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Archives: Medical Journal Reviews

Medical Journal Review

Posted: August 2008

Reviewed by Prof. Richard F. Lockey, MD, WAO Web Editor-in-Chief

1. Comparison of adjustable-and fixed-dose budesonide/formoterol (BF) pressurized metered-dose inhaler and fixed-dose fluticasone propionate/salmeterol (FS) dry powder inhaler in asthma patients
This is a randomized, open-label, multicenter study of 1225 subjects, 12 yrs and older, with moderate-to-severe persistent asthma. After 10 to 14 days of current therapy, patients were randomized 2:1 to fixed-dose BF (160/4.5 µg x 2 inhalations [320/9 µg] twice daily) or fixed-dose FS (250/50 µg x 1 inhalation twice daily) for one month, after which the fixed-dose FS group continued therapy and the fixed-dose BF group was randomized 1:1 to fixed-dose BF or adjustable-dose BF (adjustable from two inhalations [320/9 µg] twice daily to two inhalations [320/9 µg] once daily or four inhalations ([640/18 µg] twice daily) for six months. There were no significant between-group differences for asthma exacerbations (primary objective), asthma symptoms, or lung function during the 7-month treatment period. The authors conclude that adjustable-dose and fixed-dose BF versus fixed-dose FS demonstrate no difference in asthma control or tolerability. Editor's comment: Most patients respond to comparable fixed-dose inhalers containing both a long-acting beta-agonist and a glucocorticosteroid. Busse WW, et al., NCBI 2008 Jun;121(6):1407-14

2. Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants
Aluminium adjuvants are used in human and animal vaccines worldwide. The authors show that aluminium adjuvants activate an intracellular innate immune response system, called the Nalp3 (also known as cryopyrin, CIAS1 or NLRP3) inflammasome. Production of the pro-inflammatory cytokines, interleukin-1β and interleukin-18 by macrophages, in response to alum in vitro, require intact inflammasome signaling. Mice deficient in Nalp3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) or caspase-1 fail to mount a significant antibody response to an antigen administered with aluminium adjuvants, whereas the response to complete Freund's adjuvant remains intact. Editor's comment: Understanding how aluminium adjuvants work will help design more specific adjuvants. Eisenbarth SC, et al., Nature 2008; 453:1122.

3. T-cell regulation in chronic paranasal sinus disease
Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by a TH2-skewed eosinophilic inflammation, whereas chronic rhinosinusitis without nasal polyps (CRSsNP) represents a predominant TH1 milieu. Nasal mucosa tissue from 13 patients with CRSsNP, 16 with CRSwNP, and 10 control patients were analyzed. The authors demonstrate a decreased expression of FOXP3 in nasal polyp tissue, reflecting a deficiency or dysfunction of Treg cells, in CRSwNP. In addition, low levels of TGF-β1 protein expression and an upregulation of the transcription signals for TH1 (T-bet) and TH2 (GATA-3) subpopulations point to a defective suppression of their upregulation by Treg cells. The authors conclude by stating that a lack of Treg cells may contribute to the severe persistent TH2-skewed inflammation in CRSwNP, not present in the CRSsNP group. Editor's Comment: A lack of Treg cells may contribute to the pathogenesis of nasal polyps in CRSwNP. Van Bruaene N, et al., JACI 2008; 121:1435.

4. Induction and effector functions of TH17 cells
The TH17 cell, a third subset of effector T helper cells, is the subject of intense research to understand their role in immunity and disease. An excellent review of emerging data suggests that the TH17 cells have an important role in host defense against specific pathogens, some of which include Propionibacterium acnes, the Gram-negative Citrobacter rodentium, Klebsiella pneumoniae, Bacteroides spp. and Borrelia spp., the acid-fast Mycobacterium tuberculosis, and fungi such as Candida albicans. They are also potent inducers of autoimmunity and tissue inflammation. In addition, differentiation factors responsible for TH17 generation reveal an interesting reciprocal relationship with regulatory T (Treg) cells, which prevent tissue inflammation and mediate self-tolerance. Editor's comment: A fantastic review of a subject of interest to all allergists/immunologists. A must read. Bettelli E, et al., Nature 2008; 453:1051.

