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Archives: Medical Journal Reviews

Medical Journal Review

Posted: March 2011

Reviewed and edited by Dr. Juan Carlos Ivancevich and Dr. Phil Lieberman

1. Clinical and laboratory characteristics of allergic rhinitis and nonallergic rhinitis.
Allergic rhinitis (AR) and nonallergic rhinitis (NAR) are distinguished from one another by the presence of skin test reactivity or allergen specific IgE present in AR, but may have other overlapping clinical and laboratory characteristics. To find additional variables predictive of AR, the authors investigated 1,511 consecutive patients (ages 18-81 years, 56% female) diagnosed with rhinitis. The patients underwent a complete allergic evaluation including skin prick test, blood and nasal eosinophil counts, peak nasal inspiratory flow (PNIF) measurement and evaluation of nasal symptoms using a visual analog scale (VAS). The majority (n = 1,107, 73%) had AR as diagnosed by skin prick test, and 404 (27%) had NAR. AR was associated with higher blood and nasal eosinophil counts, higher PNIF, higher VAS symptoms scores, more sneezing and nasal pruritus, more severe symptoms and recurrent conjunctivitis. Patients with NAR were older and predominantly female and more frequently had nasal obstruction and rhinorrhea, as well as slightly more frequent episodes of recurring headaches and olfactory dysfunction. In a final logistic regression model, 10 variables distinguished AR from NAR: age (odds ratio [OR] 0.97), sneezing (OR 4.09), nasal pruritus (OR 3.84), mild symptoms (OR 0.21), intermittent/severe nasal symptoms (OR 3.66), VAS (OR 1.06), clinical response to antihistamines (OR 22.59), conjunctivitis (OR 4.49), PNIF (OR 1.01) and nasal eosinophil counts (OR 1.14). Receiver operating characteristic analysis showed high predictive accuracy for a model including these variables with a cutoff >0.74, independent of the diagnosis of AR/NAR. These clinical and laboratory parameters may help to reinforce or exclude the diagnosis of AR obtained by skin prick testing.
Editor's comment: Demographic and clinical characteristics in addition to the result of skin prick testing can help distinguish allergic rhinitis from its nonallergic counterpart.
Di Lorenzo G, Pacord ML, Amodioc E et al. Differences and Similarities between Allergic and Nonallergic Rhinitis in a Large Sample of Adult Patients with Rhinitis Symptoms. International Archives of Allergy and Immunology 2011; 155(3):263-270.

2. Bacillus Calmette-Guérin (BCG) vaccination and allergy prevention.
Childhood vaccinations can exert an important early influence on the development of the immune system. BCG induces a T-helper 1 stimulatory effect, which alters cytokine response patterns in such a way that the T-helper 2 immunologic response is inhibited, thus antagonizing atopy. This phenomenon has been demonstrated in both animal models and human subjects. On this basis, it has been postulated that BCG vaccination administered in infancy might have a protective effect against the development of atopic diseases. To investigate this hypothesis, the authors performed a systematic review and meta-analysis of the published studies, assessing the association between BCG vaccination in childhood and the risk of developing allergic sensitization, asthma, eczema/atopic dermatitis, allergic rhinoconjunctivitis, and other allergic conditions. In total, 17 published studies met criteria for inclusion in the final analysis. These included 16 epidemiologic investigations and one randomized controlled trial. Analysis of the pooled data revealed no significant evidence for a protective effect of BCG vaccination against the risk of sensitization, as assessed by serum allergen specific IgE or skin prick tests. Furthermore, there was no significant evidence for a protective effect of BCG vaccination against atopic eczema/dermatitis or allergic rhinoconjunctivitis. However, the team did find evidence for a modest protective effect of BCG vaccination against the risk for developing asthma, but they noted that this was unlikely to be due to the prevention of allergic sensitization and could be explained by publication bias. The authors concluded that preschool BCG vaccination does not reduce the risk of allergic sensitization, atopic eczema, or allergic rhinoconjunctivitis. However, its possible role in reducing the risk of some cases of childhood asthma warrants further investigation.
Editor's comment: There is little evidence to indicate that Bacillus Calmette-Guérin (BCG) vaccination against tuberculosis also protects children against the development of allergic disease.
Arnoldussen DL, Linehan M, Sheikh A. BCG vaccination and allergy: A systematic review and meta-analysis. The Journal of Allergy and Clinical Immunology. 2011; 127(1): 246-253.e21.

