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Archives: Medical Journal Reviews

Medical Journal Review

Posted: March 2009

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

1. Gene therapy for immunodeficiency due to adenosine deaminase (ADA) deficiency.
Lack of the enzyme ADA causes a fatal severe combined immunodeficiency (SCID). This report presents successful results of transplant of autologous CD34+ cells transfected with a viral vector containing the human ADA gene into ADA-deficient patients pretreated with busulfan as a nonmyeloablative conditioner. The ADA vector (GIADAI) is based on the Moloney murine leukemia virus. The 10 patients were diagnosed with ADA deficiency at a median age of 2 months and underwent gene therapy at a median age of 1.7 years (range, 0.6 to 5.6 yr). The follow-up is 1.8 to 8.0 years and all 10 subjects are alive and pursuing a normal lifestyle. In 8 patients, the blood cells produce ADA normally and there are no signs of toxic purine metabolites. Numbers of T and B lymphocytes increased and immune responses improved. Editor's Comment: This gene therapy involves 10 subjects and the lack of adverse events is encouraging. Aiuti A, et al. New Eng J Med 2009; 360:447-458. (also see the accompanying editorial by DB Kohn and F Candotti, pp. 518-521)

2. Long-acting beta agonists (LABAs): a review of formoterol (F) safety data from asthma (A) clinical trials.
Questions about the safety of salmeterol in treating A in combination with other A drugs have precipitated a widespread reexamination of the data from clinical trials of LABAs. This study examines the results of all AstraZeneca trials for deaths involving F categorized as A-related, cardiac-related or other. Comparing patients (n = 49,906) taking F to non-LABA patients (n = 18,098), there were 8 A-related deaths in the former versus 2 in the latter group, but the difference is not significant because the sample size is too small to provide the necessary statistical power. There was no increased risk of cardiac-related death in patients taking F compared to non-LABA patients. There was, however, a significant reduction in severe adverse events in the F group. Editor's comment: There are problems with combining and analyzing data from multiple studies and the jury is still out on the issue of LABA safety. Sears MR et al., Eur Resp J 2009; 33:21-32. (also see the accompanying editorial by Beasley R et al, pp. 3-5)

3. Pre-emptive use of high-dose fluticasone (FP) for virus-induced wheezing in young children.
The optimal treatment of viral infections in young children to prevent wheezing is not satisfactorily defined. A group of 129 children, age 1 to 6 years, were given a high dose of inhaled FP, 750 µg, or placebo twice a day at the beginning of a respiratory virus infection and continued up to 10 days. Use of rescue oral corticosteroids was the primary outcome with symptom scores, use of beta agonists, hospitalization and change in growth and bone mineral density as some of the secondary metrics. Of the children taking FP, only 8% needed rescue medication in comparison to 18% of the placebo group. Their symptoms were less severe and of shorter duration, and they used less beta agonist and had fewer hospitalizations than in the placebo group; however, the FP group showed a small but significantly reduced height and weight. Editor's comment: The inhibition of growth in the FP group is cause for concern and longer term studies are necessary. Ducharme FM et al., New Engl J Med 2009; 360:339-353.

4. Oral prednisolone (P) for preschool children with acute virus-induced wheezing (VIW).
A short course of oral P is often used with VIW in preschoolers but the effectiveness of this treatment is unknown. This randomized DBPC study enrolled 700 children between the ages of 10 months and 5 years who presented to the hospital with VIW. The treatment group received oral P, 10 mg, once a day for the 10 to 24 months age group and 20 mg per day for the older children. There was no statistical difference between the placebo and P groups in albuterol use or time to discharge from the hospital. There also was no difference in the 7-day symptom scores, the home use of albuterol or the number of readmissions to the hospital for wheezing. The conclusion is that oral P for VIW induced mild-to-moderate wheezing in preschool children is no more effective than placebo. Editor's comment: This study may not have been sufficiently powered to detect small differences in outcome. Panickar J, et al. New Engl J Med 2009; 360:329-338.

5. Adaptive immune features of natural killer (NK) cells.
NK cells share some characteristics of CD8+ T cells but are commonly associated only with the innate immune response. This report provides evidence using a mouse model of cytomegalovirus (CMV) infection that NK cells are able to undergo self-renewal as antigen-specific memory cells. Upon activation, the memory NK cells have elevated expression of interferon gamma and other effector cytokines similar to memory T cells. The NK memory cells are capable of a 100-fold expansion in the spleen after exposure to CMV and are able to protect neonatal mice against CMV when adoptively transferred. Editor's comment: This new role of NK cells in immune memory may be exploited to produce better vaccines. Sun JC et al. Nature 2009; 457:557-561.

6. Childhood asthma and increased airway responsiveness (AR).
This paper addresses the key question of what is the initial age at which the onset of AR correlates with later onset of asthma. In this birth cohort of 253 subjects, AR was measured at 1, 6 and 12 months of age, and presence of asthma was determined at 11 years of age. AR in infancy was determined by a rapid thoracoabdominal method (VmaxFRC) before and after histamine challenge and spirometry was performed in childhood. Among those who had at least one incident of increased AR in infancy, 50% had increased AR in childhood. Parental history of asthma, respiratory infection during infancy and atopy increase the likelihood of childhood AR. Persistent childhood wheeze is associated with late onset AR (12 mos) but not with early (1 mo) or mid (6 mo)-infancy. Editor's comment: Intervention in late infancy to prevent increased AR may be effective in reducing the risk of childhood asthma. Turner SW et al. Am J Resp Crit Care Med 2009; 179:98-104.

