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Archives: Medical Journal Reviews

Medical Journal Review

Posted: April 2009

Reviewed by Gary Hellerman, PhD, in collaboration with Richard F. Lockey, MD, WAO Web Editor-in-Chief.

1. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia.a
These researchers treated a group of severe corticosteroid-resistant asthma patients with the IL-5 antibody, mepolizumab (Mep), which blocks the eosinophil-promoting activity of IL-5. The primary outcome was the % of patients in the test group vs. the placebo group who had exacerbations during the 26-week test period. Secondarily, the reduction in prednisone dose relative to the maximum reduction was determined. Spirometry was performed on the subjects and they were asked to fill out the Juniper Asthma Control Questionnaire. Eosinophils in induced sputum were counted. The placebo group (n = 10) experienced 12 exacerbations while the Mep group (n = 9) had one. Mean prednisone dose was reduced from 11.9 to 3.9 mg in the Mep group compared to the placebo group where the dose went from 10.7 to 6.4 mg. Eosinophilia in sputum and blood was significantly reduced by treatment with Mep and there were no significant alterations in blood chemistry. A second paper in this issue of the Journal, Mepolizumab and exacerbations of refractory eosinophilic asthma,b examined Mep therapy for severe eosinophilic asthma and demonstrated a significant reduction in the number of exacerbations and improvement in quality of life. Editor's comment: Although these are relatively small studies, the results are very promising for helping this group of severe asthmatics.
aNair P et al., New Eng J Med 2009; 360:985-993.
bHaldar P et al., op. cit., 973-984.
Also see editorial by Sally Wenzel, pp. 1026-1028
Both studies were funded by an educational grant from Glaxo-SmithKline

2. Do childhood respiratory infections continue to influence adult respiratory morbidity?
Viral bronchiolitis during infancy can increase the risk of asthma in young adults, but there are few studies that monitor the effects of childhood respiratory infections on lung function in adults. This meta-analysis examines data from a prior study in which 9,175 individuals, age 20-44 yr, completed questionnaires to provide a family history and previous allergic and respiratory symptoms and underwent lung function testing. The subjects were reinvestigated an average of 8.9 years later. In the initial study, 9.6% reported a serious respiratory infection (SRI) before the age of 5 and in the second study, 2.4% reported being hospitalized for lung disease (HLD) before the age of 2. SRI was associated with increased risk of wheeze and asthma and reduced lung function. Similar results were found for HDL. An even stronger correlation for risk of adult lung disease was found among children with SRI or HLD from households with maternal smoking. Editor's comment: The implication of this study is that severe respiratory infections during the first 3-4 years of life can cause permanent changes to the airway manifesting in lung disease in adulthood.
Dharmage SC et al., Eur Resp J 2009; 33:237-244.

3. Cell-mediated immunity in recent-onset type I diabetic children.
Type I diabetes mellitus (T1DM) is an autoimmune disease caused by destruction of pancreatic beta-cells by specific T lymphocytes. The exact T cell subset involved is unknown, but since immune tolerance is maintained by regulatory T cells (Tregs), primarily of the CD4+CD25+ phenotype, it is logical to suspect that Tregs may also be associated with the pathogenesis of T1DM. In this study, 20 children (4-12 yr old) with T1DM were evaluated for percentages of CD4+, CD8+, CD4+CD25+ and CD8+CD25+ T cells in peripheral blood and compared to a control group. No difference in % of CD4+ T cells or CD4+CD25+ Tregs was seen between diabetic and control groups. The % of CD8+ T cells and CD8+CD25+ Tregs, however, was significantly lower in the diabetics indicating possibly that CD8+ cells have migrated to the pancreas from the blood at this early stage of diabetes. A loss of blood glucose control (as evidenced by the level of hyperglycosylated hemoglobin) was also found in the early-onset diabetics. Editor's comment: This finding of early changes in T lymphocyte populations in T1DM suggests that intervention at this point might alter progression of the disease.
Ibrahim WE et al., Egypt J Pediatr Allergy Immunol 2009; 6:69-76. (Abstract not available)

4. Comparison of weight-loss diets with different compositions of fat, protein, and carbohydrates.
There is much controversy and disagreement about the relative efficacy of low-fat, high-carbohydrate diets vs. low-carb, high-protein diets. In this comparison, a group of 811 overweight adults was randomly placed on one of four diets: two low-fat diets (20%); two high-fat diets (40%); two average-protein diets (15%); and two high-protein diets (25%). Carbohydrates ranged from 35 to 65%. The diets all included a caloric deficit of 750 kcal per day from calculated baseline need. Group and individual counseling sessions were held periodically, 90 minutes per week of exercise was recommended and compliance monitoring was done by an individual daily food intake diary and a Web-based self-monitoring tool. Participants and investigators were blinded as to the type and purpose of the diets. The trial lasted 2 years and the outcome shows that all these diets are equally effective in reducing weight, promoting optimal HDL/LDL balance and providing satiety and satisfaction. Editor's comment: This study demonstrates that weight loss can be achieved by reducing calories regardless of the type of diet.
Sacks FM et al., New Eng J Med, 2009; 360:859-873.
Also see editorial by MB Katan, pp. 923-925.

