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Archives: Medical Journal Reviews

Medical Journal Review

Posted: June 2009

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

1. Safety and immunogenicity of a new tuberculosis vaccine, MVA85A, in Mycobacterium tuberculosis (M.t.) -infected individuals.
An estimated one-third of the world's population is infected with M.t. and persons with latent tuberculous infection (LTBI) have a 5-10% risk of developing tuberculosis from reactivation of the dormant bacterium. A new Modified Vaccinia Ankara recombinant subunit vaccine, MVA85A, expressing antigen 85A, has been developed. The purpose of this study is to evaluate its safety and effectiveness in persons with LTBI. Participants (n = 12) were in good health and had LTBI as defined by a positive test for IFN gamma in peripheral blood cells exposed in vitro to M.t. antigens but no clinical evidence of TB (e.g., abnormal chest X-ray). Subjects were vaccinated intradermally with MVA85A. Blood samples were taken over the 52-week study period and a high-resolution tomographic scan was done before vaccination and at 10 weeks after. Subjects reported no adverse reactions during the 7 days after vaccination, and there was no change in inflammatory markers or in tomography. A strong IFN gamma and IL-2 immune response occurred and continued for 52 weeks.
Editor's comment: This study shows that the MVA85A vaccine can be used safely and effectively in persons with latent tuberculosis infection.
Sandler CR et al., Am J Resp Crit Care Med 2009;179:724-733. Also see editorial by Dockrell HM & Zhang Y, pp. 628-629 (Abstract not available)

2. Nonfatal fall-related injuries associated with dogs and cats-United States, 2001-2006.
The major cause of nonfatal injuries in the U.S. is falls, which sent 8 million people to the ER in 2006. The CDC examined fall statistics from the National Electronic Injury Surveillance System All Injury Program for 2001 to 2006 and found a yearly average of 86,629 fall injuries attributable to dogs and cats, with dogs causing the lion's share at 88%; females are more than twice as likely as males to suffer an injury. The majority of injuries occurred inside or in the area just outside the home.
Editor's comment: Cats and dogs not only cause allergy, but are also associated with pet-related injuries.
Stephens JA, MMWR 2009;58:277-281.

3. Vitamin D beyond bones in chronic obstructive pulmonary disease (COPD).
Vitamin D regulates genes associated with the cardiovascular and immune systems in addition to those involved in bone and calcium homeostasis. This Pulmonary Perspective paper evaluates the potential of vitamin D for the treatment of COPD. The 3rd USA National Health and Nutrition Survey data show a suggestive but not statistically significant inverse relationship between serum levels of the circulating form of vitamin D, 25-hydroxy vitamin D (25OHD), and FEV1/FVC. This is the only study which compares pulmonary function with 25OHD levels. More than 50% of patients with advanced pulmonary disease had vitamin D deficiency and 68% of a cohort of COPD patients had osteoporosis or osteopenia. Vitamin D-deficiency may result in increased respiratory infections that can be associated with severe exacerbations of COPD. Muscle weakness is a common characteristic of COPD patients and improvements in muscle strength and balance in the elderly have been demonstrated with vitamin D supplementation.
Editor's comment: Vitamin D and calcium are indicated to help prevent and treat osteopenia and osteoporosis in COPD patients. Perhaps vitamin D is also helpful to treat COPD.
Janssens W et al., Am J Respir Crit Care Med 2009;179:630-636.

