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Archives: Medical Journal Reviews

Medical Journal Review

Posted: January 2008

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

1. Computed tomography (CT)-an increasing source of radiation exposure.
Compared to regular X-rays, CT scans result in much higher cumulative doses of radiation. This review describes various procedures, typical doses, uses and the biological effects of ionizing radiation. No major studies of the health risks from CT scans have been done, but extrapolation from known CT doses to those received in other circumstances suggests caution, especially in light of the very large numbers of people undergoing CT procedures. Editor's comment: Because a CT results in high doses of ionized radiation, other procedures (including an extensive and accurate history and physical), such as MRI or ultrasound, may provide satisfactory diagnostic results when substituted for a CT. Brenner DJ et al., N Eng J Med 2007; 357:2277-2284.

2. Determinants of response to fluticasone propionate (FP) and salmeterol/fluticasone propionate combination (SFC) in the Gaining Optimal Asthma control (GOAL) study.
Asthmatics with uncontrolled disease were given either FP alone or SFC. The GOAL data analysis seeks to determine the factors affecting outcomes and how to better manage asthma. Subjects were categorized into totally controlled (TC), well-controlled (WC) or not well-controlled (NWC) groups. Statistical methods were used to establish the odds ratios for specific factors which reduced the chances for improvement. The primary determinant for the NWC group was smoking, even though all groups improved, especially with SFC. Editor's Comment: The take-home message is clear: tell your asthma patients, if they want to get better, they must stop smoking. Pederson SE et al., J Allergy Clin Immunol 2007; 120:1036-1042.

3. Comparative study of budesonide inhalation suspension (BIS) and monteleukast (M) in young children with mild persistent asthma.
This study compares BIS to M over one year in children 2 to 8 yrs with mild persistent asthma. Subjects (395) in multicenter groups were randomized to receive BIS (0.5 mg) or M (4-5 mg) daily. Outcomes were length of time to first exacerbation and subsequent additional treatment for exacerbation, rates of exacerbation, PEF and QoL assessment. Both BIS and M provided good asthma control, but B was better. Editor's comment: While BIS improves asthma control better than M, the ease of use of the latter sometimes may be advantageous, particularly in young children. Szefler SJ et al., J Allergy Clin Immunol 2007; 120:1043-1050.

4. Genetic effect of CCR3 and IL5RA gene polymorphisms on eosinophilia in asthmatic patients.
Two factors which affect the eosinophil numbers are the chemokine receptor, CCR3, and the eosinophil survival mediator, IL-5. In this study, single-nucleotide polymorphisms (SNPs) in the genes for CCR3 and IL-5 receptor alpha subunit in a group of 576 Korean asthmatic patients and 180 healthy persons are correlated with asthma susceptibility and eosinophilia. Among the SNPs in the CCR3 gene, all are located in introns and none are associated with asthma susceptibility. However, some asthmatic subjects with CCR3 alterations had lower eosinophil numbers compared to the more common SNPs associated with eosinophilia. IL5RA SNPs resulted in increased eosinophil numbers in asthmatic subjects and when paired with a CCR3 SNP, the effects on eosinophilia were enhanced. Editor's comment: The statistical association of specific SNPs with asthma contributes to the knowledge of asthma pathology. Lee J-H et al., J Allergy Clin Immunol 2007; 120:1110-1117.

5. Defective T-cell activation caused by impairment of the TNF receptor 2 co-stimulatory pathway in common variable immunodeficiency (CVID).
CVID is characterized by decreased production of B cells and immunoglobulins and an increased susceptibility to bacterial infections. Hereditary defects in T-cell receptor signaling are implicated, but in most cases, the exact abnormality is unknown. This paper examines the TNF-mediated co-stimulatory pathway of T-cell activation in a group of CVID patients compared to healthy controls. The CVID subjects have a normal primary TCR signal (CD69) as well as normal calcium store flux and PKC-theta activation, however, TCR co-stimulation through TNF-RII was severely impaired. Editor's comment: CVID is a complex disorder and understanding genetic defects is important to design new therapies. Aspalter RM et al., J Allergy Clin Immunol 2007; 120:1193-1200.

6. Genetics of Asthma: Potential implications for reducing asthma disparities.
This review presents what is known about specific gene alterations in minorities and points out areas where there are weaknesses due to small sample size or genetic and environmental heterogeneity. Polymorphisms (SNPs) in the disintegrin and metalloprotease 33 (ADAM33) gene, the IL-4 receptor, the HLA loci and others are discussed in African-American or Hispanic populations compared to whites. Significant differences in the frequency of SNPs and haplotypes are seen. Editor's comment: Elucidation of asthma pathology mechanisms depends on obtaining information on all racial groups. Scirica CV and Celedon JC, Chest 2007; 770S-781S.

