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Archives: Medical Journal Reviews

Medical Journal Review

Posted: January 2009

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

1. Cigarette smoke combined with Toll-like receptor 3 (TLR3) signaling triggers exaggerated epithelial RANTES (regulated upon activation, normal T-cell-expressed and -secreted)/CCL5 expression in chronic rhinosinusitis (CRS).
Patients with CRS often suffer acute bacterial infections suggesting that a defect in innate immunity might be associated with the disease. In this study, epithelial cells from middle turbinate biopsies of 9 healthy persons and 11 CRS patients were cultured. The cells were exposed to cigarette smoke extract (CSE) or medium then stimulated with lipoteichoic acid (TLR2 agonist), lipopolysaccharide (TLR4) or double-stranded RNA (TLR3), and analyzed for TLR-2, -3 and -4 expression. CSE alone stimulated RANTES production 35-fold in CRS patients but not in healthy controls. The greatest increase in RANTES (12,115-fold) was seen in nasal epithelial cells treated with CSE and double-stranded RNA (dsRNA) compared to a 1500-fold increase in cells from healthy controls. IL-1β, IL-6 and IL-8, TNF-α, HBD2 and MCP-2 were all synergistically increased by CSE plus dsRNA. Exacerbations of CRS may be more severe in smokers because of CSE-induced excess RANTES production. Editor's comment: Although the mechanism whereby RANTES might contribute to CRS in viral infection is unclear, the large increase in CSE-induced RANTES seen here merits further study in vivo. Yamin M, et al. J Allergy Clin Immunol 2008; 122:1145-1153.

2. The asthma-mental health nexus in a population-based sample of the United States.
This study examines the likelihood of having current asthma in an adult cross-section of the U.S. population with perceived mental health problems. The Behavioral Risk Factor Surveillance System (BRFSS) survey was used to assess mental health and to place subjects into one of five categories from 0 days per month of poor mental health to 22 to 30 days per month. Asthma status was assigned by asking subjects if a physician had ever told them they have asthma and whether they have asthma now. Other factors considered included overall health status, urban environment, age, gender, smoking status, obesity, exercise, socioeconomic level, ethnicity and marital status. The entire BRFSS database of 355,710 subjects was screened using a multinomial logistic regression model to determine correlation between mental health and asthma. Women reported worse mental health than men, and any history of smoking correlated with a reduction in mental health, as also did poor overall health, lack of exercise, and obesity. The odds of having asthma showed a "dose response" as the number of days of poor mental health per month increased from 1.38 for ≤ 1 week of poor mental health to 2.75 for ≥ 3 weeks per month. Editor's comment: A relationship between asthma and mental health has been proposed for many years and this study adds significant information to the analysis, but the exact mechanism remains elusive. Chun TH, et al. Chest 2008; 134:1176-1182.

3. Relationship between gastroesophageal reflux disease (GERD) and COPD in UK primary care.
Patients with a first diagnosis of GERD or COPD were identified from the UK General Practice Database and the incidence of combined GERD/COPD in the diagnosed group over a five-year follow-up was compared with that in a matched healthy cohort. Medication use, comorbidities, demographics and lifestyle factors were also examined. The relative risk of COPD in GERD patients was 1.17 while the risk of GERD in COPD patients was 1.46. Older patients (≥ 70 years) with GERD were 3.7 times as likely as controls to be diagnosed with COPD. A prior diagnosis of asthma was also associated with increased risk of COPD in GERD patients (odds ratio, 10.9). Editor's comment: The complex interrelationship between GERD, asthma and COPD needs to be examined carefully when assessing a patient's diagnosis and medication requirements. García-Rodríguez LA, et al. Chest 2008; 134:1223-1230.

4. Clinical and molecular profile of a new series of patients with immune dysregulation, poly endocrinopathy, enteropathy, and X-linked syndrome (IPEX): Inconsistent correlation between forkhead box protein 3 (FOXP3) expression and disease severity.
IPEX is a rare disease caused by mutations in the FOXP3 gene. It is characterized by a range of symptoms including diarrhea, chronic dermatitis, diabetes and thyroiditis. FOXP3 is principally expressed on regulatory T cells but also on effector T cells and FOXP3 deficiency compromises immune tolerance. Fourteen patients with early-onset IPEX were screened for FOXP3 mutations and expression level. Seven of the patients had previously identified FOXP3 gene mutations and the other seven had novel mutations. In five of eight IPEX patients tested, FOXP3 protein levels were not affected although FOXP3 mutations were present and IgE and eosinophils were elevated. Diagnosis of IPEX should be made based on genetic analysis for FOXP3 mutations rather than on measurement of FOXP3 protein. Editor's comment: Although IPEX is relatively rare, infants with enteropathy or diabetes and elevated IgE should be genotyped for FOXP3. Gambineri E, et al. J Allergy Clin Immunol 2008; 122:1105-1112.

