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Archives: Medical Journal Reviews

Medical Journal Review

Posted: July 2009

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

1. Exploring the association between severe respiratory syncytial virus (RSV) infection and asthma (A).
Does RSV cause A, or do those infants who later develop A have a genotype that both predisposes them to A and makes them more susceptible to severe RSV infection? That question is explored in this population-based study of hospitalization data from all Danish twins born alive between 1994 and 2000 (8280 twin pairs). The diagnosis of RSV infection was based on hospital diagnosis and/or RSV identification by ELISA. Presence of A was assessed by hospital discharge diagnosis and parental questionnaire. Among the children with RSV infections, 50% were hospitalized before the age of 6 mo and 75% before 12 mo. 95% had been hospitalized before 24 mo. Twins hospitalized for RSV were more likely to have A. The data were subjected to statistical analysis and direction of causation (DOC) modeling. Monozygotic twins showed a higher correlation for A than dizygotic twins, suggesting a genetic component in disease susceptibility; but for RSV there was no such correlation, meaning that environmental factors play a larger role. When data were fitted to a DOC model, it was found that the best fit occurred for RSV infection resulting from the underlying susceptibility to A rather than vice-versa.
Editorís comment: These data support the concept that RSV is associated with but does not cause A implying unknown genetic factors are involved.
Thomsen SF et al., Am J Resp Crit Care Med 2009; 179:1091-1097. Also see editorial by Kuehni and Silverman, pp. 1079-80 (Abstract not available online)

2. Urine concentrations of cysteinyl leukotrienes (CysLTs) in children with obstructive sleep-disordered breathing (SDB).
Adenotonsillar tissue from children (C) with SDB shows high levels of CysLTs and their receptors that may contribute to this disorder. C with SDB were compared to C with no evidence of SDB but with a history of recurrent tonsillitis. Subjects with asthma, respiratory tract infection or chronic inflammatory disorders were excluded along with those using antihistamines or intranasal corticosteroids. An obstructive apnea-hypopnea index (OAHI) was determined by overnight polysomnography and tonsillar size graded. Morning urine samples were assayed for CysLTs. A total of 92 C were enrolled and results were evaluated according to OAHI. C with OAHI ≥5 episodes/hr had significantly higher urine CysLT levels than those with mild or no SDB. Higher BMIs and larger tonsils were also predictors of SDB. These data support the hypothesis that SDB is associated with inflammation as well as anatomical factors, but whether the SDB is more severe because of the increased CysLTs or severe SDB causes an increase in CysLTs cannot be determined.
Editorís comment: This study suggests that there is a link between SDB and inflammation.
Kaditis AG et al., Chest 2009; 135:1496-1501.

3. Venom immunotherapy (VIT) reduces large local reactions (LLRs) to insect stings.
LLRs to Hymenoptera occur in 10% of adults and have significant effects on QOL, often requiring oral corticosteroids. This 4 yr controlled pilot study was performed to determine the effectiveness of VIT in reducing the severity of LLRs. Enrollees had a history of LLRs and skin sensitivity to venom. Those with previous sting anaphylaxis were excluded. A baseline sting challenge was performed at entry and only those with skin induration of at least 16 cm were included. 19 subjects (there were 10 untreated controls) achieved a maintenance dose in 7 weeks. Sting challenges were administered and patients recorded the size of induration at 1, 12, 24, and 48 hr after the sting. No additional medications (e.g., antihistamines) were allowed until 48 hr after the sting. The size and duration of LLRs decreased significantly with increasing time of VIT. Patient satisfaction was >90%.
Editorís comment: Several studies now indicate that VIT is effective to treat LLRs induced by Hymenoptera stings.
Golden DBK et al., J Allergy Clin Immunol 2009; 123:1371-1375.

4. Overweight and changes in weight status during childhood in relation to asthma (A) symptoms at 8 years.
A symptoms in relation to body mass index (BMI) were assessed at 3, 6 and 8 yrs in a group of 3756 children in a birth cohort. Yearly questionnaires were returned by parents reporting the childís weight and height and whether they had A symptoms- wheeze and/or dyspnea and/or a prescription for inhaled corticosteroids in the previous year. At age 8, a subgroup of children gave a blood sample analyzed for a panel of specific IgE. Bronchial hyperresponsiveness (BHR) also was determined. A high BMI at an earlier age was not associated with dyspnea in children who were at normal weight at 8 yr. Eight year-old children who had A symptoms and BHR were significantly more likely to have had a high BMI at 6-7 yr but not at earlier ages. IgE levels did not correlate with BMI.
Editorís comment: High BMIs in children at certain ages may be associated with the onset of asthma and BHR.
Scholtens S, et al., J Allergy Clin Immunol 2009; 123:1312-1318. Also see editorial by Schwartzstein and Gold, pp. 1319-20.

