Medical Journal Review
Posted: December 2008
Reviewed by Gary Hellerman, PhD, in collaboration with Richard F. Lockey, MD, WAO Web Chief Editor.
1. NANOPARTICLE-MEDIATED CELLULAR RESPONSE IS SIZE-DEPENDENT
Nanoparticles engineered from a variety of polymers and compounds are being tested as carriers for targeted drug and DNA delivery. This report emphasizes that nanoparticles should not be viewed as inert vehicles, but rather as agents that can be fine-tuned to stimulate their entry into targeted cells to modify a specific cell response. Many important cellular processes such as apoptosis are controlled through cell-surface receptors that interact with specific ligands. Here gold nanoparticles (GNPs) 2 to 100 nm in diameter were coated with various amounts of the ErbB2 ligand herceptin. Entry of the multivalent GNPs into cancer cells and intracellular localization was determined. Greatest uptake occurred with 40-50 nm GNPs, and entry was accompanied by a concomitant increase in cancer cell death. Editor's comment: Therapeutic use of nanoparticles will become more and more widespread as their unique properties are better understood. Jiang W, et al., Nature Nanotech 2008; 3:145.
2. EFFECT OF 17q21 VARIANTS AND SMOKING EXPOSURE IN EARLY-ONSET ASTHMA
An increased risk of asthma is associated with specific DNA variants at the 17q21 locus. Genetic, medical and demographic data from 1511 subjects were examined for correlations with time of asthma onset. Of the 36 single-nucleotide polymorphisms (SNPs) analyzed, 11 were associated with asthma (p<0.01) and 3 were strongly associated (p<0.001). There was almost a 3-fold increase in risk of early-onset (≤4 yr of age) asthma with the strongest effect in subjects exposed to environmental tobacco smoke. There was no association with late-onset asthma. Editor's comment: The fact that chromosome variants can affect early-onset but not late-onset asthma suggests a difference in the pathogenesis of the two disease types. Bouzigon E et al., New Eng J Med 2008; 359:1.
3. SPUTUM EOSINOPHILIA, AIRWAY HYPERRESPONSIVENESS AND AIRWAY NARROWING IN YOUNG ADULTS WITH FORMER ASTHMA
Adolescents often outgrow asthma and appear to be symptom-free as young adults, but may later redevelop the disease. The question is whether those in remission are really disease free. Here, a group of 326 adults (age 21-34) were screened for asthma history and categorized according to those with current physician-diagnosed asthma, those with former asthma and those with no history of asthma. Participants who had been free of symptoms and taken no asthma medication for at least 10 years prior to the study were tested for FEV1, PC20, maximal mid-expiratory flow (MMF) and sputum eosinophilia. The results showed that former asthma patients in remission had significantly lower FEV1, PC20 and MMF and greater eosinophilia than subjects with no history of asthma. In addition, 18% of those with no history of asthma also showed decreased FEV1 and PC20. The long-term prognosis of these subjects needs to be examined. Editor's comment: This investigation brings up the question of whether treatment of symptom-free former asthmatics might prevent the reappearance of asthma. Hara J, et al., Allergology Internatl 2008; 57:211.
4. RAPID EFFECT OF INHALED CICLESONIDE (CIC) IN ASTHMA
The purpose of this clinical trial was to determine how quickly CIC acted to decrease airway hyperresponsiveness (AHR), exhaled nitric oxide and eosinophilia in subjects with mild persistent asthma (FEV1≥70%). In this double-blind, placebo-controlled, crossover study, CIC was administered at 320 µg qd and 640 µg bid. Single doses of CIC gave significant reductions in AHR within 2.5 hr of administration, and there was no drop in serum cortisol and few oropharyngeal adverse events. Editor's comment: The rapid improvement in FEV1 within a few hours of CIC inhalation by subjects with mild asthma is impressive. Erin EM, et al., Chest 2008; 134:740.
5. ADRENAL SUPPRESSION IN BRONCHIECTASIS AND THE IMPACT OF INHALED CORTICOSTEROIDS (ICS)
A potential side effect of ICS is suppression of the hypothalamic-pituitary-adrenal axis resulting in a measurable decrease in serum cortisol. In this study, a group of 50 bronchiectasis patients, 33 of whom were on ICS, were tested for adrenal suppression using the short Synacthen test (SST) and for quality of life by the St George's respiratory questionnaire. Of the patients on ICS, 48.5% had adrenal impairment. These patients were more likely to report fatigue, dizziness, nausea, and vomiting than the non-suppressed group. The authors advocate caution in prescribing ICS for bronchiectasis patients, speculating that the presence of damaged airway walls may enhance systemic drug uptake. The dynamic SST for adrenal insufficiency is simple and effective and should be more widely used to monitor effects of ICS use. Editor's comment: This important finding in patients with bronchiectasis may also be applicable to other inflammatory airway diseases such as COPD and asthma in which ICS are commonly used. Holme J, et al., Eur Resp J 2008; 32:1047.