5. Prevention of mast cell activation disorder-associated clinical sequelae of excessive prostaglandin D2 (PGD2) production.
Mast cell activation disorder (MCAD) produces symptoms similar to those experienced by patients with systemic mastocytosis (SM)-flushing, palpitations, light-headedness, syncope, and chest pain among others. Exercise-induced or idiopathic anaphylaxis can also mimic MCAD. This retrospective review of four patients with excessive prostaglandin D2 (PGD2) release sought to determine if MCAD was the cause. None of the patients had evidence of SM in bone marrow biopsies and histamine was not released during exacerbations. Baseline levels of PGD2 were normal to slightly elevated but increased significantly during activation episodes. Symptoms were effectively reduced by aspirin treatment. Editor's comment: Whether MCAD is an entity separate from idiopathic anaphylaxis is still controversial, but the absence of histamine release in these MCAD patients may be distinctive. Butterfield JH and Weiler CR, Int Arch Allergy Immunol 2008; 147:338-43.

6. Evidence of a causal role of winter virus infection during infancy in early childhood asthma.
Infant bronchiolitis has been linked to later onset of asthma and most commonly associated with viral respiratory tract infections, so it is not unreasonable to suppose that the season of birth may influence the risk of asthma. To test this hypothesis, the medical histories of a group of 95,310 children from birth to about 5 ½ years of age were examined for a correlation between age at time of first winter virus infection peak and development of high-risk asthma as defined by one or more hospitalizations or ER visits or a course of corticosteroids. Infants between the ages of 118 and 126 days at the time of winter virus peak had the highest risk of significant bronchiolitis, and those 118 to 131 days old at virus peak had the greatest likelihood of developing high-risk asthma-about 30% higher than infants who were one year old at peak. The timing of the age at highest risk shifted in synchrony with variation in the date of peak virus infections. Viral bronchiolitis at about 4 months of age could produce a chronic inflammation with long-lasting effects on lung development and immune maturation. Editor's comment: The significant correlation between age at time of winter virus peak and incidence of asthma suggests a strong potential for therapeutic intervention and avoidance of infection in this group of children. Wu P, et al. Am J Resp Crit Care Med 2008; 178:1123-1129.

7. Inhaled corticosteroids (ICS) in patients with stable chronic obstructive pulmonary disease (COPD).
COPD affects 10-15 million people in the U.S. and is the fourth leading cause of death. This meta-analysis of the existing literature on the use of ICS by stable COPD patients focused on 11 randomized controlled trials involving a total of 14,426 participants. ICS use did not decrease mortality during follow-up periods of up to three years and was associated with a 34% increase in the incidence of pneumonia. However, ICS did improve quality-of-life scores for COPD but did not increase the fracture rate. The analysis suffered from some limitations in that an unequivocal distinction between pneumonia and COPD exacerbation was not always made and there was considerable diversity in the type and dosage of ICS used. Thus, it is always necessary to weigh the risks in COPD of increased respiratory infection against the benefits of improved quality of life. Editor's comment: In spite of the limitations of this meta-analysis, the results raise important questions about the use of ICS to treat stable COPD. Drummond MB, et al. JAMA 2008; 300:2407-2416.

8. Asthma and allergic symptoms in relation to house dust endotoxin: Phase Two of the International Study on Asthma and Allergies in Childhood (ISAAC II).
Six centers in five different countries supplied data on the incidence of asthma and atopy in 840 children, age 9 to 12 years, in relation to endotoxin levels in living room floor dust. Standardized questionnaires were used for demographics, wheezing, allergy and eczema, and atopy was defined as serum IgE reaction to one or more airborne allergens. Overall, there was an inverse relationship between exposure to dust endotoxin levels in this age group and both atopic and non-atopic asthma, but not hay fever. Editor's comment: The controversy over whether endotoxins protect against or exacerbate asthma continues, but this study provides substantial evidence of a protective effect among children in a wide range of settings. Gehring U et al. Clin Experimental Allergy 2008; 38:1911-1920.