4. Serum vitamin D levels and markers of severity of childhood asthma in Costa Rica.
A cohort of 616 Costa Rican children aged 6-14 years with physician-diagnosed asthma participated in this study. Serum levels of the circulating form of vitamin D, 25-hydroxy vitamin D (25-OHD), were insufficient (between 20 and 30 ng/ml) in 24% of the children and deficient (<20 ng/ml) in 3.4%. Statistical analyses were done for both unadjusted and multivariate models. Serum 25-OHD levels were inversely proportional to serum IgE, peripheral blood eosinophil counts and hyperresponsiveness to methacholine. Specific IgE and skin test reactions to dust mite were also inversely proportional to serum vitamin D levels. Higher 25-OHD levels were associated with a decreased incidence of hospitalization from asthma compared to the year prior to the study.
Editor's comment: More clinical trials with larger numbers of subjects are needed to determine if vitamin D supplementation can reduce asthma severity or even prevent it.
Brehm JM et al., Am J Respir Crit Care Med 2009; 179:765-771. Also see editorial by Devereux G et al., pp. 739-740 (Abstract not available)

5. Alergológica - 2005, a compilation of epidemiologic, clinical and socioeconomic information on allergic patients in Spain.
This is a special issue of the Journal of Investigative Allergology and Clinical Immunology, the official organ of the Spanish Society of Allergology and Clinical Immunology. Data on 4991 patients treated by 340 allergologists throughout Spain in 2005 were collected, analyzed and summarized in this report, which contains an introduction and 11 articles. A similar study was published in 1992 and the new information in Alergológica - 2005 is evaluated in comparison to the previous data. A description of the clinical and epidemiological characteristics of the patients; the condition (rhinoconjunctivitis, asthma, urticaria/angioedema, atopic and contact dermatitis, food and drug allergies, allergies to insect stings, etc.); the geographical region; seasonal variability; the diagnostic procedures used; the method of treatment and prevention; the effects of allergic illness on quality of life, leisure and work activities; and the aspects of the healthcare infrastructure that affected the care outcome are all presented in this series of articles.
Editor's comment: This collection of papers about allergic diseases in Spain provides a useful framework for other countries to develop similar databases.
J Invest Allergol Clin Immunol 2009;19s2:1-68.

6. Modulation of dendritic cells (DCs) using granulocyte-macrophage colony-stimulating factor (GM-CSF) delays type 1 diabetes (T1D) by enhancing CD4+CD25+ T cell function.
The hypothesis of this paper is that T1D may be prevented by altering the activation of DCs to suppress the CD4+ T effector cells that destroy pancreatic beta cells. DCs can induce CD4+CD25+ regulatory T cells (Tregs) that block autoimmunity. Injection of non-obese diabetic mice (NOD), a surrogate for human T1D, with GM-CSF before diabetes occurred significantly delayed the onset of the disease. DCs from GM-CSF-treated NOD mice had reduced levels of inflammatory cytokines and increased IL-10 relative to non-treated mice, and repeated GM-CSF treatments prolonged suppression of T1D. The Treg population in GM-CSF-treated mice was expanded and transplantation of these cells into non-treated mice prevented T1D. At later stages of the disease, after insulitis had occurred, GM-CSF was still able to prevent hyperglycemia.
Editor's comment: Susceptibility to T1D may be associated with DC defects that could be corrected by GM-CSF.
Cheatem D et al., Clin Immunol 2009;131:260-270.

7. Accessory cell-dependent NK cell-mediated PBMC IFN-γ production is defective in HIV infection.
Co-infection of HIV-positive patients with hepatitis C virus (HCV) is common. The innate antiviral response depends on myeloid dendritic cell (MDC) activation of natural killer (NK) cells, which may be defective in HIV- or HCV-infected patients. In this study, peripheral blood mononuclear cells, PBMCs, were isolated from HIV+, HCV+ or HIV/HCV+ patients and analyzed for NK cell numbers and IFN-γ production in response to DC activation with poly (I:C). PBMCs from HIV+ and HIV/HCV+ subjects showed reduced IFN-γ and NK cell numbers. Incubation of poly (I:C)-treated PBMCs with IL-12 restored IFN-γ levels, indicating that the defect was in cell-dependent NK activation rather than in direct IL-12 activation. PBMCs from HIV+ patients had fewer myeloid dendritic cells (MDCs) than controls. This may, in part, explain the lower NK numbers.
Editor's comment: Restoring MDC numbers in AIDS patients may be a viable therapeutic goal.
Yonkers NL et al., Clin Immunol 2009;131:288-297.