7. HLX1 gene variants influence the development of childhood asthma (A).
The homeobox transcription factor HLX1 works in cooperation with the T-box transcription factor T-bet to maintain a Th1 phenotype with production of interferon gamma. Genetic polymorphisms in the HLX1 gene may affect susceptibility to A in children. The International Study of Asthma and Allergy in Children phase II examined 5269 schoolchildren from 9-11 years of age with spirometry, skin-prick tests, questionnaires and serum IgE measurements. Physician-diagnosed A or a positive skin-prick test to one or more of 6 common allergens were used to define the asthmatic or atopic child, respectively. A total of 3099 children were screened for polymorphisms in the HLX1 gene and functional properties of the alterations were determined by using luciferase reporter constructs and electrophoretic mobility shift assays. 19 HLX1 polymorphisms were identified and two in the promoter region were associated with A at an odds ratio of 1.44. The mutations caused a decreased transcription of the HLX1 gene. Editor's comment: These findings demonstrate a correlation between defects in HLX1 transcription and A susceptibility. Suttner K, et al. J Allergy Clin Immunol 2009; 123:82-88.

8. High-dose inhaled corticosteroids (ICSs) versus add-on long-acting beta-agonists (LABAs) in asthma (A): an observational study.
Using a large dataset from the UK, these researchers evaluated the data for patients whose A required the addition of a LABA to their ICS regimen (n = 17,418) and compared it with a group who chose to increase the ICS concentration or switch to a different ICS (n = 46,930). Age, gender, socioeconomic status, body mass index, smoking history, comorbidity, use of short-acting beta agonists (SABAs), oral corticosteroids (OCS) or other medications were taken into account in the primary outcome of treatment success during a 12-month period. Although symptomatic control and rescue bronchodilator use may be improved by the addition of a LABA to ICS, there may be a lower risk of severe exacerbations and hospitalizations from ICS dose increase. Editor's comment: This report provides some needed and useful data about the risk-benefit analysis of LABA add-on therapy. Thomas M, et al. J Allergy Clin Immunol 2009; 123:116-121.

9. The causal direction in the association between respiratory syncytial virus (RSV) hospitalization and asthma (A).
This prospective study looks at 18,614 Danish twins admitted to hospital for RSV and compares the data bidirectionally in terms of risk of A after RSV and risk of RSV in existing asthmatics. For infants <6 mo of age, the rate of hospitalization for RSV in Denmark is 3.4% and the rate of rehospitalization among this group may be as high as 20% during the first year after RSV infection. RSV seems to increase the risk of A in many studies, while having an early asthmatic condition increases the risk of severe lower respiratory tract infection and RSV. In the multivariable model used to analyze the data, gender, gestational age, maternal smoking status, socioeconomic and educational levels and seasonality were included as confounders. 4.8% of the cohort had an RSV-associated hospitalization within the first 5 years of life. The increased risk of A within the first 2 months after RSV was 6.2-fold but at 1 yr after RSV the difference was no longer significant. The relative RSV risk for asthmatics was 3.0 and was independent of time and age. RSV infection has a short-term effect on bronchial responsiveness that manifests as A, while asthmatics appear to have a host factor that puts them at increased risk for RSV infection. Editor's comment: This report demonstrates that the bidirectional connection between A and RSV has both genetic and environmental components. Stensballe LG et al. J Allergy and Clin Immunol 2009; 123:131-137.

10. Special topics reviews on lipid mediators: Leukotriene B4 (LTB4) in allergic disease, resolution of airway inflammation, prostaglandin D2 (PGD2) in asthma and hyperleukotrieneuria in asthma (A) and inflammation.
This series of four comprehensive reviews by different authors provides an in-depth overview of this important area. Lipid mediators include both proinflammatory types, such as leukotrienes and prostaglandins, and anti-inflammatory lipoxins and resolvins. LBT4 is a potent chemoattractant for neutrophils, eosinophils, monocyte/macrophages, mast cells, dendritic cells and effector T cells, and promotes inflammation in severe persistent A, exercise- and aspirin induced-A, allergic rhinitis and atopic dermatitis. This review is an excellent discussion of corticosteroid resistance and the LTB4 pathway. Resolution of airway inflammation is the goal of A therapy and new research findings outlined in this paper offer hope of improved treatments to boost the 'pro-resolving' lipid mediators. Avoidance of allergens and use of inhaled corticosteroids can improve A quality of life but a new shift in focus towards a more proactive intervention to boost production and activity of anti-inflammatory mediators could restore airway homeostasis. Additional articles in this series review the role of PGD2 in the pathophysiology of A and the use of urinary measurements of excreted leukotrienes as biomarkers of disease and treatment effectiveness. Editor's comment: This series of reviews is a must-read for clinicians, students and researchers who need to understand the role of lipid mediators in lung inflammation. Allergology International 2008; 57:291-320. (For a TOC of abstracts and full text, go to: Click on: December 2008 [Vol. 57 Issue 4 Page 291-443])