5. Respiratory pathogens in children with and without respiratory symptoms.
New techniques for detection of pathogens have resulted in a marked increase in the number of organisms, primarily viruses, found in children with respiratory infections. The question arises, however, whether these microbes are causing the illness or simply taking advantage of the disease condition to colonize the airway. In this study, 19 healthy children, 0 to 7 years of age, were sampled by nasal and throat swab every two weeks during a 6-month winter season regardless of symptoms of a respiratory infection. The swabs were analyzed by PCR for 11 respiratory viruses and 2 atypical bacteria. Rhinovirus and coronavirus were commonly found in asymptomatic as well as symptomatic children, and younger children were more likely to be symptomatic when pathogens were detected. Multiple pathogens were more frequently associated with symptomatic conditions and greater disease severity. Editor's comment: The small number of subjects precludes drawing any conclusions about the effects of asymptomatic pathogen colonization on subsequent respiratory illness in children.
Van der Zalm MM et al., J Pediatr 2009; 154:396-400.

6. Different respiratory phenotypes are associated with isocyanate exposure in spray painters.
Occupational asthma has been linked to exposure to a number of substances among which D-isocyanates (NCOs) are some of the most common. The hypothesis of this investigation is that exposure to oligomeric isocyanates causes not only sensitization but also decreases lung function and increases inflammatory markers. A total of 229 workers from 38 painting companies in The Netherlands volunteered for the study. Environmental levels of NCOs in the companies' work areas were all within occupational health limits. Spray painters had the highest exposure to NCOs while other workers had lower exposures down to zero in office workers. NCO exposure estimates were made by measuring workplace NCO levels and utilizing employee time-activity descriptions. Spirometry before and after methacholine challenge was done, serum levels of specific IgE and IgG to hexamethylene di-isocyanate determined and exhaled nitric oxide eNO measured. Those workers with the highest NCO exposure showed the greatest BHR in response to challenge and had the lowest FEV1 under non-challenge conditions. Those showing BHR were also more likely to have IgG antibodies to NCO; but increases in IgE were not demonstrated. There was no correlation between eNO and NCO exposure. While NCO exposure was associated with asthma-like symptoms, it also correlated with COPD-like symptoms. Editor's comment: The study's conclusions may be affected by the presence of other potentially confounding environmental factors in the workplace environment.
Pronk A et al., Eur Resp J 2009; 33:494-501.
Also see editorial by J. Bourbeau and J. van der Palen, pp 459-460

7. Glucocorticoid therapy increases COX-2 gene expression in nasal polyps in vivo.
The COX-2 gene encodes a cyclooxygenase involved in the synthesis of prostaglandins and is inducible under most inflammatory conditions. COX-2 expression is downregulated in nasal polyps, however, and whether the low COX-2 activity promotes polyposis or is a result of the condition is unknown. Glucocorticoids (GCs) are used to treat polyposis and, in general, suppress transcription of target genes including COX-2; but in some studies, GCs have either not affected COX-2 expression or actually increased it. Here the level of COX-2 in nasal biopsies was compared in polyposis patients treated with or without GCs (prednisone, 30 mg/day for 4 days, tapering 5 mg every 2 days, plus intranasal budesonide, 400 µg b.i.d. for 2 weeks, followed by budesonide alone, 400 µg b.i.d. for 10 weeks). GC treatment reduced polyp size and improved breathing. COX-2 mRNA in polyps was elevated at the end of the 2-week GC treatment period. There was a concomitant decrease in polyp eosinophils and an increase in neutrophils. The authors hypothesize that aggressive oral GC treatment may suppress the expression of genes whose products repress the transcription of COX-2. Editor's comment: The mechanism of prostanoid regulation needs additional study to deduce the mechanism of GC upregulation of COX-2.
Pujols L et al., Eur Resp J 2009; 33:502-508.

