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Archives: Medical Journal Reviews

Medical Journal Review

Posted: December 2009

Reviewed by Juan Carlos Ivancevich, MD, in collaboration with Phil Lieberman, MD.

1. Identification of asthma phenotypes (AP) using cluster analysis in the severe asthma research program (SARP).
To identify novel AP using an unsupervised hierarchical cluster analysis of the SARP cohort that includes subjects with persistent asthma, the authors reduced an initial 628 variables to 34 core variables by elimination of redundant data and transformation of categorical variables into ranked ordinal composite variables. They performed a cluster analysis on 726 subjects who met the American Thoracic Society (ATS) definition of severe asthma. Five groups were identified. Cluster 1 (n=110) had early onset atopic asthma with normal lung function treated with ≤ 2 controller medications (82%) and minimal health care utilization. Cluster 2 (n=321) were subjects with early onset atopic asthma and preserved lung function but increased medication requirements (29% on ≥ 3) and health care utilization. Cluster 3 (n=59) was a unique group of mostly older obese women with late onset nonatopic asthma, moderate reductions in FEV1 and frequent oral corticosteroid use. Clusters 4 (n=120) and 5 (n=116) had severe airflow obstruction with bronchodilator responsiveness, but they differed with regards to their ability to attain normal lung function, age of asthma onset, atopic status, and use of oral corticosteroids.
Editor's comment: These data support clinical heterogeneity in asthma and the need for new approaches for the classification of disease severity.
Moore WC, Myers DA, Wenzel SE et al. Identification of Asthma Phenotypes using Cluster Analysis in the Severe Asthma Research Program. American Journal of Respiratory and Critical Care Medicine 2009; published ahead of print on November 5.

2. The association between allergy skin testing (AST), atopic respiratory conditions (ARC), and stroke mortality in middle-aged and elderly adults.
An analysis was performed of the National Health and Nutrition Examination Survey II Mortality Cohort to determine whether positive AST was associated with an increased risk of fatal stroke and having both positive AST and an ARC was associated with a particularly high risk of stroke-related death. The authors found that patients with positive AST had a hazard ratio for stroke mortality of 1.56 versus those without. Patients with both positive AST and an ARC had a hazard ratio for stroke mortality of 2.31. Individuals with both positive AST and an ARC have more than a 2-fold increased risk of fatal stroke.
Editor's comment: This novel risk factor has substantial implications for a large segment of the population not previously considered at risk.
Matheson EM. Mainous AG, Carnemolla MA. The Association Between Allergy Skin Testing, Atopic Respiratory Conditions, and Stroke Mortality in Middle-Aged and Elderly Adults, The Journal of the American Board of Family Medicine 2009;22(6):604 -609.
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3. Food allergy (FA) among children in the United States.
An analysis of previously published cross-sectional surveys of data on food allergy in children < 18 years of age was performed. Five previously reported surveys were reviewed. In 2007, 3.9% of US children < 18 years of age had reported FA. The prevalence of reported FA increased 18% from 1997 through 2007. In 2005-2006, specific Immunoglobulin E (IgE) to peanut was detectable for 9% of US children. Ambulatory care visits tripled between 1993 and 2006. From 2003 through 2006, there were an estimated average of 317,000 FA-related, ambulatory care visits per year. Hospitalizations with any recorded diagnoses related to FA also increased between 1998-2000 and 2004-2006, from 2,600 to 9,500 discharges per year.
Editor's comment: Food allergy prevalence and/or awareness have increased among US children in recent years.
Branum AM and Lukacs SL. Food Allergy Among Children in the United States, Pediatrics 2009;124(6):1549-1555.

4. The minimal clinically important difference (MCID) in allergic rhinitis (AR).
In the presentation of results from clinical measurements or research findings, the MCID illustrates the relationship between the outcome measures and the patient's perception of change, by calculating the smallest change in a given outcome measurement that is meaningful to a patient. To calculate MCIDs for common subjective and objective outcome measures in allergic rhinitis (AR), the authors analyzed nine randomized, blinded, placebo-controlled clinical trials in intermittent and persistent AR (pooled subjects, n=204) using anchor- and distribution-based approaches, applying regression and meta-analysis techniques. MCIDs were obtained for the Mini Rhinoconjunctivitis Quality of Life Questionnaire, peak nasal inspiratory flow, total nasal symptoms score, and nasal nitric noxide (NO). The MCIDs for each variable were: 0.4 units for the Mini Rhinoconjunctivitis Quality of Life Questionnaire; 5L/minute for the nasal inspiratory flow; and 0.55 units for the total nasal symptom score. There was no correlation between nasal NO measurements and the patients' perception of benefit.
Editor's comment: Taking into account these data we can begin to employ objective measures that will be likely to correlate with our patients' subjective sense of improvement.
Barnes ML, Vaidyanathan S, Williamson PA et al, The Minimal Clinically Important Difference in Allergic Rhinitis. Clinical & Experimental Allergy 2009; published online ahead of print 5 November.