3. Antibiotic exposure before 6 months of age and risk of childhood asthma.
Although an association has been reported between antibiotic use and an increased risk of childhood asthma, respiratory tract infections in small children may be difficult to distinguish from early symptoms of asthma. Some studies may therefore have been confounded by ''protopathic'' bias if antibiotics were used to treat respiratory conditions that were in fact early symptoms of asthma. To clarify these issues, the authors examined the association between antibiotic use within the ?rst 6 months of life and asthma and allergy at 6 years of age. Pregnant women were recruited at 71 clinics from 1997 to 2000; the cohort was designed so that 40% of mothers had asthma. Interviews were conducted within 1 month of delivery and again at the child's sixth birthday (±3 months). Children diagnosed with asthma before 6 months of age were excluded from all analyses with asthma as the outcome. Antibiotic exposure before 6 months of age was associated with an increased risk of asthma after 6 months (adjusted odds ratio [OR] 1.52, 95% concidence interval [CI]: 1.07, 2.16) or 3 years (OR 1.66, 95% CI: 0.99, 2.79) of age, and increased exposure increased the risk. In children with no history of lower respiratory infection in the first year of life, the OR was 1.66 (95% CI: 1.12, 3.46), supporting the absence of protopathic bias. The adverse effect of antibiotics was most evident in children with no family history of asthma (OR 1.89, 95% CI: 1.00, 3.58). Early antibiotic use was also associated with positive allergy tests.
Editor's comment: The association of antibiotics with asthma risk should encourage physicians to avoid prescribing antibiotics unnecessarily, particularly in children with no genetic predisposition to asthma.
Risnes KR, Belanger K, Murk W et al. Antibiotic Exposure by 6 Months and Asthma and Allergy at 6 Years: Findings in a Cohort of 1,401 US Children. American Journal of Epidemiology 2011; 173(3): 310-318.

4. Intranasal corticosteroids for the ocular symptoms of allergic rhinitis.
Allergic rhinitis is frequently accompanied by ocular symptoms of tearing, itching, and redness in addition to nasal symptoms. Intranasal corticosteroids (INCS) may be effective at treating both ocular and nasal symptoms. To assess the efficacy of INCS for ocular symptoms of allergic rhinitis, the authors performed a systematic review of randomized trials published in English from 1973 to 2009 that included "intranasal corticosteroid," "allergic rhinitis," "ocular symptoms," "allergic conjunctivitis," and "rhinoconjunctivitis" as key words. Quality of the 32 eligible studies was assessed using the Jadad score (maximum score, 13). Continuous data were analyzed statistically by weighted mean difference or standardized mean difference. The studies were separated into three different groups depending on whether they examined individual eye symptoms, a total ocular symptom score, or both. The overall weighted mean obtained from the Jadad score was 9.29 (95% CI, 8.7-9.88). For studies reporting both total OS scores and individual symptoms (10 studies), the weighted mean was 10.17 (95% CI, 9.34-11). For studies reporting only individual symptoms (nine studies), the weighted mean was 10.09 (95% CI, 9.55-10.63). For studies reporting total eye symptom scores but no individual symptoms (13 studies), the weighted mean was 8.56 (95% CI, 7.66-9.46). These studies support the efficacy of INCS for treating the ocular symptoms of allergic rhinitis.
Editor's comment: Clinical studies show that intranasal corticosteroids have a positive impact on the ocular symptoms of allergic rhinitis.
Hong J, Bielory B, Rosenberg, JL et al. Efficacy of intranasal corticosteroids for the ocular symptoms of allergic rhinitis: A systematic review. Allergy and Asthma Proceedings 2011; 32(1): 22-35.

