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Archives: Medical Journal Reviews

Medical Journal Review

Posted: April 2008

Reviewed by Prof. Richard F. Lockey, MD, WAO Web Editor-in-Chief and Guest Reviewer Gary Hellermann, PhD

1. Exhaled nitric oxide distinguishes between subgroups of preschool children with respiratory symptoms.
The goal of the Tucson Children's Respiratory Study is to identify the factors that predispose nonwheezing and wheezing children less than four yrs to develop chronic lung disease. Measurement of fractional exhaled nitric oxide (FeNO) is suitable even for infants and is useful in predicting exacerbations and monitoring therapy in older children. This study of 391 children demonstrates that FeNO levels are highest in children with frequent recurrent wheeze and a stringent index for prediction of asthma at school years. Editor's Comment: FeNO may be useful to predict asthma susceptibility later in life. Moeller A et al. J Allergy Clin Immunol 2008; 121:705. Bacharier LB, editorial, 710.

2. Intrinsically defective skin barrier function in children with atopic dermatitis (AD) correlates with disease severity.
AD is a disease with multiple environmental and genetic factors. Research implicates defects in the skin barrier layer as one cause of the pathology. This study compares transepidermal water loss (TEWL) in a group of African American and white children with AD, children with asthma or allergic rhinitis but no AD, and healthy controls. Increased TEWL correlates with a defective skin barrier and AD severity using the SCORAD index. Editor's Comment: TEWL may be a useful biomarker for AD severity, but whether this skin barrier defect contributes to AD remains unknown. Gupta J et al. J Allergy Clin Immunol 2008; 121:725.

2b. Impaired Th17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome (HIES).
HIES is a serious disease that impairs the immune system's ability to fight off infections and is associated with atopic dermatitis and abnormalities of bone and connective tissue. Mutations in the signal transducer and activator of transcription 3 (STAT3) are present in some HIES patients. This clinical study looks at healthy individuals, HIES patients with STAT3 mutations and HIES patients with only some manifestations of disease. T cells isolated from peripheral blood were sorted by flow cytometry and analyzed for intracellular cytokines after stimulation with staphylococcal enterotoxin B. IL-17- producing T cells were found in the blood of HIES patients without STAT3 mutations but not in those with the mutations. This suggests a link between susceptibility to infection and the activity of Th17 regulatory lymphocytes and between STAT3 activity and Th17 generation. Editor's Comment: The observation of HIES-like effects in those patients with normal STAT3 means that factors in addition to Th17 exist. Milner JD et al., Nature Letters advanced online publication 12 March 2008.

3. Treatment of patients with hypereosinophilic syndrome (HES) with mepolizumab (M).
Proliferation of eosinophils (E) from precursor cells requires IL-5 and targeting this cytokine may be useful in treating HES, a disease that can result in severe organ damage. Here 85 patients with HES and negative for F1P1L1-PDGFRA fusion gene were given the anti-IL-5 antibody, M, or placebo in an international, randomized, DBPC trial with the goal of reducing the amount of prednisone (P) to 10 mg per day or less required to control their illness. M treatment was effective in P sparing in 84% and also reduced E in 95% of the patients. Adverse events were similar in the M and P groups. Editor's comment: M significantly reduces P -induced side-effects in HES. Rothenberg ME et al. New Engl J Med 2008; 358:1215. Wechsler ME, editorial, 1293.

4. Chronic exposure to beta-blockers attenuates inflammation and mucin content in a murine asthma model.
Data from the mouse model of allergic asthma show that chronic treatment with beta blockers improves airway hyperresponsiveness (AHR). This report examines the mechanism of the effects of chronic inhibition of beta adrenoceptor activity in this model. Administration of beta blockers for 28 days reduced total cell counts, eosinophils, and IL-13, IL-10, IL-5 and TGF-β1 levels in the bronchoalveolar lavage and attenuated epithelial mucin content and morphologic changes. Editor's Comment: Manipulation of the beta adrenoceptor pathway for asthma treatment needs to be reexamined. Nguyen LP et al. Am J Resp Cell Molec Biol 2008; 38:256.

5. Allergen induces the migration of platelets (P) to lung tissue in allergic asthma.
There is substantial evidence that P activation is associated with increased lung inflammation and bronchoconstriction. Ovalbumin (OVA)-allergic mice were challenged with OVA and their lungs examined for P recruitment. Comparisons with mice lacking FcξRIγ showed platelet migration from the blood into the lungs in response to allergen in wild-type (WT) but not in mice deficient in IgE receptor. Platelets isolated from human allergy patients as well as those from WT (but not FcRγ-/-) mice also migrate in vitro toward the relevant allergen. Editor's Comment: The role of platelets in lung inflammation needs to be elucidated along with other inflammatory cells. Pitchford SC et al. Am J Resp Crit Care Med 2008; 177:604.