5. Glucocorticoid (GC) use and risk of atrial fibrillation (AF) or flutter (F).
The authors identified all patients with a first hospital diagnosis of AF or F from January 1, 1999 through December 31, 2005, in Northern Denmark. For each case they selected 10 population controls and obtained data on GC prescriptions within 60 days (current users) or longer before (former users), comorbidities, and medications from medical databases. Among 20,221 patients with AF or F, 1,288 (6.4%) were current GC users and 2,375 (11.7%) were former users. Among 202,130 population controls, 5,245 (2.6%) were current GC and 19,940 (9.9%) were former users. Current GC use was associated with an increased risk of AF or F compared with never used (OR, 1.92). Among new GC users, the OR was 3.62 and among long-term users it was 1.66. Former GC use was not associated with increased risk (OR, 1.00).
Editor's comment: Glucocorticoid use is associated with an almost 2-fold increased risk of atrial fibrillation or flutter.
Christiansen CF, Christensen S, Mehnert F et al, Glucocorticoid Use and Risk of Atrial Fibrillation or Flutter, A Population-Based, Case-Control Study. Archives of Internal Medicine 2009;169(18)1677-1683.

6. Establishing the sequential progression of multiple allergic diagnoses in a UK birth cohort using the General Practice Research Database.
To study the sequential progression of multiple allergic conditions throughout childhood in a national birth cohort, the authors constructed a birth cohort of 43,477 children born in 1990 and registered in United Kingdom (UK) general practices within a year of birth. 24,112 children with complete follow-up until 18 years of age were studied in order to understand disease progression and to estimate the absolute and relative risks (RR) of developing second and third allergic diagnoses following an index allergic condition. 52.1% of the children were diagnosed with at least one condition. Eczema (E) was the most likely index condition with 60.7%. For those with a diagnosis of E, the RR of being diagnosed with asthma (A) followed by rhinitis (R), and R followed by A, were 1.59 and 0.54. For those diagnosed with A first, the RR of being diagnosed with E followed by R, and R followed by E, were 1.0 and 0.27. For those diagnosed with R first, the RR of being diagnosed with E followed by A, and A followed by E, were 0.64 and 0.47.
Editor's comment: The most common trajectory of "the allergic march" is the diagnosis of eczema followed by asthma.
Punekar YS and Sheikh A, Establishing the Sequential Progression of Multiple Allergic Diagnoses in a UK Birth Cohort Using the General Practice Research Database. Clinical & Experimental Allergy 2009;39(12):1889-1895.

7. Hypersensitivity and oral tolerance in the absence of a secretory immune system.
To assess the effect of a lack of secretory antibodies on the production of mucosally induced tolerance against food antigens, the authors used polymeric Ig receptor (pIgR) knockout (KO) mice, which cannot export SIgA or SIgM, to study the effect of the absence of secretory antibodies on the induction of oral tolerance and immediate hypersensitivity. They found that a remarkable systemic hyperreactivity was observed in pIgR KO mice, as 50% died after intradermal OVA challenge. Oral tolerance induced by OVA completely protected the sensitized pIgR KO mice against anaphylaxis and suppressed antibody levels (particularly IgG1) as well as delayed-type hypersensitivity (DTH) to OVA. This effect was largely mediated by CD25+ T cells.
Editor's comment: The defective secretory antibody-mediated immune exclusion requires compensatory regulatory T-cell function to avoid the potentially catastrophic effects of systemic immune hyperreactivity.
Karlsson MR, Johansen F.-E, Kahu H et al, Hypersensitivity and Oral Tolerance in the Absence of a Secretory Immune System. Allergy 2009; published ahead of print 3 November.

8. Levels of nitric oxide oxidation products are increased in the epithelial lining fluid (ELF) of children with persistent asthma.
The authors of this study obtained bronchial lavage fluid from asthmatic children of varying severity and non-asthmatic children and non-smoking adults to assay nitric oxide (NO) oxidation products (nitrate, nitrate and nitrotyrosine). The collected fluid was divided into proximal and distal portions. They evaluated 15 children with mild-to-moderate asthma, 30 with severe allergic asthma, 5 non-asthmatic, and 20 nonsmoking adults. They found that children with mild-to-moderate and severe allergic asthma had increased concentrations of NO oxidation products in the proximal ELF. Similar results were seen in the distal ELF, although the concentrations were significantly lower. The multivariate analyses revealed F(ENO) values to be a significant predictor of NO oxidation in asthmatic children.
Editor's comment: NO oxidation products are increased in the ELF of asthmatic children.
Fitzpatrick AM, Brown LAS, Holguin F et al, Levels of Nitric Oxide Oxidation Products Are Increased in the Epithelial Lining Fluid of Children with Persistent Asthma. The Journal of Allergy and Clinical Immunology 2009;124(5):990-996.e9

