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Archives: Medical Journal Reviews

Medical Journal Review

Posted: May 2009

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

1. Efficacy of esomeprazole (Eso) for treatment of poorly controlled asthma (A).
Asthmatics frequently have gastric esophageal reflux disease (GERD) as determined by symptoms and/or esophageal pH, but often, overt symptoms are lacking. In this multicenter, parallel-group, DBPC trial, 412 patients with poorly-controlled A (moderate-high doses of ICSs, JACQ score of 1.5 or higher, or more than one unscheduled medical care visit in the past year) but with no symptoms of GERD were given either placebo or 40 mg of the proton-pump inhibitor (PPI), Eso 2X/day for 24 weeks. Ambulatory pH measurements were done to identify GERD in asymptomatic subjects [41% in placebo (P), 40% in Eso]. Participants kept daily symptom diaries, completed asthma questionnaires and had spirometry monthly. There was no improvement in A control in the Eso vs P groups, even in those who had GERD documented by pH probe. Editor's comment: Eso and possibly other PPIs should not be prescribed for asthmatics who do not have documented GERD or symptoms.
American Lung Association Asthma Clinical Research Centers, Mastronarde JG et al., New Engl J Med 2009; 360:1487-1499
(See also the comment by Asano & Suzuki, pp. 1551-1553)
[Conflict: Dr. Lockey participated in this trial.]

2. Multicenter, double-blind, randomized, placebo-controlled trial assessing the efficacy and safety of proton pump inhibitor (PPI) lansoprazole (Lan) in infants with symptoms of gastroesophageal reflux disease (GERD).
Although there are no FDA-approved guidelines for prescribing PPIs in children younger than one year of age, their use is increasing. This study compares treatment with placebo (P) versus Lan with the primary outcome of reducing feeding-related crying by 50% and secondarily by changing other symptoms and global assessments and other alleged GERD symptoms. Infants (n = 162) with symptomatic GERD were randomized to P or Lan (0.2-0.3 mg/kg/day for ?10 wks of age; 1.0-1.5 mg/kg/day for ≤10 wks of age) groups and treated for 4 weeks. Number and duration of feeding-related crying episodes were recorded and a modified Infant Gastroesophageal Reflux Questionnaire was completed daily. No change in symptom scores was found with Lan versus P, and there were significantly more adverse events (AE), particularly lower respiratory tract infections, in the Lan group.
Editor's comment: The lack of efficacy of the PPI, together with the increase in AE, suggest that these medications should not be routinely used in infant GERD.
Orenstein SR et al., J Pediatr 2009; 154:514-520
(See also the editorial by Putnam PE, pp. 475-476)

3. Effect of formoterol (F) with or without budesonide (B) in repeated low-dose allergen challenge.
This report compares the effects of F (4.5 μg) monotherapy with combination F (4.5 μg) /BUD (160 μg) and placebo (P) on the dose of methacholine necessary to cause a 20% drop in FEV1 (PD20), fraction of exhaled nitric oxide (FeNO), eosinophilia (E) and prostaglandin G2 (PGD2) levels in induced sputum, short-acting beta-agonist use, FEV1 and daily symptom scores. The study was done as a 3-period, double-blind, crossover study on 15 intermittent allergic asthmatics given low levels of the inhaled allergen (8, cat; 4, birch; 2, timothy; 1, dog) to which they were allergic for seven days. F/BUD prevented the allergen-induced increase in AHR, while F treatment alone did not. Allergen-induced sputum E and PGD2 levels increased with F but were unchanged with P or F/BUD. There was no difference between F and F/BUD asthma scores, which were improved, and in use of short-acting beta-agonist relative to P. Editor's comment: The observation that sputum E numbers and PGD2 levels increase with F monotherapy but not with F/BUD therapy suggests that treatment with the combination is desirable. Dahlen B et al. Eur Resp J 2009; 33:747-753.
(This study received financial support from AstraZeneca Sweden, among others.)

