October 2005 World Medical Journal Review
Reviewed by Richard F. Lockey, M.D., Editor-In-Chief
1. TUMOUR NECROSIS FACTOR (TNFa), A NOVEL THERAPEUTIC TARGET FOR CORTICOSTEROID-DEPENDENT ASTHMA?
Asthma, as it becomes more severe and chronic, becomes refractory to corticosteroids. The influx of neutrophils suggests an altered inflammatory profile consistent with a Th1-type response vs. a Th2 response. TNFa may play a role in this form of asthma. In an open label uncontrolled clinical study, soluble TNFa receptor-IgG1Fc fusion protein, etanercept (Enbrel®), was administered to patients with severe asthma, who had significantly higher levels of TNFa. Etanercept was associated with improvement in asthma symptoms, lung function and bronchial hyperresponsiveness. Double-blind controlled studies are needed to confirm these data. Editor's comment: Perhaps etanercept will be useful to treat severe asthma unresponsive to usual treatment. Howarth PH, et al. Thorax Online 2005; doi:10.1136/thx.2005.045260
2. HIGH-RESOLUTON COMPUTED TOMOGRAPHY SCAN AND AIRWAY REMODELING IN CHILDREN
A high-resolution computed tomography scan was obtained in 37 children with severe asthma to determine whether the bronchial wall thickness (BWT) score correlated with markers of airway remodeling and inflammation. The BWT score significantly correlated with reticular membrane thickening (r=0.34; p=.04) and NO production by the airway wall (r=0.45; p=.02). There was also a correlation with eosinophil cationic protein level (r=0.40; p=.05) but no correlation with the IFN-?/IL-4 ratio, FEV1 or forced expiratory flow at 25% to 75% of forced vital capacity. Editor's comment: This may be a new way subjects with asthma can be followed to better understand airway remodeling and its treatment. De Blic J, et al. J Allergy Clin Immunol 2005; 116: 750.
3. SEVERE ASTHMA IS ASSOCIATED WITH DIMINISHED LIPOXIN BIOSYNTHESIS
Patients with severe vs moderate asthma had decreased lipoxin A4 levels. In contrast, mean levels of cysteinyl leukotrienes were increased, leading to the postulation that the persistent inflammation characterized by neutrophils could be secondary to the underproduction of lipoxins that serve to restrain the inflammatory response. Editor's comment: Perhaps rather than directing treatment to antagonize proinflammatory mediators and leukocyte effectors, emphasis should be placed on augmenting natural counterregulatory pathways. Levy BD, et al. Am J Respir Crit Care Med 2005; 172: 824.
4. IL-4 RECEPTOR SIGNALING IN CLARA CELLS REQUIRED FOR ALLERGEN-INDUCED MUCUS PRODUCTION
The Th2 cytokines, IL-4 and IL-13, are implicated in allergen-induced mucus production, inflammation, and airway hyperreactivity. The authors used a cell type-specific inducible gene-targeting strategy to selectively disrupt the IL-4Ra gene in Clara cells, an airway epithelial cell population that gives rise to mucus-producing goblet cells, to address the question as to whether allergen-induced mucus production is strictly dependent on the direct effects of IL-4 and IL-13. Clara cell specific IL-4Ra deficient mice were nearly completely protected from allergen-induced mucus production; otherwise, they developed similar elevations as did controls of serum IgE levels, airway inflammatory cell numbers, TH2 cytokine production, and airway reactivity following ovalbumin sentitization and challenge. The authors conclude that direct effects of IL-4 and/or IL-13 on Clara cells are required for allergen-induced mucus production in airway epithelium. Editor's comment: It may be possible to target the IL-4Ra receptor to decrease mucus production in asthma. Kuperman DA, et al. Journal of Immunol 2005; 175: 3746.
5. ASSESSMENT OF INHALED CORTICOSTEROID THERAPY FOR ASTHMA TREATMENT DURING PREGNANCY
Charts of 592 women with asthma were studied in a retrospective analysis of pregnancy between January 1987 and December 2003. Treatment, pregnancy/delivery course, and perinatal abnormalities were assessed. Pregnant women with asthma receiving asthma treatment was 17.5% at the beginning of the study and increased to 41% in the later part of the study. Among those treated, the use of inhalational glucocorticosteroids (ICSs) increased from 0% at the beginning to 83% at the end of the study. The incidence of perinatal abnormalities in the treated patients decreased from 60% to 26% and the total incidence of perinatal abnormalities was significantly higher in the non-ICS group. The authors conclude that the ICS are safe for use during pregnancy and decrease perinatal abnormalities. Editor's comment: Asthma itself is a risk factor for pregnancy, not ICS. Otsuka H, et al. Allergology International 2005; 54: 381.
