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Archives: Medical Journal Reviews

Medical Journal Review

Posted: February 2009

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

1. Predicting worsening asthma control following the common cold.
The effects of rhinovirus infection on asthmatics vary, but upper respiratory infections commonly worsen asthma and lead to exacerbations. In this multicenter study, 413 adult asthmatics were followed for over a year to determine if the severity of a cold could predict loss of asthma control. To quantify the loss of asthma control, subjects completed the mini-Asthma Control Questionnaire (mini-ACQ) and to measure cold severity, the Wisconsin Upper Respiratory Symptom Survey-21 (WURSS-21). The questionnaires were done about every 8 weeks, and upon the onset of a cold, the WURSS-21 was completed daily for the duration of the cold and the mini-ACQ was done at 7 and 14 days after its onset. Significant loss of asthma control occurred in 134 subjects and the WURSS-21 scores on the second day were predictive of subsequent worsening of asthma. Editor's comment: Documentation of cold symptoms by asthmatics may help reduce the post-cold loss of asthma control. Walter MJ et al., Eur Respir J, 2008; 32: 1548-1554.

2. Azathioprine or methotrexate maintenance for ANCA-associated vasculitis.
Patients with Wegener's granulomatosis (WG) or microscopic polyangiitis (MP) can be induced into remission by a course of i.v. corticosteroids and cyclophosphamide. Either methotrexate (Mtx) or azathioprine (Aza) can then be given as an immunosuppressant for post-treatment maintenance. This study compares the efficacy and safety of Mtx vs Aza administered to 126 WG or MP patients in remission. One group of 63 randomized patients received 2.0 mg/kg Aza per day while the other was given 0.3 mg/kg Mtx per week, increased to 25 mg per week, for 12 months. Adverse events (AEs) requiring discontinuation of the drug or causing death were the primary endpoints recorded over a mean period of 29±13 months. During maintenance therapy, 29 Aza patients (46%) and 35 Mtx patients (56%) had one or more AEs and among these individuals, 7 in the Aza group and 12 in the Mtx group had AEs severe enough to cause discontinuation or death. The relapse-free survival rates were 71.8% for Aza compared to 74.5% for Mtx, and the hazard ratio for risk of relapse with Mtx vs Aza was 0.92. The conclusion is that the safety and efficacy of Mtx and Aza are not statistically different. Editor's comment: Given the equivalency of the two medications, the decision of which one to use for maintenance control of ANCA-associated vasculitis can be made based on the individual's tolerance. Pagnoux C, et al. N Engl J Med 2008; 359:2790-2803.

3. A syndrome with congenital neutropenia and mutations in G6PC3.
Mutations in several different genes are linked to severe congenital neutropenia (SCN) with susceptibility to bacterial infection, lack of mature neutrophils, heart and urogenital defects and increased risk of leukemia. A genome-wide linkage analysis of two consanguineous families of children with SCN resulted in the identification of a homozygous mutation in the gene for glucose-6-phosphatase, G6PC3, that abolished G6P activity. The parents were heterozygous for the mutation. An additional seven unrelated SCN patients were found to have biallelic G6PC3 mutations. None had hypoglycemia commonly seen in glycogen storage disorders also associated with neutropenia. The defect in glucose-6-phosphatase caused loss of mature neutrophils through apoptosis and was associated with increased susceptibility to infection, heart defects, superficial vein prominence and urogenital abnormalities. Mutant G6PC3 activity measured by in vitro glucose production was at background levels compared to the wild type enzyme. Neutrophils, hematopoietic progenitor cells and other cells such as fibroblasts from SCN patients showed an increased rate of spontaneous and induced apoptosis. The tendency to apoptosis in myeloid progenitor cells was reversed by transfection with a plasmid expressing wild type G6PC3. Enzymatic analysis of neutrophils from SCN patients revealed a decrease in the anti-apoptotic protein Mcl-1 which may account for the increased apoptosis. Editor's comment: This paper should be read as a model for excellence in experimental design, data analysis and presentation. Boztug K et al. New Engl J Med 2009; 360:32-43. (also see the editorial by Dale and Link, pp 3-5