4. Clinical and immunological response to attenuated tissue-cultured smallpox vaccine LC16m8.
LC16m8 vaccine is a live-attenuated, tissue culture-produced combination of vaccinia virus and viral proteins or DNA that was developed and tested for high immunogenicity and safety. In this trial, 1529 first-time vaccinees and 1692 previously-vaccinated subjects were administered LC16m8 intraepidermally. Outcomes measured were vaccine 'take' (characteristic skin reaction), presence of neutralizing antibodies and adverse events. Vaccine-na´ve subjects showed 94.4% take and 90.2% seroconversion, while individuals who had been vaccinated with a first-generation vaccine (not LC16m8) prior to the study (vaccine scar) showed 86.6% take and 60% booster response, respectively. No severe adverse events occurred. There was one case each of dermatitis and erythema multiforme attributable to the vaccine. Editor's comment: The successful testing of this 3rd generation tissue-cultured vaccine is important in a day and age of possible bioterrorism. Saito T et al., JAMA 2009; 301:1025-1033.

5. Asthma (A), airway inflammation and epithelial damage in swimmers and cold-air athletes.
Endurance athletes have a higher incidence of airway hyperresponsiveness (AHR). The purpose of this study was to quantitate the effects of such training on AHR and sputum eosinophilia (E)/neutrophilia. Subjects included 32 elite swimmers and 32 cold-air athletes, approximately 1/5 of whom had physician-diagnosed asthma. They were compared to 32 healthy non-athletes and 32 non-athletes with mild A. Histories, skin-prick tests, spirometry, methacholine challenge and induced sputum for cell analysis were performed. 69% of the swimmers and 28% of the cold-air athletes had AHR. E counts were higher in swimmers than in healthy subjects but not as high as in mild asthmatics. The cold-air athletes had normal E sputum levels. The number of epithelial cells in sputum from swimmers was higher than in other groups, possibly indicating airway damage. Editor's comment: Additional studies are necessary to determine the long-term effects of intense exercise training on the mechanisms that contribute to asthma. Bougault V et al., Eur Resp J 2009; 33:740-746
(See also editorial by Carlsen K-H, pp. 713-714)

6. Acute exacerbations of asthma (A): epidemiology, biology and the exacerbation-prone phenotype.
Respiratory viruses are associated with the majority of A exacerbations (AE). Such an AE seems to predispose some patients to more AEs, which suggests that there is a subset of asthmatics that are 'exacerbation-prone'. Genetics play a role in disease susceptibility but so do obesity, cigarette smoking, gastroesophageal reflux disease, psychosocial factors, and noncompliance, among others. A clearer understanding of these comorbid conditions and genetics in AEs is important to develop therapeutic strategies for A.
Editor's comment: This is a timely review of an important area of A research. Dougherty RH and Fahy JV, Clin Exp Allergy 2009; 39:193-202.

7. A randomized, double-blind, placebo-controlled study of tumor necrosis factor-α (TNFα) blockade in severe persistent asthma (SPA).
309 patients, 18 years or older, with severe, uncontrolled A for >1 yr were randomized to receive placebo or golimumab (anti-TNF mAb) 50, 100, or 200 mg administered monthly by subcutaneous injection. Primary outcomes were changes in FEV1 and number of exacerbations through week 24. Secondary measurements included PEF, asthma QoL questionnaire and rescue medication use. No significant differences were observed between placebo and test drug for primary or secondary outcomes. The study was ended at 24 weeks because of serious adverse events and a poor risk-benefit profile. Both serious infections and pneumonia were more common and one death and 8 malignancies occurred in the golimumab groups. Editor's comment: Treating severe, corticosteroid-resistant A remains a challenge. Wenzel SE et al., Am J Resp Crit Care Med 2009; 179:549-558.
(This study was supported by Centocor, Inc. and Centocor BV.)

8. Salmeterol (S) restores secretory functions in cystic fibrosis (CF) airway submucosal gland serous cells.
CF is a genetic disease in which a transmembrane chloride channel, the CFTR, is defective, resulting in highly viscous mucus, impaired clearance of lung secretions, inflammation and chronic bacterial infection. It is regulated by G-protein-coupled receptors such as the β2-adrenergic receptor. The hypothesis of this study is that normal activity of a mutant CFTR (delF508) can be restored with the use of the long-acting β2 agonist, S. A human tracheal gland serous cell line, CF-KM4, homozygous for the delF508 mutation, was used as an experimental model. Cells in culture were exposed to the vehicle S for 24 h and then analyzed for chloride efflux, conductivity, cAMP levels, ion and water content. Confocal microscopy, to determine CFTR trafficking to the apical membrane, and atomic force microscopy, to obtain sizes of secretory granules isolated from CF-KM4 cells, were utilized. S increased the accumulation of delF580-CFTR at the apical membrane and restored conductivity and ion and water balance. Secretory granule size increased to near normal after S treatment. Several potential mechanisms for the activity of S on delF508-FCTR are discussed. Editor's comment: The restoration by S of partial cystic fibrosis conductivity regulator function in vitro offers hope to CF patients.
Delavoie F et al., Am J Resp Cell Mol Biol 2009; 40:388-397.
(Also see the editorial by Collawn JF et al., pp. 385-387)