5. Autoinactivation of human 5-lipoxygenase.
Leukotrienes and lipoxins are metabolic products of arachadonic acid (AA). Both play important roles in the inflammatory response that occurs from AA metabolism. The synthesis of both proinflammatory leukotrienes and anti-inflammatory lipoxins requires the enzyme 5-lipoxygenase (5-LOX). When leukocytes are activated, AA is released from the nuclear membrane and 5-LOX is translocated to the nuclear membrane, where the two interact. 5-LOX activity is short-lived, apparently in part because of an intrinsic instability of the enzyme. This loss of activity may limit the synthesis of its pro- and anti-inflammatory products. By comparison with LOX homologs that are more stable, the authors identified a 5-LOX-specific sequence that is responsible for destabilizing the enzyme. This sequence is involved in orienting the carboxyl terminus, which binds the catalytic iron. Replacing it with the corresponding sequence from 8R-LOX creates a stable 5-LOX mutant amenable to crystollographic analysis. These structural studies revealed that the active site of 5-LOX is distinct from that of its homologs.
Editor's comment: Knowledge of the 5-LOX structure and how it regulates the activity of the enzyme could guide the development of 5-LOX-specific inhibitors.
Gilbert NC, Bartlett SG, Waight MT et al. The Structure of Human 5-Lipoxygenase. Science 2011; 331(6014): 217-219.

6. Link between skin integrity and the susceptibility to asthma.
Eczema (atopic dermatitis) frequently precedes airway diseases such as asthma and allergic rhinitis-the so-called "atopic march." This short review discusses possible mechanisms linking epicutaneous sensitization with airway diseases. Genetic studies have implicated a number of molecules in the pathophysiology of eczema, and the best understood is filaggrin. Filaggrin is required for the maintenance of the skin barrier; mutations in filaggrin are strongly associated with asthma accompanied by eczema and also affect the severity of asthma. Another asthma-susceptibility gene, ORMDL3, may also play a role in the integrity of the skin barrier. In the absence of altered barrier functions, a "danger signal" such as a protease, adjuvant, or mechanical damage to the skin may be necessary for sensitization. Once epicutaneous sensitization has occurred, airway responses are mediated by Th2 cytokines, CCR3 chemokines, STAT6 signaling, and, most importantly, a Th17-type response. Thymic stromal lymphopoietin release from the skin may also lead to Th2-mediated airway hyper-responsiveness.
Editor's comment: Excellent review describing updated genetic and immunological evidence that support a relationship between skin barrier-related molecules and the pathology of asthma.
Suzuki Y, Kodama M, Asano K. Skin barrier-related molecules and pathophysiology of asthma. Allergology International 2011; 60(1):1-5.
Full Text PDF, Open Access