6. Cetuximab(C)-induced anaphylaxis (A) and IgE specific for galactose-α-1,3-galactose.
C is a humanized monoclonal antibody against epidermal growth factor receptor (EGFR) used to treat colorectal and squamous-cell carcinoma of the head and neck. Its use is accompanied by a relatively high incidence of A. This study shows that there were 25 hypersensitivity reactions in 76 patients undergoing C treatment for cancer. IgE to the sugar, galactose-α-1,3-galactose, present on the antibody heavy chain, were found in 17 of these 25 subjects versus one of 51 subjects without A. A occurred in some subjects the first time they received C indicating that the offending IgE was already present. While all humans have IgG against galactose-α-1,3-galactose, only some individuals develop the corresponding IgE. Editor's Comment: Patients under consideration for C will most likely benefit from screening for IgE against this oligosaccharide. Chung CH et al. New Engl J Med 2008; 358:1109.

7. Factor analysis in the Genetics of Asthma International Network (GAIN) family study identifies five major quantitative asthma phenotypes.
The pathogenesis of asthma involves a complex interplay of genetic and environmental influences, and this report attempts to identify distinct asthma phenotypes by factor analysis. Six countries and 11 centers form the database for the GAIN study and from it was drawn a group of asthmatic subjects, age 7-35. They and their symptomatic siblings were subjected to factor analysis for asthma phenotype and five distinct factors were identified: FEV1 and FVC, allergen skin prick test (SPT), self-reported allergies, rhinitis symptoms and asthma symptoms. Comparisons among siblings show that these factors are consistent with shared genetic and environmental influences. Factor scores correlate with IgE levels, methacholine PC20, age and asthma severity and may be better for defining asthma phenotypes than SPT or IgE alone. Editor's Comment: While this is an important study, the fact that it is cross-sectional rather than longitudinal is a weak point. Pillai SG et al. Clin Exp Allergy 2008; 38:421.

8. Factors predicting anaphylaxis (A) to peanuts (P) and tree nuts (TN) in patients referred to a specialist center.
Data from a group of 1094 patients with P and TN allergy compiled over 12 years were compared in terms of whether P or TN were involved, severity of associated disease (eczema, asthma and rhinitis), allergen-specific IgE and SPT results, and in 122 patients, the serum level of angiotensin-converting enzyme (ACE) and aminopeptidase P (APP). The analysis found a higher rate of pharyngeal edema in patients with severe rhinitis and low ACE levels. Severe bronchospasm tended to occur in those with severe versus mild asthma and severe eczema with altered consciousness. Editor's comment: The "allergen shock organ" and low ACE levels help predict the clinical manifestations of A. Summers CW et al. J Allergy Clin Immunol 2008; 121:632.

9. A comparison of inflammatory mediators released by basophils (B) of asthmatic and control subjects in response to high-affinity IgE receptor aggregation.
B are a small but important set of leukocytes in allergic reactions and their effects are mediated through activation of the FcξRIs on their surface. Human B from 16 healthy and 12 asthmatic volunteers were analyzed in this study for cytokine and chemokine levels before and after binding of IgE to the receptors and correlated with histamine release and skin prick test (SPT). Both normal and asthmatic B produced GM-CSF, MIP-5 and eotaxin. Leptin was also produced in most samples and IL-8 in response to IgE cross-linking. No difference in cytokine release from B was seen in healthy versus asthmatic subjects. Editor's Comment: The secretion of leptin by B is an interesting finding that needs confirmation. Gilmartin L et al. Int Arch Allergy Immunol 2008; 145:182.

10. Primary nasal epithelium exposed to house dust mite (HDM) extract shows activated expression in allergic individuals.
Epithelial cells (EC) are more than just bystanders in the establishment of an immune response. Here EC from nasal biopsies of five allergic and five healthy individuals were cultured with or without HDM extract and isolated RNA was used for gene expression profiling by microarray analysis. Results were verified by quantitative real-time PCR. HDM triggered up-regulation of two transcription factors (NFkappaB and AP-1) in healthy epithelium, as well as a number of chemokines, growth factors and structural proteins. In allergic individuals, however, these pathways were already activated and HDM did not change the expression of NFkappaB but did down-regulate AP-1. Editor's Comment: The finding of specific differences in allergen-induced gene expression response in allergic individuals may point the way to new diagnostic and therapeutic tools. Vroling AB et al. Am J Resp Cell Molec Biol 2008; 38:293.

11. Phenotypic characterization of T lymphocytes in COPD: abnormal CD4+CD25+ regulatory T-lymphocyte response to tobacco smoking.
Why do some smokers develop COPD and others not? That was the question posed in this investigation of 23 patients with moderate COPD, 29 healthy smokers and seven never-smoker volunteers. T cells were isolated from bronchoalveolar lavage fluid (BALF) and from peripheral blood and characterized as CD4+ or CD8+, according to the maturation (CD45RA and CD45RO), activation CD28 markers and to explore potential Treg abnormalities. Results show that BALF T cells from COPD patients have higher CD8+CD45RA+ levels and lower CD8+CD45RO+ levels than smokers with normal lung function. Compared with never-smokers, smokers with preserved lung function showed a prominent up-regulation of Tregs absent in COPD. T cells from peripheral blood did not show any significant differences among the three groups of patients. Editor's Comment: The lower Treg activity in the lungs of COPD patients may be involved in pathogenesis of the disease. Barcelo B et al. Eur Resp J 2008; 31:555.

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