9. Variability in the prevalence of premenstrual asthma (PMA).
To analyze the differences in the prevalence of PMA according to a set of criteria and the relationship between them and asthma severity, the authors selected 103 fertile asthmatic females that answered "Yes" to: "Does your asthma get worse during the premenstrual phase?." A daily respiratory symptoms register was taken during two consecutive menstrual cycles. For the semi-objective deterioration (SOD), an exacerbation of ≥20% was required. Objective deterioration (OD) was a premenstrual worsening of ≥20% of peak flow. Subjective premenstrual deterioration was perceived in 43.7%. SOD in the first cycle occurred in 44.7%, and in 22.3% in both. A total of 54.3% of females with SOD in the first cycle perceived a subjective deterioration of symptoms, versus 35.1% of those without SOD. PMA was present at all levels of asthma with no clear link to the degree of severity.
Editor's comment: It is important to investigate the possible premenstrual deterioration in all fertile asthmatic females.
Pereira Vega A, Ramos JLS, Pérez JAM et al, Variability in the Prevalence of Premenstrual Asthma. European Respiratory Journal 2009; published online before print 6 November.

10. Synergistic induction of macrophage inflammatory protein-3α/CCL20 production by IL-17A and TNF-α; in nasal polyp fibroblasts.
Macrophage inflammatory protein-3α (MIP-3α/CCL20) is a chemokine involved in the migration of T cells and immature dendritic cells (DCs) into inflammatory tissues. To demonstrate the expression of MIP-3α/CCL20 in nasal polyp fibroblasts after stimulation with proinflammatory cytokines such as IL-17 and TNF-α, the authors established fibroblast lines from nasal polyps and evaluated MIP-3α/CCL20 mRNA expression by real-time RT-PCR, and measured the amount of MIP-3α/CCL20 in the supernatants by ELISA. They found that IL-17A and TNF-α; synergistically induced MIP-3α/CCL20 production by nasal polyp fibroblasts in a dose- and time-dependent manner. This synergy was observed by stimulation with TNF-α plus IL-17A or IL-17F, but not IL-17E.
Editor's comment: Nasal polyp fibroblasts play an important role in the recruitment of T cells and DCs in upper airways.
Nonaka M, Ogihara N, Fukumoto A et al, Synergistic Induction of Macrophage Inflammatory Protein-3α/CCL20 Production by Interleukin-17A and Tumor Necrosis Factor-α in Nasal Polyp Fibroblasts, World Allergy Organization Journal 2009;2(10):218-223.

11. Sleep actigraphy evidence of improved sleep after treatment of allergic rhinitis (AR).
To evaluate sleep impairment in children with AR using actigraphic evaluation, the authors enrolled 14 children (7-16 years) with grass pollen-sensitized seasonal AR. The children completed the Total 4-Symptom Score (T4SS) scoring system for AR and the Pittsburgh Sleep Quality Index (PSQI) questionnaire for sleep quality, and underwent actigraphy for 3 days pretreatment. After topical corticosteroid and antihistamine treatment for 8 weeks, actigraphy, the T4SS, and the PSQI were repeated. 14 healthy children (8-16 y) underwent actigraphy and completed the PSQI questionnaire as controls. They found that pretreatment PSQI and actigraphy scores were worse in the AR group versus controls. After treatment there were no differences in actigraphy and PSQI scores between the 2 groups.
Editor's comment: Actigraphy may be used as an objective tool to evaluate sleep disturbance in children with AR.
Yuksel H, Sogut A, Yilmaz H et al, Sleep Actigraphy Evidence of Improved Sleep after Treatment of Allergic Rhinitis. Annals of Allergy, Asthma and Immunology 2009;103(4):290-294.

12. The connection between early life wheezing and subsequent asthma: The viral march.
The author reviewed several new lines of evidence suggesting that alterations in immune responses which predispose to bronchial obstruction during acute respiratory infection, especially with rhinoviruses, may explain to a considerable extent the link between early life wheezing and subsequent asthma. The nature of these alterations is currently the subject of considerable scrutiny, but cross-sectional studies suggest that deficits in innate immune responses mediated by interferon type I and III are present in lung macrophages and epithelial cells of adult asthmatics. Similarly, long-term follow-up studies suggest that deficits in interferon gamma responses in the first year of life predispose to recurrent episodes of wheezing from the preschool years and into early adolescence. A better understanding of the "viral march" could yield new therapeutic approaches for the prevention and treatment of acute severe airway obstruction during childhood.
Editor's comment: Excellent review on viral infections and bronchial obstruction in children.
Martínez FD, The Connection between Early Life Wheezing and Subsequent Asthma: The Viral March. Allergologia et Immunopathologia (Madr) 2009;37(5):249-251.
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