Medical Journal Review

Reviewed by Prof. Richard F. Lockey, MD, WAO Web Editor-in-Chief and Guest Reviewer Gary Hellermann, PhD

1. Palivizumab (P) prophylaxis, respiratory syncytial virus (RSV) and subsequent recurrent wheezing.
There is substantial evidence that lower respiratory tract infections of children with RSV within the first two years of life predispose them to wheezing. Preterm infants are at especially great risk of RSV bronchiolitis within the first year of life, and prophylaxis with the anti-RSV antibody P helps reduce their risk of respiratory infections. Whether or not this treatment translates into a reduction in subsequent wheezing is the subject of this study. Preterm infants (≤35 weeks gestation) without chronic lung disease were selected from 27 different sites according to whether they had received P or not. Recurrent wheezing was assessed monthly over a period of 24 months. The results show a significant reduction of about 50% in the incidence of recurrent wheezing in preterm infants receiving P. Editor’s comment: While palivizumab has a proven track record in reducing RSV infections in high risk infants, its cost precludes its widespread prophylactic use. The development of an effective RSV vaccine is still a desirable goal. Simoes EA et al. J Pediatr 2007; 151:34.

2. Effect of inhaled interleukin-5 (IL-5) on eosinophil (E) progenitors in the bronchi and bone marrow of asthmatic and non-asthmatic volunteers.
There is a shift in our understanding of the role of the E in asthma. They are now seen less as misguided pathogenic cells bent on creating an inflammatory condition and more as players in a complex scenario where many factors contribute to the condition. In this report, the role of E progenitor numbers in the bone marrow was examined in asthmatic vs non-asthmatic subjects. IL-5 induces the expansion and proliferation of Es in bone marrow and upregulates IL-5 receptor expression. Healthy and mild atopic asthmatic subjects were randomized into two groups, one of which received recombinant human IL-5 by inhalation and the other vehicle only. Spirometry was measured at baseline and 6 h after IL-5 inhalation. Blood samples were taken at 0, 6 and 24 h and at 24 h bronchial and bone marrow biopsies were done along with bronchoalveolar lavage. IL-5 significantly decreases the number of CD3+ E progenitor cells in the bone marrow of asthmatics and increases Es in bronchial mucosa of healthy persons.  There was no effect on FEV1 or airway hyperreactivity. Editor’s comment: The demonstration of a signaling axis between IL-5 levels in the lung and eosinophil progenitor production in bone marrow suggests that more comparisons between local and systemic effects of inflammatory mediators need to be done. Menzies-Gow AN et al. Clin Exp Allergy 2007; 37:1023.

3. A GABAergic system in airway epithelium is essential for mucus overproduction in asthma.
Type II lung epithelial cells express the gamma-aminobutyric acid subtype A receptor (GABAAR) and this study shows that activation of GABAAR in OVA-sensitized/-challenged mice caused depolarization of these cells. Similar results were obtained using bronchial epithelial cells from human asthmatics. Cells from the asthmatic mice as well as humans show an increase in GABAARs upon allergen challenge that correlates with an increase in goblet cell hyperplasia and mucus production. Inhibition of GABAAR reduces goblet cells and mucus in mice. IL-13 is also upregulated in OVA-treated mice and human cells and represents a critical factor in allergic enhancement of GABAAR activity. Editor’s comment: This study is the first report of the existence of a GABAergic signaling pathway involved in mucus overproduction in asthma and may provide a new therapeutic target. Xiang Y-Y et al. Nature Medicine (Letters) 2007; 13:862.

4. Mast cells (MCs) promote atherosclerosis by releasing proinflammatory cytokines.
MCs are found in atherosclerotic lesions, and it is thought that they cause inflammation by secreting cytokines that can attract other immune cells and alter endothelial or smooth muscle cell activity and proteases involved in vascular remodeling. MCs isolated from arterial lesions show significant amounts of IFN-gamma and IL-6 which can activate caspases and proteases and stimulate cell proliferation. This report looked at Ldlr-/- mice that lack the receptor for LDL which increases in the blood and causes atherosclerosis in mice fed a high fat ‘Western’ diet. The plaques that develop contain MCs. The authors created a double knockout mouse combining the Ldlr-/- mutation with a defective kit gene which prevents maturation of mast cells and found that the plaques were much smaller and had no MCs. Editor’s comment: The reduction in atherogenesis in mice deficient in mast cell production suggests an important link between mast cells, chronic arterial inflammation and plaque formation. Sun J, et al. Nature Medicine (Letters) 2007; 13:719.