6. BRONCHIAL RESPONSIVENESS (BHR) ASSOCIATED WITH SMOKING
These authors analyzed changes in BHR in an international longitudinal community study of 3,993 participants who had BHR measured in 1991-93, when aged 20 to 44 yr, and subsequently in 1998-2002. The only risk factor for changes in BHR was in individuals who continued to smoke or restarted smoking. Neither baseline IgE sensitization nor change in sensitization was a risk factor for increased BHR. Editor's comment: Smoking is contraindicated in all people particularly in subjects with asthma. Chinn S, et al. Am J Respir Crit Care Med 2005; 172: 956.
7. DOES INHALATIONAL TOXICITY FROM MOLD EXIST?
These authors describe symptoms of 50 people with alleged "mold toxicity," 61% of whom were smokers or former smokers. The most common complaints were upper and lower airway problems (nasal congestion, shortness of breath or cough), nonspecific body complaints, and neurological problems (dizziness, headaches, memory loss, mood disorders, and insomnia). The clinical presentation in perceived mold-induced toxicity is characterized by a disparate constellation of symptoms, some of which were preexisting or psychogenic. Great similarities exist between "toxic mold syndrome" and other pseudo-diagnostic categories such as "sick building syndrome" and "idiopathic chemical intolerance". Editor's comment: Scientific evidence to support the existence of "toxic mold syndrome" is lacking. Khalili B, et al. Annals of Allergy, Asthma & Immunology 2005; 95: 239.
8. ANTIINFLAMMATORY ACTIONS OF GLUCOCORTICOIDS-NEW MECHANISMS FOR OLD DRUGS
Inflammation plays a major role in allergic diseases, asthma, autoimmune diseases and sepsis. Glucocorticoids are indicated for treatment, however, there are risks-benefits associated with their use. This article reviews the mechanisms whereby glucocorticoids inhibit inflammation and outlines their therapeutic limitations. It also provides a prospectus for research on new drugs that could dissociate the beneficial and detrimental effects of glucocorticoids. Editor's comment: This ten-page paper is a concise and sophisticated review about glucocorticoids. Rhen T, et al. N Engl J Med 2005; 353: 1711.
9. AVIAN INFLUENZA A (H5N1) INFECTION IN HUMANS
This WHO review article outlines evidence indicating that Avian influenza has the potential to cause a pandemic. H5N1 has a variable incubation period, as short as 2 to 5 days and up to 8 to 17 days, causes pneumonia with a high mortality, affects infants and young people more than other influenza viruses, and is susceptible to treatment with oseltamivir and zanamivir. Doses of oseltamivir, as high as 150mg 2x daily in adults, for 10 days are considerations in treating patients with severe infections. Transmission between humans is limited at present but warrants monitoring. Editor's comment: Physicians should be aware of this potential threat to human health and urge their institutions and governments to take appropriate precautionary steps to prepare for this potential pandemic. World Health Organization Committee. N Engl J Med 2005; 353: 1374.
An excellent article on drug therapy with neuraminidase inhibitors for influenza accompanies this article. Moscona A. N Engl J Med 2005; 353: 1363.
10. OUTDOOR SPIDER MITES AND ALLERGIC ASTHMA?
This article indicates that spider mites are an important cause of occupational asthma in fruit farmers. The authors review the world's literature about spider mite occupational induced asthma. Editor's comment: This article is of interest, in particular, for allergists who reside in rural areas in which fruit farming (apple, pear, and citrus) is common. Yoon-Keun Kim. Allergy Clin Immunol Int- J World Allergy Organization 2005; 17: 193.
11. PATHOGENESIS AND MANAGEMENT OF ASPIRIN-INTOLERANT ASTHMA
Knowledge about and the diagnosis and treatment of aspirin-intolerant asthma has been enhanced in the last 15 to 20 years. During this time, a great deal of information has been learned about its pathogenesis. This article reviews aspirin-intolerant asthma and contains 152 references about this unique phenotype of asthma. Editor's comment: The late Professor Kenneth Mathews (University of Michigan), my mentor, taught us that understanding aspirin-intolerant asthma is a key to understanding all asthma. Yasushi Obase, et al. Treat Respir Med 2005; 4: 325.
12. ADVERSE REACTIONS TO BIOLOGIC AGENTS
Increasing numbers of biologic agents are available to treat a variety of different diseases including asthma and other allergic diseases and autoimmune, neoplastic, cardiovascular, and infectious diseases. This article reviews indications and recorded side effects. Editor's comment: Allergists need to know about the indications for and potential side effects of new biological agents. Lee SJ, et al. J Allergy Clin Immunol 2005; 116: 900.
13. ASSESSMENT AND TREATMENT OF ACUTE ASTHMA IN CHILDREN
This is a very nice review about assessing the severity and treatment of asthma in children. In the U.S.A., up to 35% to 50% of the direct cost for asthma are spent in the emergency departments or hospitals. The authors include discussions on determining severity, predictive scoring indexes, and treatment. Editor's comment: A review of a subject of interest to all. Chipps BE, et al. J Pediatr 2005; 147: 288.