9. Allergic airway hyperresponsiveness, inflammation, and remodeling do not develop in phosphoinositide 3-kinase (PI3K) γ-deficient mice.
PI3Ks phosphorylate phosphatidylinositols, which signal activation of downstream molecules such as protein kinase B (Akt), play a role in migration, proliferation and differentiation of various inflammatory cells. This report examines the effects of PI3K-deficiency in allergic airway inflammation in the ovalbumin (OVA)-sensitized mouse model. Both wild type (WT) and deficient mice were repeatedly challenged with OVA over a 5-week period to create chronic allergic airway inflammation. PI3K-deficiency reduced airway hyperresponsiveness, inflammation and remodeling compared to the WT. The number of lymphocytes, eosinophils and total cells in bronchoalveolar lavage fluid was lower in deficient animals. Goblet-cell mucus production and thickness of the peribronchial collagen layer were also reduced in PI3K-deficient mice compared to WT. Levels of OVA-specific IgE were similar in both WT and deficient mice. Editor's comment: The prevention of airway remodeling in PI3K-deficient mice suggests a potential new target for pharmacotherapy to treat allergic inflammation. Takeda M et al., J Allergy Clin Immunol 2009; 123:805-812.

10. Special Topics: Et tu, Basophil? aHuman basophils and cytokines/chemokines; bNew roles for basophils in allergy; and, cOrigin of basophils and mast cells.
This issue of Allergology International contains a trio of reviews on that neglected leukocyte, the basophil (B). Here is a summary of the current knowledge on Bs together with an exciting cross-section of brand-new data and hypotheses. There is evidence that Bs are involved in the allergic late-phase reaction and that their function is regulated by IL-33, which enhances their eotaxin-directed migration, IL-4 production and histamine release. Observations that B depletion has a protective and anti-inflammatory effect in animal models support the hypothesis that they may play a greater role in immune regulation and diseases such as asthma and allergy. They are able to drive Th2 polarization through IL-4 secretion and appear to be involved in IgG-mediated anaphylaxis in mice, but their role in anaphylaxis and chronic allergic inflammation in humans remains unknown. Bs and mast cells arise from hematopoietic stem cells in bone marrow but, unlike mast cells which mature in target organs, the Bs are mature when released. Editor's comment: Although Bs comprise less than 1% of peripheral blood leukocytes, their functions are important in allergic inflammation. aYamaguchi M et al, Allergol Internat 2009; 58:1-10
bMukai K et al., Allergol Internat 2009; 58:11-19
cArinobu Y et al., Allergol Internat 2009; 58:21-28

11. Mechanisms and treatment of allergic disease in the big picture of regulatory T cells.
Understanding the control of the immune response in health and why it fails in disease is the holy grail of immunological research. So far, the extreme complexity of the immune regulatory system combined with the variety of immune phenotypes has foiled attempts at developing a unified theory of cellular control in peripheral tolerance. The T cell is at the heart of this conflict. This review provides a comprehensive summary of current knowledge about CD4+CD25+ T regulatory (Treg) cells as well as other subsets of T cells with regulatory powers. Their interaction with other cells, such as dendritic cells, is covered in detail and the roles of key cytokines such as IL-10 and TGF-β in immunoregulation and allergic disease are discussed. Lastly, advances in knowledge about the suppression of allergen-specific T effector cells and inflammatory responses by Tregs in allergen-specific immunotherapy are summarized and the clinical implications discussed. Gaps in understanding are highlighted as guideposts for future research. Editor's comment: This issue is a timely and much-needed review article on immune regulation, particularly, as it pertains to allergic diseases. Akdis CA et al., J Allergy Clin Immunol 2009; 123:735-746.

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