4. Use of prescription and over-the-counter medications and dietary supplements among older adults in the United States.
The over-55 group has the highest per capita rate of prescription use and is most at risk for drug-related adverse events. At least one in 25 older Americans is at risk of a major drug-drug interaction because of the combination of medications and supplements. This report utilized a representative probability survey of 3305 noninstitutionalized U.S. individuals 57 to 85 years of age to determine patterns of medication use and potential drug interactions. Professional interviews were conducted in-home and all regular (daily or weekly) use of prescription and over-the-counter (OTC) drugs, as well as supplements, herbals and alternative medicines was verified by the interviewer. 81% of the sample population used at least one prescription drug while about half used at least one OTC drug. Women were more likely than men to use a prescription drug or dietary supplement. The use of more than five prescription or OTC drugs or supplements was observed in more than half of older adults and 68% of prescription users also used OTC drugs or supplements. 46 potential interactions between the 20 most common drugs and the 20 most common dietary supplements were identified, 11 of which could cause severe reactions. Editor's comment: This study emphasizes the importance for the physician to be aware of all medications and supplements taken by their patients. Qato DM et al. J Am Med Assoc 2008; 300:2867-2878.

5. Viral infection in adults hospitalized with community-acquired pneumonia (CAP)-prevalence, pathogens, and presentation.
The viral etiology of CAP has not been studied extensively and treatment guidelines are not as complete as those for bacterial pneumonia. Nasal swab secretions were acquired from 193 individuals hospitalized with CAP and analyzed by the nucleic acid amplification test (NAT) for influenza, rhinovirus (RV), human metapneumovirus (hMPV), respiratory syncytial virus (RSV), parainfluenzavirus (PIV), coronavirus and adenovirus. Serum samples were tested for bacterial infection by immunofluorescence methods. Pathogens were identified in 39% and among those, 29 had a viral infection only, 38 had a bacterial infection only, and 8 had both viral and bacterial infections. The most common were influenza, hMPV and RSV. In patients with bacterial infection, Streptococcus pneumoniae was most common (37%). Viral infection occurred more frequently in older patients (median 76 yrs) than younger (median 64 yrs) and was seasonal (October to May), whereas bacterial infections occurred year round. Morbidity and mortality rates were similar for viral and bacterial infections. Editor's comment: The observation that hMPV occurs as frequently as influenza virus in CAP suggests that this pathogen is more common than previously documented. Johnstone J, et al. Chest 2008; 134:1141-1148.

6. The Brussels Declaration: the need for change in asthma management.
The incidence of asthma, rhinitis and sinusitis continues to increase worldwide and difficulties in diagnosis, lack of effective control and poor education are still serious problems. To address these issues, the Asthma, Allergy and Inflammation Research Charity sponsored a conference that produced the Brussels Declaration which points out the inadequacies in asthma management and urges action on the part of governments and public health groups to recognize these problems and make the necessary changes to improve diagnosis, control and prevention. This paper describes the key points in the declaration and summarizes the evidence supporting the call to action. Areas of focus include the difficulty of accurate diagnosis, the role of inflammation in asthma pathology, the causes of poor asthma control, special problems in pediatric asthma, new areas of research, and the role of public health groups in education and community action. Editor's comment: The emphasis on evidence-based guidelines in developing strategies for improving asthma management is the strong point of this document. Holgate S, et al. Eur Respir J 2008; 32:1433-1442.