5. Lower airways inflammation in allergic rhinitics: a comparison with asthmatics and normal controls.
Allergic rhinitis (AR) is thought to predispose to asthma. The purpose of this paper is to compare lung inflammation in AR subjects with that in asthmatics and healthy controls. This is the first report to compare lower airways for a wide range of variables among these three groups. Lower airway bronchial biopsies were done and examined by histochemical staining and reverse transcriptase-PCR. Biopsies from AR subjects demonstrate increased numbers of eosinophils and mast cells plus increased expression of TNF-alpha relative to controls, but less so than asthmatics. There are no differences among the three groups in numbers of neutrophils, macrophages and CD4+ lymphocytes. IL1-beta and vascular cell adhesion molecule-1 are increased in AR subjects relative to asthmatics and controls. IFN-gamma levels in AR were lower than controls but not as low as in biopsies from asthmatics. Editor’s comment: The inflammatory state of the lung in persons suffering from allergic rhinitis appears to be midway between that of healthy individuals and asthmatics. Brown JL et al. Clin Exp Allergy 2007; 37:688.

6. Human bronchial epithelial cells (HBECs) express an active and inducible biosynthetic pathway for leukotrienes B4 and C4.
Leukotrienes are potent mediators of bronchoconstriction, mucus hypersecretion and attraction of eosinophils and neutrophils. It is thought that the 5-lipoxygenase (5-LO) pathway that generates leukotrienes is restricted to leukocytes such as mast cells, eosinophils, basophils, neutrophils and monocytes, but evidence is presented in this paper showing primary human bronchial epithelial cells (HBECs) also possess a functioning 5-LO pathway. Expression of 5-LO mRNA and protein is demonstrated in HBECs and could be blocked by dexamethasone, while an antibody to 5-LO activating protein prevented production of leukotrienes B4 and C4. Editor’s comment: This finding that HBECs produce LTC4 and LTB4 suggests that they may play a substantial role in the bronchoconstriction and inflammation observed in asthma. Jame AJ, et al. Clin Exp Allergy 2007; 37:880.

7. Montelukast as add-on therapy to β-agonists and late airway response.
The early response of the asthmatic airway to allergens involves primarily bronchoconstriction and responds well to beta-agonist therapy, while the late-phase inflammation is treated effectively with corticosteroids. Leukotriene inhibitors such as montelukast can reduce both early and late allergic responses, but the effects of a single oral dose on late effects after allergen challenge have not been documented. A group of 35 atopic adults with mild asthma were enrolled in a randomized, double-blind, placebo-controlled study of the effects of single-dose montelukast on the allergic reaction to dust mite. After dust mite challenge, subjects received salbutamol once and then were randomized into placebo or montelukast groups. Spirometry was done at baseline and hourly thereafter up to 8 hours post-challenge. Nitric oxide levels in exhaled breath were also measured. Results show that single-dose montelukast after allergen exposure significantly reduces the late allergic response with improved FEV1 and lower NO levels. Editor’s comment: The lack of anti-inflammatory effect of add-on montelukast in this study needs further investigation. Rosewich M et al. Eur Resp J 2007; 30:56.

8. Food Anaphylaxis
Severe reaction to food allergens is one of the commonest causes of anaphylaxis worldwide, especially in children. Most people suffering food-mediated anaphylaxis know the allergen they are sensitive to yet in many cases they are unaware that it was contained in the food they consumed. Education in how to avoid problem allergens is required. This is a state-of-the-art review that describes the clinical features of anaphylaxis, the modifying factors such as asthma, how to distinguish food-induced anaphylaxis from food poisoning and other conditions, the occurrence of biphasic reactions, the problem of lack of reliable diagnostic tests and the best methods for treatment of food-induced anaphylaxis. Editor’s comment: Food allergy is the major cause of emergency room visits for anaphylaxis and rapid differential diagnosis is a critical step in the treatment. Wang J and Sampson A, Clin Exp Allergy 2007; 37:651.

