of the epidermis and the formation of the skin barrier by aggregating keratin filaments, causing keratinocytes to collapse in the stratum corneum. Thus, filaggrin is essential for retaining epidermal moisture. Loss-of-function mutations in FLG, the gene that encodes the filaggrin precursor profilaggrin, results in ichthyosis vulgaris, a common disorder characterized by dry, scaly skin. About 40 such mutations have been identified, but the patterns of mutations vary between European and Asian populations and among specific Asian populations. FLG mutations have also been strongly associated with atopic dermatitis and, to a lesser degree, with eczema occurring with asthma and allergic rhinitis. Recent studies have hypothesized that the skin barrier defects caused by FLG mutations lead to atopic disorders, including asthma, by allowing allergens to penetrate the epidermis, where they interact with antigen-presenting cells and thus initiate a Th2 immune response. Early intervention to restore skin barrier function and reduce sensitization to allergens may be a feasible approach to prophylaxis in patients with FLG mutations.
Editor's comment: Filaggrin mutations can play an important role in the development of allergic diseases.
Osawa R, Akiyama M, Shimizu H. Filaggrin Gene Defects and the Risk of Developing Allergic Disorders. Allergology International 2011. [Published online before print. doi: 10.2332/allergolint.10-RAI-0270].
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