6. TOLL-LIKE RECEPTOR 4 POLYMORPHISMS AND ASPERGILLOSIS IN STEM CELL TRANSPLANTATION
Patients receiving allogeneic bone marrow transplant therapy are at increased risk of infection by opportunistic pathogens such as Aspergillus. This report looked at polymorphisms in the TLR-2, -3, -4 and -9 genes of the donors in relation to aspergillosis risk in recipients of allogeneic transplants. Only the TLR-4 SNP was a significant risk factor. TLR-4 recognizes bacterial lipopolysaccharide and the variant allele confers weaker immunoresponsiveness that may make an individual more susceptible to aspergillosis. Presence of the TLR-4 SNP in the recipient did not increase the risk. Editor's comment: The finding of a TLR-4 mutation in transplant donors that increases the incidence of aspergillosis in recipients is surprising because TLR-4 recognizes bacterial lipopolysaccharide. This suggests other microbial products may bind to TLR-4. Bochud P-Y et al., New Eng J Med 2008; 359:1766. (editorial: Pamer, pp. 1836)
7. AGEING AND THE IMMUNE SYSTEM
A series of review articles appeared in the August 2008 Current Allergy & Clinical Immunology that focus on the topics of immunosenescence¹, asthma and allergic diseases in the elderly² and inflammation, immunity and Alzheimer's disease (AD)³. As the average age of the world's population increases, the effects of ageing on the body's systems become more and more important. Immunosenescence, the gradual decline in immune response with advancing years is partly due to thymic insufficiency but also in large part to environment, diet, stress, exercise, infections, smoking and other factors that may be controllable. Improved vaccines are one answer to reduced immunocompetence in the elderly, but studies need to be done to define immunoprotective interventions that can be done to prolong the longevity of the immune system. Asthma and rhinitis present special problems in the elderly because of complications in diagnosis, comorbid conditions and potential drug interactions. Immune components of Alzheimer's disease are still being elucidated. Anti-amyloid therapies are being tested but remain experimental. The one characteristic feature tying immune responsiveness to AD, Parkinson's and other neurodegenerative disorders is the inflammatory status. Inflammation in the brain may be affected by age-related immune system changes in the periphery. Editor's comment: Research focused on understanding the ageing process as it relates to the immune system and new ways to intervene prophylactically and therapeutically should be one of the major goals of medical science in this century. ¹Kalula SZ, et al., Curr Allergy Clin Immunol 2008; 21:126-130. ²De Villiers L, et al., 120. ³Combrinck M, et al., 132.
8. ANALYSIS OF SAFETY, RISK FACTORS AND PRETREATMENT METHODS DURING RUSH HYMENOPTERA VENOM IMMUNOTHERAPY (VIT)
VIT is a safe and effective method of inducing tolerance in persons with a history of sting reactions, but severe adverse events (SAEs) do occur. This retrospective study examined records from a single institution of 118 patients with a history of anaphylactic reaction undergoing a 5-day rush VIT and found side effects in 18 (15.2%) with SAEs in 7 (5.9%). The number of reactions was highest on the 4th day (100 µg/ml allergen) and highest among females. All patients received H1 receptor antagonist and 45 also received H2 antagonist. Those pretreated with H1 antagonist alone had fewer systemic effects than those getting both H1 and H2 antagonists. Editor's comment: Rush VIT is less costly and time-consuming than conventional VIT and warrants additional studies to enhance tolerogenesis without causing potentially severe reactions. Gorska L et al., Internatl Arch Allergy Immunol 2008; 147:241.
9. FLUTICASONE PROPIONATE (FP) REDUCES BACTERIAL AIRWAY EPITHELIAL INVASION
COPD patients receiving FP experience less severe bacterial exacerbations but the mechanism is unknown. Both S. pneumoniae (S. p.) and H. influenzae (H. i.) enter bronchial epithelial cells through binding to platelet activating factor receptor (PAFR). PAFR is elevated in the airways of COPD patients. These individuals are also commonly infected with S. p. and H. i. In this study, cultured human epithelial cell lines, A549 and 16HBE14o-, were treated with various doses of FP then challenged with S. p. or H. i. PAFR levels and intracellular bacterial loads were reduced by FP. FP (10 µg/mouse) was also tested on mice prior to inoculation with S. p. and reduced lung colonization nearly 50%. Similar results were obtained when cells or mice were pretreated with a PAFR antagonist rather than FP. Editor's comment: Further studies need to be undertaken to pinpoint the mechanism of FP action on PAFR and to examine long-term effects. Barbier M et al., Eur Resp J 2008; 32:1283.