7. Diagnosing hypersensitivity to quinolones.
Immediate hypersensitivity reactions to quinolone antibiotics have been reported, but diagnostic tests to verify these reactions are controversial. Skin testing can produce false-positive results, and drug provocation tests can be dangerous in patients who have anaphylactic reactions. In vitro measures of specific IgE responses are therefore needed. This study evaluated the sensitivity and specificity of two in vitro tests, a Sepharose radioimmunoassay (RIA) and a basophil activation test (BAT). Thirty-eight patients with confirmed immediate allergic reactions (anaphylaxis, anaphylactic shock, or urticaria) to quinolones and 35 controls with known tolerance of quinolones were included. The quinolines involved were moxifloxacin (N=24), ciprofloxacin (N=11) and levofloxacin (N=3). All samples (blood or serum) were tested with each of the quinolones. Of the patient samples, Sepharose-RIA was positive in 12 cases (31.6%) and BAT in 27 (71.1%). Sepharose-RIA showed similar positive rates to all 3 quinolones, but with BAT, 23 (60.5%) were positive to ciprofloxacin, 12 (31.6%) to moxifloxacin and 8 (21%) to levofloxacin. BAT was positive in 3 of 25 control samples (12%) and Sepharose-RIA in none. The specificity of the Sepharose-RIA was demonstrated by inhibition tests. The reactions were confirmed to be mediated by IgE by using the PI3K inhibitor wortmannin, which inhibited the BAT when anti-IgE, but not fMLP, was used as the basophil stimulator in combination with the various quinolones. Sepharose-RIA and BAT were repeated in positive samples 1 year later. In all cases, the response was lower than in the original measurement, and four became negative, demonstrating IgE clearance.
Editor's comment: Immediate hypersensitivity reactions to quinolones do exist, and the basophil activation test may be a useful, and safe, method for diagnosing quinolone allergy.
Aranda A, Mayorga C, Ariza A, et al. In vitro evaluation of IgE-mediated hypersensitivity reactions to quinolones. Allergy 2011; 66(2): 247-254.

8. The role of osteopontin (OPN) in human asthma.
OPN is a cytokine that mediates cell adhesion, migration and survival. It is produced by most cells of the immune system, including T cells, B cells, macrophages, neutrophils, eosinophils, natural killer cells, and mast cells, as well as structural cells, such as fibroblasts, and smooth muscle and epithelial cells. Increased OPN expression has been observed in a number of T-helper 1-mediated lung diseases, including granulomatous diseases and pulmonary fibrosis, and some evidence suggests it also contributes to T-helper-2-linked inflammation. To investigate the role of OPN in asthma, the team studied serum samples collected from 35 patients with mild-to-moderate (MMA) asthma and 19 with severe asthma (SA) during exacerbations (n = 17) and while stable, as well as from 17 healthy controls. Of these, 29 stable asthma patients and nine controls also underwent bronchoscopy with bronchoalveolar lavage fluid (BALF) collection. Overall, asthma patients had significantly higher mean serum OPN levels than controls, at 47.92 versus 20.25 ng/mL, with no significant differences between MMA and SA patients. Among asthma patients, mean serum OPN levels were significantly lower during exacerbations than when stable, at 50.33 versus 58.97 ng/mL. OPN levels were also significantly increased in the BALF of asthma patients compared with that of controls, at 1.108 versus 0.746 ng/mL. Biopsy sample analysis revealed that bronchial epithelial and subepithelial cells expressed significantly more OPN in asthma patients (40% and 21%, respectively) than in controls (5% and 2%, respectively). OPN expression by subepithelial infiltrating cells was also higher in asthma patients than in controls, with SA patients exhibiting significantly higher OPN expression than MMA patients. The researchers also found that, in asthma patients, OPN expression in the bronchial epithelium, and especially the subepithelium, correlated inversely with FEV1. In addition, OPN expression correlated with reticular basement membrane thickness, which was increased in patients with asthma, and more so in patients with SA than MMA. OPN expression in human asthma is thus associated with remodeling changes and correlates with disease severity.
Editor's comment: OPN levels are increased in patients with asthma, and subepithelial OPN expression in the airways is associated with asthma severity.
Samitas K, Zervas E, Vittorakis S et al. Osteopontin expression and relation to disease severity in human asthma. The European Respiratory Journal 2011; 37(2): 331-341.