8. Interleukin-13-induced MUC5AC is regulated by the 15-lipoxygenase 1 (15LO1) pathway in human bronchial epithelial cells.
Asthmatics have higher levels of 15LO1 and MUC5AC in mucosal epithelial cells compared to healthy persons. IL-13 induces both 15LO1 and MUC5AC. Three-dimensional ex vivo epithelial cell cultures grown with air-liquid interface were prepared from bronchoscopy specimens obtained from asthmatics and healthy individuals with no respiratory illness. Expression of 15LO1protein (but not mRNA) was higher in asthmatics and increased with severity. Increased MUC5AC expression colocalized with increased 15LO1 in 3D bronchial epithelial cell sections, and the addition of the primary active metabolite of 15LO1, 15-hydroxyeicosatetraenoic acid (15-HETE), had a similar effect. Addition of IL-13 to epithelial cell cultures stimulated 15LO1 and MUC5AC expression in both healthy and asthmatic specimens, and this expression was prevented when an inhibitor of 15LO1 was present. SiRNA against 15LO1 also blocked the IL-13-induced MUC5AC expression.
Editor's comment: Inhibitors of 15LO1 may be a useful adjunct therapy to treat chronic airway disease.
Zhao J et al., Am J Resp Crit Care Med 2009;179:782-790.

9. β2-adrenergic receptor polymorphisms affect response to treatment in children with severe asthma exacerbations.
A mutation in the β2-adrenergic receptor (β2-AR) at amino acid position 16 resulting in glycine (Gly/Gly) rather than arginine (Arg/Arg or Arg/Gly) has been associated with enhanced responsiveness to β2-AR agonist therapy. Here, 37 children from 2-18 years of age, admitted to hospital ICU with a severe asthma exacerbation, were genotyped for β2-AR SNPs at position 16. Children with the Gly/Gly genotype spent significantly less time in the ICU and required less albuterol and oxygen therapy and were less likely to require i.v. β2-AR therapy than those with the Arg/Gly or Arg/Arg alleles.
Editor's comment: The debate about different β2-adrenergic receptor polymorphisms continues. Determination of β2-AR genotype in severe asthmatic children may be useful in assessing a treatment regimen.
Carroll CL et al., Chest 2009;135:1186-1192.

10. Epinephrine (Epi) and dexamethasone (Dex) in children with bronchiolitis.
A multicenter, placebo-controlled trial of 800 infants, 6 weeks to 12 months of age, from 8 Canadian pediatric emergency departments was conducted to test the effectiveness of combined Epi/Dex therapy for treating bronchiolitis. The infants were evaluated in the ER using a respiratory distress index (RDAI) score of 4-15 and randomized into one of four groups (~200/group). One group received nebulized Epi (3 ml of a 1:1000 solution) plus 6 oral doses of Dex (1.0 mg/kg body wgt), the second group received Epi only, the third group Dex only, and the fourth group received only placebo. The primary outcome was admission to hospital within 7 days after enrollment and secondary outcomes included change in heart and respiratory rates, RDAI score, oxygen saturation, time to discharge from ER or hospital and patient's return for bronchiolitis symptoms within 22 days of enrollment. Infants in the Epi and the Epi/Dex groups had significantly lower RDAI scores and breathing rates than the placebo group. Adverse events were uncommon with no significant differences among the groups. Combination Epi/Dex therapy gave a relative risk reduction for admission to the hospital of 35% which was independent of the severity of the illness. Infants in the combination treatment group also were discharged earlier and recovered quicker than those in the placebo group.
Editor's comment: The combination of nebulized Epi and oral Dex seems best for children with bronchiolitis.
Plint AC et al., New Engl J Med 2009;360:2079-2089.

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