9. Alterations of food antigen-specific serum immunoglobulins G and E antibodies in patients with irritable bowel syndrome and functional dyspepsia.
In this study, IgG and IgE levels together with symptom scores are compared in IBS patients and those with functional dyspepsia (FD) to healthy controls with respect to a panel of 14 common food allergens. Higher food antigen-specific IgG titers were found in IBS and FD subjects than controls, but IgE levels were not significantly different. Those persons with more severe IBS, however, did not show correspondingly higher IgGs than people with mild IBS. The exact cause of the increased IgG in IBS patients has not been identified. Increased mucosal permeability to antigens is one possible explanation, and avoidance of the offending food helps reduce IBS symptoms. Editor’s comment: The authors do not speculate on the potential clinical usefulness of measuring food-specific IgGs as a diagnostic for IBS or FD, but this area should be studied further. Zuo XL et al. Clin Exp Allergy 2007; 37:823 (Editorial: Whorwell PJ, 37:805)

10. Eosinophils (Es): singularly destructive effector cells or purveyors of immunoregulation?
Es with their peroxidase and eosinophil cationic protein are thought of primarily as the classic attackers of helminths and as promoters of inflammation in diseases such as asthma. More recent studies, however, show another side to this cell—that of immunosuppressor and regulator of immune homeostasis. This comprehensive review covers the latest evidence for an essential role of eosinophils in tissue remodeling and repair and immunoregulation. In fact they can even be immunosuppressive by promoting regulatory T cells through expression of IL-10, thymocyte development, lymphocyte chemotaxis, and production of Th1 cytokines, IFN-γ and IL-12. Editor’s comment: The lesson here is that new data on the immune system need to be quickly assimilated and evaluated and that shifts in thinking about the roles of various cells in innate and adaptive immunity may need to be made to keep pace with an evolving model. Jacobsen EA et al. J Allergy Clin Immunol 2007; 119:1313.

11. Macrolides, quinolones and amoxicillin/clavulanate for chronic bronchitis: a meta-analysis.
About half of chronic bronchitis (CB) exacerbations are due to bacterial infection with mortality of 3-6%, so there is a definite need for establishing the best treatment regimen. Antibiotics are proven effective in preventing bacterial exacerbation of CB, but there is no clear consensus about the best choice of antibiotic to use. The emergence of drug-resistant bacterial strains has rendered the first-line agents, amoxicillin, trimethoprim/sulfamethoxazole or doxycycline ineffective in more and more patients. Fewer failures have occurred when quinolones, amoxicillin/clavulanate (A/C) or azithromycin were used. In this meta-analysis, randomized, controlled trials in which macrolides are compared with quinolones, A/C with quinolones or A/C with macrolides were evaluated. Trials in which the three drugs are compared to a different drug or placebo are excluded. All patients enrolled in the trials are at least 18 years old, and drugs were not given prior to the trial nor were any other antibacterial drugs given. There is no difference in outcome between patients treated with quinolones compared to macrolides or amoxicillin/clavulanate compared to quinolones or macrolides, but there is somewhat better microbiological success with quinolones compared to macrolides. Editor’s comment: The results need to be weighed carefully in terms of the statistical strength of the studies, patient stratification and type of antibiotic used. Siempos II et al. Eur Resp J 2007;29:1127.

12. Host resistance to lung infection mediated by major vault protein in epithelial cells.
Resistance to Pseudomonas aeruginosa infection requires expression of the cystic fibrosis transmembrane conductance regulator (CFTR) on airway epithelial cells. This innate immune response is defective in cystic fibrosis patients, most of whom develop P. aeruginosa infections that eventually prove fatal. The CFTRs are associated with lipid rafts on epithelial cells and this report studied the proteins associated with rafts from infected compared to uninfected cells. They found abundant recruitment of the major vault protein (MVP) into rafts from infected wild type epithelial cells but not those in which the CFTR is defective. MVP is strongly expressed in both lung and intestinal epithelium as well as in dendritic cells and macrophages. MVP-knockout mice show an increased lung burden of P. aeruginosa compared to wild type. Editor’s comment: We sometimes forget that the epithelium provides a powerful defense against bacterial invasion, and this study substantiates this important innate immune response. Kowalski MP et al. Science 2007; 317:130.

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