10. THE SAFETY OF LONG-ACTING β-AGONISTS (LABAs) AMONG PATIENTS WITH ASTHMA USING INHALED CORTICOSTEROIDS (ICS)
Several studies support the claim that LABAs increase mortality in asthma patients, but much of these data come from cases in which ICS were not used regularly in combination with LABAs. In this review, a search was done for blinded, randomized, controlled trials of patients using ICS with or without concomitant LABAs. Analysis of 62 such studies involving over 29,000 participants revealed 3 asthma-related deaths and 2 asthma-related intubations, all among those using LABAs. These numbers were too low to permit statistical analysis. The risk of hospitalization or serious adverse affects was not increased with LABA use in those patients regularly using ICS. Editor's comment: Because of the low incidence of mortality, caution is advised in forming conclusions based on these data in comparison to other published analyses. Jaeschke R et al., Am J Respir Crit Care Med 2008; 178: 1009.
11. ASSOCIATION OF ANGIOTENSIN I-CONVERTING ENZYME (ACE) GENE POLYMORPHISMS WITH ASPIRIN INTOLERANCE IN ASTHMATICS (AIA)
AIA affects 5-10% of asthmatics and is associated with increased leukotriene levels. An additional pathway involving ACE may contribute to AIA. A cohort of 581 Korean asthmatics (81 with AIA) and 181 healthy controls were screened for a panel of mutations in the ACE gene. No correlation between a specific single nucleotide polymorphism (SNP) in the ACE gene and the presence of asthma was seen. Among those with AIA there was a significantly greater frequency of two ACE promoter mutations. AIA patients homozygous for the promoter SNPs showed a larger drop in FEV1 after aspirin challenge than those with the normal alleles. Fusing the mutant promoter sequence to a luciferase reporter resulted in a significant decrease in luciferase activity compared to a normal promoter, which suggests that those who are homozygous for this mutation produce less ACE and may have accumulations of inflammatory mediators that predispose them to AIA. Editor's comment: This new information on genetic susceptibility to AIA may be useful in designing new therapies. Kim T-H et al., Clin Experimental Allergy 2008; 38:1727.
12. DACLIZUMAB (DAC) IMPROVES ASTHMA CONTROL IN PATIENTS WITH MODERATE TO SEVERE PERSISTENT ASTHMA
DAC is a humanized antibody specific for CD25, the IL-2R alpha subunit. DAC blocks binding of IL-2 to its receptor inhibiting subsequent signaling events. In this randomized, double-blind, placebo-controlled multicenter trial, patients with moderate to severe persistent asthma on ICS were switched to an equivalent dose of triamcinolone acetate acetonide (TAA) during the run-in period and given i.v. injections of DAC (90 subjects) or placebo (30 subjects) every 2 weeks during the study. After the first 12 weeks, the TAA dose was tapered 25% every two weeks for 12-20 weeks. Changes in FEV1, frequency and severity of asthma exacerbations, PEF, use of rescue medication and symptom scores were monitored. DAC treatment resulted in significant improvements in FEV1 and daytime symptom scores, decreased use of rescue meds, lower numbers of peripheral eosinophils and reduced eosinophilic cationic protein. The frequency of common adverse events was similar for DAC and placebo groups; however, 5 of 6 patients experiencing severe adverse events were on DAC. Editor's comment: While DAC improved asthma symptoms, the study needs to be repeated to confirm these results and to evaluate the potential safety issues. Busse WW et al., Am J Resp Crit Care Med 2008; 178:1002.
13. THE OBESITY PARADOX IN PATIENTS WITH PERIPHERAL ARTERY DISEASE (PAD)
In contrast to the general population, overweight patients with PAD have lower mortality than underweight patients. This report classified 2392 PAD patients undergoing vascular surgery into groups according to their BMI and whether they had COPD. Death from all causes was the outcome measured and follow-up was from about 2 to 8 ½ years. Nearly 50% of the patients had evidence of COPD. Underweight patients (2.6% of the total) were more likely to have moderate to severe COPD (40% of the group) and to be smokers. COPD was present in 25% of the overweight group and 22% of the obese group. After adjusting for a number of factors, the underweight subjects were 1.42 times as likely as normal weight subjects to die, while the underweight and obese patients were 0.73 and 0.68 times as likely to die, respectively, than normals. This inverse BMI relationship to mortality was eliminated when the data were corrected for COPD severity. Editor's comment: The results of this interesting study suggest that spirometry measurements on PAD patients might be useful for identifying undiagnosed COPD. Galal W et al., Chest 2008; 134:925.