5. Work group report: oral food challenge (OFC) testing.
This document is a comprehensive, practical guide to administering an OFC. The criteria for deciding when to conduct an OFC and the risk/benefit analysis are discussed with guidelines for skin-prick and serum IgE testing. The different types of OFCóopen, single-blind, placebo-controlled and double-blind are described. An open OFC may be done for simple screening while the more rigorous DBPC is primarily for research. An OFC procedure form and flow sheet are included.
Editorís comment: This is a practical and highly useful document about OFC.
Nowak-Wegrzyn et al., J Allergy Clin Immunol 2009; 123 (suppl):S365-383.

6. Reparative capacity of airway epithelium impacts deposition and remodeling of extracellular matrix (ECM).
Defective repair of damaged epithelium is linked to fibrosis and remodeling in chronic lung disease. This mouse-model study focuses on the interactions between epithelial repair systems and the regulation of ECM deposition and fibrosis. Epithelial lesions were produced by intraperitoneal injection of naphthalene and mice were examined from 0 (control) to 6 days afterwards. In repair-competent mice exposed to naphthalene, a specific phenotypic signature was seen representing airway repair, cell proliferation and ECM regulation. The ECM protein, tenascin C (Tnc), was transiently up-regulated in naphthalene-challenged wild type mice but returned to normal following epithelial repair. In mice deficient in epithelial repair cells, however, lung damage led to a significant and sustained increase in Tnc and uncontrolled matrix deposition. Lack of repair of damaged epithelium led to an accumulation of Tnc protein in the sub-epithelial mesenchyme of airways and alveoli.
Editorís comment: This study sheds additional light on the possible role of epithelial repair cells and Tnc in airway remodeling.
Snyder JC et al., Am J Resp Cell Mol Biol 2009; 40:633-642.

7. T-bet expression is regulated by EGR1-mediated signaling in activated T cells.
T-bet is a transcription factor that polarizes T cell development along the Th1 pathway and suppresses Th2-type cytokine production and stimulates expression of IFN-gamma and the IL-12 receptor. Regulation of T-bet production by early growth response gene 1 (EGR1) was studied in this report using human B and T cell lines and T cells isolated from mice. EGR1 binds to the gene promoter for T-bet in T cells and activates its expression, while depletion of EGR1 in T cells prevents induction of T-bet. NaÔve CD4+ T cells, isolated from mice and activated by antigen-presenting cells under Th0, Th1 or Th2 conditions, shows concomitant expression of EGR1 and T-bet in Th0 and Th1 cells but not Th2.
Editorís comment: EGR1 appears to be a key upstream regulator of T-bet expression.
Shin H-J et al., Clin Immunol 2009; 131:385-394.

8. Increases in urinary 9α,11β-prostaglandin F2 indicate mast cell activation in wine-induced asthma.
Wine-sensitive individuals can experience asthmatic symptoms after wine consumption. 8 participants with self-reported wine sensitivity were tested with high- and low-sulfite wines given double-blind. As primary outcome, urinary 9α,11β-prostaglandin F2 (a metabolite of prostaglandin D2, PGD2) was measured before and after consumption. With high-sulfite wines versus low-sulfite wines, the 9α,11β-prostaglandin F2 level increased 1.6- and 1.5-fold, respectively, demonstrating that sulfites probably are not linked to the asthmatic symptoms of wine consumption. PGD2 is elevated as a result of mast cell activation and urinary 9α,11β-prostaglandin F2 is currently the most sensitive indicator of degranulation. It is more likely that IgE-indpendent activation of mast cells occurs based on clinical characteristics of these subjects.
Editorís comment: The reasons why wine may exacerbate asthma remain a mystery.
Misso NLA et al., Int Arch Allergy Immunol 2009; 149:127-132.