7. Treatment with inhaled steroids in patients with symptoms suggestive of asthma but with normal lung function.
The hypothesis of this pilot study was that a pre-asthmatic condition characterized by lung inflammation exists in a significant number of individuals who are not diagnosed with asthma by traditional measures of lung function. This randomized, multicenter, DBPC trial enrolled 144 patients, 12 to 65 years of age, with symptoms suggestive of asthma to undergo treatment with mometasone furoate (MF), 400 µg per day. The subjects scored morning and evening symptoms including cough, sputum production, wheeze, and shortness of breath, among others. An initial 1-2 week screening period was used to insure that those included in the study had an average symptom score >e;1 and that those with diagnosed or verifiable asthma were excluded. Spirometry, eosinophil numbers in induced sputum and airway hyperresponsiveness were also measured. MF or placebo was administered as one puff in the evening from a metered-dose inhaler and salbutamol was used as needed by both groups. The treatment was continued for 4-8 weeks. Despite heterogeneity in the groups, overall symptom scores were lower, eosinophilia decreased and spirometry improved with MF compared to placebo. A short course of inhaled corticosteroids may be beneficial for some patients with symptoms suggestive of asthma , but careful follow-up needs to be done to determine the necessity of continued treatment. Editor's comment: This study provides a useful framework for treating that group of patients with symptoms that may or may not be pre-asthmatic. Rytilä P, et al. Eur Respir J 2008; 32:989-996.

8. Chitosan microparticles loaded with mite group 2 allergen Der f2 alleviate asthma in mice.
Allergen-specific immunotherapy is an effective way to reduce allergy but may cause adverse side effects. This study examined the use of chitosan as a carrier for synthetic allergen peptides that have reduced allergenicity but are still immunogenic. The natural polysaccharide chitosan makes an ideal delivery system because it protects peptides from degradation and enhances their uptake in the mucosa. Mice were sensitized to dust mite by injection of Der f2 and treated with chitosan microparticles loaded with the major epitope peptide, Der f2 (47-67), once daily by i.p. injection for 8 days. One week after the final injection, the mice were challenged with Der f2 and airway hyperresponsiveness (AHR) was measured followed by determination of bronchoalveolar lavage (BAL) cells and lung histology. Mice receiving Der f2 (47-67) chitosan had reduced AHR and BAL eosinophilia, less lung damage and mucus production and lower Der f2-specific serum IgE than mice treated with empty chitosan. Editor's comment: These results in a mouse model suggest that chitosan nanoparticles may be effective as a vehicle in human immunotherapy. Li J, et al. J Investig Allergol Clin Immunol 2008; 18:454-460.

9. Mice lacking 12/15-lipoxygenase have attenuated airway allergic inflammation and remodeling.
The enzyme 15-lipoxygenase (15-LO) acts on arachidonic acid to produce immunoactive compounds. 15-LO is induced by the Th2 cytokines IL-4 and IL-13 and is elevated in asthmatics suggesting a possible role in inflammation. Mice deficient in 12/15-LO (the animal ortholog of human 15-LO) were sensitized to ovalbumin (OVA) and responded with normal production of OVA-specific IgE. Upon OVA aerosol challenge, however, the 12/15-LO-/- mice showed fewer eosinophils, lymphocytes and macrophages in the lungs than wild type (WT) and reduced levels of IL-4, IL-5 and IL-13. Goblet cell hyperplasia was present in both WT and 12/15-LO-/-, but mucus production was inhibited in the latter. Measurements of smooth muscle (SM) cell proliferation revealed fewer alpha-SM actin-positive alveolar cells in the peripheral airways in 12/15-LO-/- mice. Taken together, these results suggest that arachidonic acid metabolites produced by 12/15-LO are active in allergic inflammation and remodeling. Editor's comment: Inhibitor's of the 15-LO pathway may afford some protection from allergic airway inflammation. Andersson CK, et al. Am J Respir Cell Mol Biol 2008; 39:648-656.

10. Pulmonary fibrosis.
This issue of the European Respiratory Review contains a comprehensive series of articles examining the causes, classification and latest clinical findings in pulmonary fibrosis (PF). The outcomes of recent clinical trials are discussed together with a cross-section of the current research including the role of epithelial fibroblasts in PF, the part played by apoptosis, key interactions involving endothelin, cytokines and chemokines in the lung, and more. A survey of gene expression profiles in PF is also presented. The collection ends with an evaluation of the current progress and the important targets for future study. Editor's comment: This is required reading for anyone desiring an up-to-the-minute survey of the literature on PF. Edited by TE King Jr and RM du Bois, Eur Respir Rev 2008; 17:103-170.

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