9. Mechanisms of Streptococcus pneumoniae resistance.
Streptococcus pneumoniae is a major human pathogen that easily undergoes recombination and transformation. The S. pneumoniae population is becoming increasingly resistant to antibiotics due to the spread of a few multi-drug-resistant clones, but epidemiological studies have been hampered by the difficulty in distinguishing mutations arising through direct lineage from those arising through horizontal transfer. This study characterized 240 strains of Pneumococcoal Molecular Epidemiology Network clone 1 (PMEN1), a multi-drug-resistant clone originally of serotype 23F that was isolated in Spain in 1984 and has spread worldwide. Recombination events were analyzed separately from base substitutions. Recombination had occurred more than 700 times, including 10 capsule-switching events and recombination of potential targets of protein vaccines. Other strains expanded after dominant strains were eliminated by the seven-valent pneumococcal conjugate vaccine. Drug resistance, particularly to macrolides, appeared to have arisen multiple times independently. Thus, this single lineage has repeatedly evaded vaccine pressure and acquired drug resistance over a relatively short time span.
Editor's comment: Understanding how populations of pathogenic bacteria respond to vaccine and antibiotic pressure will be necessary for developing effective control measures.
Croucher NJ, Harris SR, Fraser C et al. Rapid Pneumococcal Evolution in Response to Clinical Interventions. Science 2011; 331(6016): 430-434.

10. MeDALL (Mechanisms of the Development of ALLergy)
Allergic diseases arise from a complicated mix of genetic, epigenetic and environmental factors. The newly formed MeDALL consortium aims to provide an integrated, multidisciplinary approach to understanding how these factors produce complex allergic phenotypes. Experts in allergy, epidemiology, allergen biochemistry, immunology, molecular biology, epigenetics, functional genomics, bioinformatics and computational and systems biology will collaborate to gain understanding of the mechanisms of allergy initiation, which will be used to develop methods for early diagnosis and prevention and to identify therapeutic targets. The consortium will leverage existing European birth cohorts to identify classical and novel phenotypes of IgE-associated allergic diseases for further analysis. These phenotypes will then be used to guide collection of additional data from the cohorts in 2012-2013, when the participants will be 4 to 18 years old, for use in mechanistic studies, including characterization of allergens, epigenetic and proteomic research, transcriptomic and systems biology approaches, in vitro studies of human immunologic responses and experiments in animal models. After validation of any mechanisms identified, the findings will be used to develop clinical applications. A uniform definition of severe allergic diseases will also be proposed.
Editor's comment: The results of the MeDALL program will help to improve early diagnosis, to target primary and secondary prevention strategies and to develop novel, cost-effective treatments for allergic disorders.
Bousquet J, Anto J, Auffray C et al. MeDALL (Mechanisms of the Development of ALLergy): an integrated approach from phenotypes to systems medicine. Allergy 2011 [Published online before print. doi: 10.1111/j.1398-9995.2010.02534.x]
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11. Asthma endotypes.
Patients with asthma present with a range of symptoms, severities and responses to treatment. Whether asthma is a single disease with variable presentations or several diseases with overlapping signs and symptoms is still a matter of debate. The authors propose that asthma is actually a collection of "endotypes", or distinct disease entities, each with a defining etiology or pathophysiological mechanism. Endotypes could potentially be identified as clusters arising from clinical features, physiology, immunology, pathology, genetics, response to treatment, and other disease components. As a preliminary attempt to identify endotypes, the authors selected seven parameters (clinical characteristics, biomarkers, lung physiology, genetics, histopathology, epidemiology and treatment response) and specified that each endotype should be defined by at least five. As examples, six endotypes were proposed: aspirin-sensitive asthma, allergic bronchopulmonary mycosis, allergic asthma (adult), asthma-predictive-indices-positive preschool wheezer, severe late-onset hypereosinophilic asthma and asthma in cross-country skiers. The authors stress that much more needs to be learned about potential endotypes and the mechanisms underlying them, but this approach could lead to more appropriate clinical trials, identification of new biomarkers and better mechanism-specific treatments.
Editor's comment: Using the concept that asthma is a syndrome consisting of several endotypes to understand disease processes is likely to be challenging, but could lead to mechanism-specific treatments.
Lötvall J, Akdis CA, Bacharier LB et al. Asthma endotypes: A new approach to classification of disease entities within the asthma syndrome. The Journal of Allergy and Clinical Immunology 2011; 127(2): 355-360.

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