9. Desensitization in interferon-β1α (IFN-b) allergy: a case report.
IFN-b is the standard Rx for relapsing-remitting multiple sclerosis (MS), but an immune response to the drug can occur preventing treatment. A 41-year-old female with MS diagnosed 15 months earlier presented with urticaria and angioedema after s.c. IFN-b. Urticaria and pruritus, not associated with the injection site, appeared after the first month of Rx and grew progressively worse until periorbital and perioral angioedema developed and the IFN-b was stopped. The urticaria cleared immediately with no relapse. Skin-prick and intradermal tests with IFN-b were positive for 1:1 and =1:1000 dilutions, respectively. A desensitization schedule with incremental alternating s.c. IFN-b injections every 30 min over a period of 4 days was performed. Desensitization was successful and the patient resumed IFN-b Rx 3X/wk with no adverse effects.
Editorís comment: This is a quick and simple desensitization procedure for immediate hypersensitivity to IFN-b.
Kalpaklioglu AF et al., Int Arch Allergy Immunol 2009; 149:178-180.

10. Inhibition of non-neuronal α7-nicotinic acid receptor for lung cancer treatment.
Non-small cell lung cancer (NSCLC) tumorigenesis appears to involve nicotinic acetylcholine receptors (nAChRs). The effect of blocking the α7-nAChR with alpha-cobratoxin (α-CbT) was investigated on various human lung tumor cells and in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice engrafted with NSCLC cells. The proliferation of tumor cells in vitro was inhibited by α-CbT compared to normal bronchial epithelial cells and the degree of inhibition was proportional to the density of α7-nAChRs on the tumor cells. For the in vivo evaluation of α7-nAChR inhibition, NSCLC cells were injected into the lungs of NOD/SCID mice, allowed to grow for 7 days, after which they were treated with vehicle control, cisplatin (lung cancer chemotherapeutic agent) or α-CbT (i.v. injection 3 times/wk for 3 wks). The endpoint was length of survival from time of injection of the cells. Cisplatin improved survival 16% relative to controls, while treatment with α-CbT resulted in survival, 80% higher than cisplatin and 93% than controls. Assays on tumor cells from α-CbT-treated mice showed >80% apoptosis.
Editorís comment: This treatment offers promise as a way to slow the progression of NSCLC.
Paleari L, et al., Am J Resp Crit Care Med 2009; 179:1141-1150. Also see editorial by ER Spindel, pp. 1081-82 (Abstract not available online)

11. Bronchial airway epithelial cell damage following exposure to cigarette smoke (CS) includes disassembly of tight junction (TJ) components mediated by the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway.
CS is a mixture of many chemicals that have a variety of effects on airway epithelial cells, including changes in signaling pathways, such as those involving epidermal growth factor receptor (EGFR) and ERK1/2. CS condensate (CSC) was prepared by collecting CS particulates on a filter and dissolving the filtrate in cell culture medium. Cultured normal human bronchial epithelial cell lines were incubated with various concentrations of CSC and the effects on TJs, cytotoxicity, DNA integrity and ERK1/2 signaling were measured. CSC caused disassembly of tight junctions in a time- and dose-dependent manner. Decreased cell proliferation was seen only at the highest dose of CSC (20%) but apoptosis was seen at 10% and 20% CSC. Preincubation of cells with EGFR inhibitor blocked CSC activation of the ERK1/2 pathway and prevented both DNA fragmentation and disassembly of TJs.
Editorís comment: This in vitro evidence of ERK1/2 involvement in TJ damage warrants further study in animal models.
Petecchia L et al., Chest 2009; 135:1502-1512.

12. Acid-suppressive medication use and the risk for hospital-acquired pneumonia.
Use of proton pump inhibitors (PPIs) or histamine-2 (H2) receptor blockers for controlling acid reflux has increased and are being given routinely to many hospital inpatients. All patients ≥18 yr of age admitted to a large metropolitan hospital with a stay of 3 or more days were eligible for inclusion in this prospective cohort study. Admission to ICU was excluded. The primary outcome scored was a discharge diagnosis of pneumonia and the final cohort included 63,878 subjects. Use of acid-suppressing drugs (82% PPIs, 23% H2 blockers, and some both) was ordered for 52% of the patients and use of PPIs (but not H2 blockers) was associated with a 30% increase in the odds of having pneumonia while in the hospital.
Editorís comment: Proton pump inhibitors may increase the risk for both inpatient and outpatient pneumonia.
Herzig SJ et al., JAMA, 2009; 301(20):2120-2128.

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