8. Effect of specific allergen inhalation on serum adiponectin in human asthma.
Adipokines are soluble factors secreted by adipose tissue that are associated with asthma. Adiponectin (ADN) is an anti-inflammatory adipokine, and high levels of serum ADN appear to decrease the risk of asthma in humans while low levels of ADN are associated with asthma. However, it is not clear whether asthma causes the decrease in ADN or if low ADN promotes asthma. In this translational study, a group of overweight mild allergic asthmatics was given an allergen challenge and 24 hr later a blood sample was analyzed for ADN and other mediators. The asthmatics had significantly lower diurnal levels of ADN than healthy controls, but there was no difference after the challenge, which does not support the findings in a mouse model that asthma exacerbation causes a reduction in ADN. Editor's comment: The role of low ADN levels in the pathogenesis of asthma needs further elucidation.
Sood A, et al., Chest, 2009; 135:287-294.
Also see the editorial by AE Dixon, pp 255-56. (Abstract not available)

9. Comparison of fluticasone furoate and fluticasone propionate for the treatment of Japanese cedar pollinosis.
Fluticasone furoate nasal spray (FFNS) is an enhanced-affinity glucocorticoid proven to reduce symptoms and improve QoL scores. This multicenter study compared FFNS, 110 µg once daily, to fluticasone propionate nasal spray (FPNS) 200 µg twice daily vs. placebo for treatment of 446 patients with Japanese cedar pollinosis. Similar improvements in QoL scores, rhinoscopy and patient-reported daily activity were obtained from FFNS and FPNS with no difference in side effects. Thus, once-daily FFNS is as effective as twice daily FPNS. Editor's comment: Whenever daily drug dosing can be reduced, patient compliance increases.
Okubo K, et al., Allergy Asthma Proc, 2009; 30:84-94.
This study was funded by GlaxoSmithKline KK - FFR 100652.

10. Oral sulforaphane increases phase II antioxidant enzymes in the human upper airway.
Reactive oxygen species (ROS) are associated with inflammatory conditions and respiratory disease in humans and in animal models, and host antioxidant enzymes are necessary to reduce oxidative stress. Sulforaphane (SFN) is a naturally occurring antioxidant found in broccoli, cabbage and cauliflower that is known to activate phase II antioxidant enzymes in vitro and in animal studies. This report extends those studies to human subjects. Healthy nonsmoking subjects (n = 65) over 18 years of age were randomized into a placebo group and a group who received a standardized oral dose of SFN extract. A number of different SFN doses were tested. Baseline blood draws and nasal lavages were done at the time of enrollment. Additional doses were given on days 2 and 3. Nasal lavages were done on day 3 and blood draws were done on day 4. SFN was detected in all serum samples 24 h after the final dose. A significant dose-dependent increase in phase II antioxidant enzymes in lavage cells was measured in the SFN group vs. placebo and only mild side effects were noted. Editor's comment: Controlled clinical tests such as this one are important to provide quantifiable data for evaluation of health claims for natural products.
Riedl MA et al., Clin Immunol 2009; 130:244-251.

11. Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction.
Airway eosinophilia is a common feature of asthma and eosinophils (EOs) release proinflammatory mediators that may affect other diseases. A genome-wide scan was done for single-nucleotide polymorphisms (SNPs) associating with variations in the number of blood EOs. These data were evaluated for correlation with asthma and other diseases with inflammatory components. The initial scan was performed on 9,392 Icelanders and the most significant SNPs were then examined in 12,118 Europeans and 5,212 East Asians. Three SNPs were found associated with increased EOs and correlated with asthma. None correlated with COPD, but one was associated with increased susceptibility to myocardial infarction. Editor's comment: This study demonstrates the power of genome-wide association scans for pinpointing loci relevant to inflammatory disease.
Gudbjartsson DF, et al., Nature Genetics, 2009; 41:342-347.

12. Genetic variation in the promoter region of chitinase 3-like 1 is associated with atopy.
Allergic diseases affect 10-20% of children worldwide, but the pathogenesis of atopy is not well understood. A number of susceptibility genes and environmental factors are thought to be involved. Human chitinases are implicated in the etiology of inflammatory diseases, and a new class of chitinase-like proteins has been identified that also plays a role in inflammation. Abnormal expression of chitinase 3-like 1 (CHI3L1; aka YKL-40) is linked to rheumatoid arthritis, inflammatory bowel disease and other inflammatory diseases such as asthma. Single-nucleotide polymorphisms (SNPs) in the CHI3L1 gene promoter also have a strong association with atopy. In this report, 295 unrelated atopics and 180 controls were genotyped for the specific promoter SNP, g.-247C/T. Serum YKL-40 and IgE were measured and CHI3L1 promoter activity was determined. Subjects with the g.-247C/T SNP had higher serum YKL-40 and IgE levels and twice the activity of the normal promoter in an in vitro assay. Increased binding of transcription factors to the variant promoter could account for the increased transcription. Editor's comment: The relationship of elevated YKL-40 levels to atopy needs clarification.
Sohn MH et al., Am J Resp Crit Care Med 2009; 179:449-456.

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