5. Ciclesonide (C) improves measures of small airway involvement in asthma
16 mild-to-moderate asthma patients were randomized to receive five weeks treatment with placebo (P) vs 320 µg C once daily. Small airway parameters were assessed. Seven received P and nine C. Alveolar exhaled nitric oxide (eNO) and computed tomography (CT) measurements of expiratory lung function after methacholine (MCh) challenge decreased significantly with C vs P. It did not affect mean expiratory flow between 25 and 75% of forced vital capacity (FVC), percentage fall in FVC at the provocative dose of adenosine-5'-monophosphate or MCh causing a 20% decrease in FEV1, and single-breath nitrogen closing volume. The authors conclude that C exerts anti-inflammatory effects on the small airways. Editor's comment: Optimal treatment for some patients with asthma may require that the entire airway be treated, including the small airways. Cohen J, et al., Eur Respir J 2008; 31:1213.

6. Prevention of Herpes Zoster
The June 6, 2008 issue of the Morbidity and Mortality Weekly Report (MMWR) has an excellent article on recommendations for herpes zoster (shingles) vaccination. It is recommended for all persons aged ≥ 60 yrs who have no contraindications, including those with previous episodes of herpes zoster or those who have chronic medical conditions, regardless of their history of varicella (chickenpox) or serologically proven varicella immunity. Medical conditions include chronic renal failure, diabetes mellitus, rheumatoid arthritis, and chronic pulmonary disease. Since this is a live, attenuated vaccine, it should not be given to patients who are immunosuppressed or with immunodeficiency. Editor's comment: Pediatricians traditionally administer vaccines to children; allergists/immunologists should be the primary, or one of the specialty groups, that administer vaccines to adults. Harpaz R, et al., MMWR 2008; 57.

7. Molecular Origins of Cancer; Cancer Immunology
The immune system can respond to cancer cells by either reacting against tumor-specific antigens (molecules unique to cancer cells) or against tumor-associated antigens (molecules expressed differently by cancer vs normal cells). This knowledge has stimulated the invention of many new therapeutic antibodies, cell-based treatments, and vaccines which are currently being used in clinical practice. This therapy should result in increased and improved cancer treatment and possibly, eventually, even prevent cancer. Editor's comment: This is an excellent article on tumor immunology and the immunologic reagents approved by the FDA for cancer therapy. Finn OJ, N Engl J Med 2008; 358:2704.

8. The ABCs of Asthma Control
The authors describe four easy steps to achieve asthma control in the ambulatory practice setting: 1) a standardized assessment of asthma symptoms using a 5-question assessment tool, the Asthma Control Test (ACT), 2) a simple mnemonic, AIRESMOG, that provides a systematic review of the comorbidities and clinical variables that contribute to uncontrolled asthma, 3) directed patient education, and 4) a schedule for ongoing care. The authors conclude that almost all patients can achieve good asthma control using this approach. The AIRESMOG Mnemonic stands for: A - Allergy and Adherence to therapy, I - Infection and Inflammation, R - Rhinitis and Rhinosinusitis, E - Exercise and Error in diagnosis, S - Smoking and pSychogenic factors, M - Medications (β-blockers, angiotensin-converting enzyme inhibitor, aspirin), O - Occupational exposures, Obesity, and Obstructive sleep apnea, G - Gastroesophageal reflux disease. Editor's comment: This AIRESMOG Mnemonic will help make asthma the most treatable of all chronic diseases. Thorsteinsdottir B, et al., Mayo Clin Prac 2008; 83:814.

9. Subspecialty differences in asthma characteristics and management
2407 patients (72%) with asthma were treated by allergists and 935 (28%) by pulmonologists in the Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study. Patients treated by pulmonologists vs allergists were more likely to be African-American, less educated, have lower incomes, have more severe asthma, and use short-acting β-agonist and systemic corticosteroids more regularly. Although evidence of allergic disease was prevalent in both groups, those treated by allergists were more likely to be skin tested and receive immunotherapy. Those treated by pulmonologists also were more likely to report greater health care use for asthma in the previous 3 months. Editor's comment: Subspecialty differences do exist between allergists/immunologists and pulmonologists. Chen H, et al., Mayo Clin Proc 2008; 83:786.

10. Update on mechanisms of allergen injection immunotherapy
Allergen immunotherapy is indicated for allergic rhinitis, allergic asthma and Hymenoptera hypersensitivity. Unlike pharmacotherapy, it provides long-term clinical benefits, such as long-term disease remission, prevention of new atopic sensitizations and a reduction in disease progression from rhinitis to asthma. Editor's comment: This state-of-the-art review is outstanding. James LK, Durham SR, Clin Exp Allergy 2008; 38:1074.

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