9. ERK-mediated regulation of leukotriene biosynthesis by androgens: a molecular basis for gender differences in inflammation and asthma.
Asthma is more common in males before puberty but in females afterwards suggesting a protective effect of androgens. Leukotrienes (LTs) are proinflammatory molecules synthesized by 5-lipoxygenase (5-LO) primarily by neutrophils (NPs). Isolated NPs from female blood produced more LT-B4 than those from male blood when stimulated. In female NPs, 5-LO was localized in the cytoplasm and moved to the nucleus upon stimulation. In male NPs, 5-LO was present in both cytoplasm and nucleus but the location did not change after stimulation. The nuclear localization of 5-LO is dependent on dihydrotestosterone (DHT) and DHT suppresses LT synthesis by female NPs. Extracellular-regulated kinases (ERK1/2) were more active in male NPs, and inhibition of ERKs caused 5-LO to become cytosolic and to migrate to the nucleus as in female NPs. Editor's comment: The suppressive effect of DHT on 5-LO suggests that treatment with LT antagonists such as montelukast may have to be optimized according to sex. Pergola C, et al. Proc Nat Acad Sci 2008; 105:19881-19886.

10. Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease (COPD) exacerbations.
Frequent exacerbations in COPD patients cause rapid disease progression and poor prognosis. This randomized, double-blind, placebo-controlled trial tested long-term use of erythromycin (EM) to reduce COPD excacerbations. COPD patients (n = 115) with FEV1 30% to 70 % of predicted received either placebo or 250 mg EM twice a day for one year. Most patients were using corticosteroids at the time of the study and were allowed to continue with them. Blood and sputum samples were taken for analysis of IL-6, IL-8, C reactive protein and myeloperoxidase and spirometry was done at each visit. Subjects kept a symptom diary and reported exacerbations as soon as they occurred. One year EM treatment reduced exacerbation frequency, duration and symptom severity and caused no adverse side effects. No change in FEV1, sputum inflammatory markers or bacterial colonization was seen. Editor's comment: The use of macrolide therapy seems to be indicated as a well-tolerated way to reduce COPD exacerbations. Seemungal TAR, et al. Am J Resp Crit Care Med 2008; 178:1139-1147.

11. Increased gastrointestinal permeability and gut inflammation in children with functional abdominal pain and irritable bowel syndrome (FAP/IBS).
In this study, children aged 7 to 10 years with FAP/IBS were studied to determine if symptom severity could be correlated with GI permeability and inflammation. The Pediatric Rome II criteria for FAP and IBS were used to rate the pain frequency and intensity. Gut inflammation was measured as fecal calprotectin levels and stooling patterns were recorded by diary. The subjects included 109 children with FAP/IBS and 66 controls. Calprotectin was higher in FAP/IBS patients indicative of greater gut inflammation than healthy controls. Permeability of the proximal GI and colon as measured by sugar recovery was greater in FAP/IBS subjects. No correlation was found between GI permeability and pain levels, and increased GI inflammation was associated only with increased pain-related interference with activity. Editor's comment: The results of this study suggest that the relationship between GI permeability, inflammation and abdominal pain in children is complex. Shulman RJ, et al. J Pediatr 2008; 153:646-650.

12. Effects of average childhood dairy intake on adolescent bone health.
Supplementary calcium increases bone mineral content (BMC) in children during the bone-building phase but there have been fewer studies on the effects of dairy intake on BMC. This report examined the Framingham Children's Study data in terms of dairy intake during childhood compared to BMC, area and density measured when the children were 15 to 17 years old. BMC was determined by scan over the entire body and was used rather than BMD which is subject to error in children with larger bones. Children who ate more than two servings of dairy products a day had higher BMC and bone area than those eating less. Children who ate more dairy and had more than 4 servings per day of meat or other protein had the highest BMC and area. Editor's comment: This longitudinal study of the Framingham data reiterates the importance of adequate protein (meat) and dairy products on adolescent bone health. Moore LL, et al. J Pediatr 2008; 153:667-673.

13. Clinical and immunologic effects of H1 antihistamine preventive medication during honeybee venom immunotherapy (BVIT).
Patients undergoing BVIT are commonly given antihistamine treatment to reduce the risk of systemic allergic side effects. In this study, the effectiveness of BVIT in the presence of the histamine receptor-1 (HR1) blocker, levocetirizine (LC), was compared to placebo. BVIT patients (n = 54) were given LC from two days before BVIT to day 21 and examined for systemic allergic reactions (SARS) and allergen-specific immunity by skin test, serum Abs and cultured T cell activity. SARS were observed significantly more frequently in the placebo group with a higher use of rescue medications. The efficacy of BVIT was not altered by LC administration. Editor's comment: The potential contribution of antihistamine treatment to development of allergen tolerance needs to be better defined. Muller UR, et al. J Allergy Clin Immunol 2008; 122:1001-1007.

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