7. Diesel-enriched particulate matter (PM) functionally activates human dendritic cells (DC).
Human DC were expanded from peripheral blood by culturing them in the presence of specific cytokines and exposed to PM from cars (gas) or trucks (diesel). The activation phenotype of the DCs was determined by flow cytometry of maturation markers and endocytosis of FITC-dextran. PM from car exhaust had little effect on DC activation, but diesel PM increased secretion of TNF, IL-6 and IFN-gamma and upregulated MHC-II. Both car and diesel exhausts promoted a Th2 cytokine response. Diesel PM specifically stimulates endocytosis by DCs which is different from other activators such as LPS. The enhanced antigen uptake combined with stimulation of maturation marker expression seems to be a unique feature of diesel exhaust and may account for some of its inflammatory effects. Editor's comment: The mechanism of diesel PM effects on DCs remains to be elucidated through additional experiments. Porter M, et al., Am J Resp Cell Mol Biol 2007; 37:706-719.

8. Respiratory effects of exposure to diesel traffic in persons with asthma.
A group of 60 nonsmoking asthmatics with mild to moderate symptoms were recruited and tested during a period free from exacerbations or respiratory infections. They were allowed to continue their regular medications, but not oral corticosteroids. Participants walked for about two hours in one of two areas-a busy street with heavy diesel traffic only or a park away from traffic. Air in each area was sampled and numbers and sizes of PM determined. Spirometry was performed before, during and after the sessions and subjects were asked to record asthma symptoms. Sputum samples were collected for cell counts and analysis of cytokines and ECP. Fractional exhaled NO and breath condensate pH were also measured. Results showed a greater reduction in FEV1 in subjects walking in the city area compared to the park, and moderate asthmatics had a greater drop in FEV1 than mild asthmatics. Other measurements such as decreased pH and increase in sputum myeloperoxidase also Correlated with increased PM. Editor's comment: No difference in symptoms were reported between the city and the park groups, but the extensive physical data implicate diesel PM as pro-inflammatory. McCreanor J et al., N Engl J Med 2007; 357:2348-2358.

9. A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma.
Airway eosinophilia is a prevalent problem in chronic asthma and treatments that reduce IL-5, the cytokine involved in proliferation, survival, migration and maturation of eosinophils (E), seems an ideal target for anti-E therapy. This multicenter, DBPCS of the humanized anti-IL-5 antibody, mepolizumab, seems to argue against this conclusion. Subjects ranged in age from 18 to 55 years and had FEV1s of 50-80 % of predicted. Their asthma control required high doses of ICS (1000 micrograms beclomethasone or equivalent). Doses of mepolizumab, 250 or 750 mg, were given i.v. at monthly intervals and outcomes were measured in terms of FEV1, E counts in serum and sputum, diary cards and QoL questionnaires. There was a significant reduction in the tendency for exacerbation in the group receiving the highest dose of mepolizumab, but otherwise no change in other parameters was observed. Editor's comment: Further investigation into the reasons why anti-IL-5 treatment does not work for asthma may tell us more about its pathogenesis. Flood-Page P et al., Am J Resp Crit Care Med 2007; 176:1062-1071. (editorial by PM O'Byrne, pp. 1059-1060).

10. Ceramide: A key signaling molecule in a guinea pig model of allergic asthmatic response and airway inflammation.
Ceramide is a membrane-associated sphingolipid that is pro-inflammatory and pro-apoptotic. Using ovalbumin-sensitized guinea pigs, the authors found that lung ceramide production was elevated after allergen challenge. Bronchoconstriction, dyspnea and cough also increased. Pretreatment with an inhibitor of ceramide synthase blocked the allergen-induced inflammatory effects and epithelial cell death. Editor's comment: Pharmacological manipulation of ceramide levels may prove to be a useful therapy for inflammatory lung disease. Masini E et al., J Pharmacol Exp Ther 2007; [Nov. 27, epub ahead of print].

11. Medical progress: sarcoidosis.
First described in 1899, sarcoidosis is characterized by the formation and accumulation of benign granulomas containing activated T-cells and macrophages secreting cytokines and chemokines. The clinical characteristics, different organ involvement, the differential diagnosis, sarcoidosis in children and treatment are reviewed. Editor's comment: Great review of a disease whose etiology remains elusive. Iannuzzi MC et al., N Engl J Med 2007; 357:2153-2165.

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