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Archives: Medical Journal Reviews

Medical Journal Review

Posted: January 2011

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

1. Allergic rhinitis as a predictor for wheezing onset in school-aged children.
To investigate whether the development of rhinitis in early life predicts wheezing between the ages of 5 and 13 years, the researchers studied 1,314 children who participated in the German Multicentre Allergy Study. All the children were monitored from birth, and their parents completed regular questionnaires assessing respiratory symptoms and other health issues. Specific immunoglobulin (Ig)E levels were measured annually and airway hyper-responsiveness was assessed at the age of 7 years. They found that rhinitis prevalence was highest at the age of 3 years, at 9.2%, and ranged from 2.5% to 7.7% throughout the other years. By the age of 13 years, the cumulative incidence of rhinitis was 47.8%. The prevalence of wheezing was highest at the end of the second year of life, at 19.8%, and decreased to less than 7.0% in following years. The cumulative incidence of wheezing was 40.5% by the age of 13 years. After accounting for factors such as parental atopy, gender, maternal smoking during pregnancy, and number of siblings, the researchers found that children who suffered from allergic rhinitis before the age of 5 years were 3.82 times more likely to develop wheeze between the ages of 5 and 13 years than those who did not. Indeed, 41.5% of all children who developed wheeze had previously developed allergic rhinitis. The association between allergic rhinitis and wheeze was not linked to type or severity of sensitization. The authors concluded that allergic rhinitis in preschool children is a risk factor for subsequent wheezing onset. Preschool children with rhinitis might benefit from early assessment of allergic sensitization.
Editor's comment: The present analysis suggests that the first manifestation of allergic rhinitis occurs in preschool children, in whom it's a risk factor for subsequent wheezing onset.
Rochat MK, Illi S, Ege MJ et al. Allergic rhinitis as a predictor for wheezing onset in school-aged children. Journal of Allergy and Clinical Immunology 2010; 126(6): 1170-1175.

2. Multi-symptom asthma and nasal blockage, rhinorrhea and symptoms of chronic rhinosinusitis.
The aims of this study were to determine whether multi-symptom asthma is related to signs of severe asthma, and to investigate the association between multi-symptom asthma and different symptoms of allergic and chronic rhinosinusitis. This study analyzed data on asthma symptoms, rhinitis, and chronic rhinosinusitis from the 2008 West Sweden Asthma Study, which is an epidemiologically based study using the OLIN and GA²LEN respiratory and allergy focused questionnaires. To be considered as having multi-symptom asthma, a subject was required to report physician-diagnosed asthma and asthma medication and attacks of shortness of breath and recurrent wheeze and at least one out of the following: wheeze, dyspnoea, breathlessness on exertion, breathlessness in cold, and breathlessness-exertion in cold. For the purpose of this paper all subjects reporting physician-diagnosed asthma and not fulfilling the requirements of multi-symptom asthma are referred to as having fewer-symptom asthma. Multi-symptom asthma was present in 2.1% of the general population. Subjects with multi-symptom asthma had more than double the risk of having night-time awakenings caused by asthma compared with those with fewer asthma symptoms. The prevalence of allergic rhinitis was similar in the fewer- and multi-symptom asthma groups, but nasal blockage and rhinorrhea were significantly increased in those with multi- versus fewer-symptom asthma. Having any or one to four symptoms of chronic rhinosinusitis significantly increased the risk of having multi- versus fewer-symptom asthma. An epidemiologically identified group of individuals with multiple asthma symptoms harbor to greater extent those with signs of severe asthma. The degree of rhinitis, described by the presence of symptoms of nasal blockage or rhinorrhea, as well as the presence of any or several signs of chronic rhinosinusitis, significantly increases the risk of having multi-symptom asthma.
Editor's comment: Multi-symptom asthma is likely to describe a population with more severe disease.
Lotvall J, Ekerljung L and Lundback B. Multi-symptom asthma is closely related to nasal blockage, rhinorrhea and symptoms of chronic rhinosinusitis - evidence from the West Sweden Asthma Study. Respiratory Research 2010; 11(1): 164
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3. An increased intake of fruit would be associated with a reduced risk for asthma symptoms and sensitization to inhalant allergens.
To address the effects of long-term dietary exposure or differences in effects of dietary habits at early or later age, the authors studied data on 4,146 children who were followed up from birth until the age of 8 years as part of the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) study. Associations between intake of fruit, vegetables, brown/wholemeal bread, fish, milk, butter, and margarine in early (2-3 years of age) and later (7-8 years of age) childhood, as well as long-term intake, were compared with asthma and atopy outcomes at the age of 8 years. Complete dietary data from 2 to 8 years of age for at least one of the investigated food groups were obtained for 2,870 children. Overall, 13.0% of the children had asthma symptoms (composite variable of wheeze, dyspnea or inhaled steroid use) and 32.1% were sensitized to inhalant allergens at the age of 8 years. After accounting for potential confounding factors, such as parental atopy, maternal smoking, breast feeding, and birth weight, the researchers found that long-term intake of fresh fruit was significantly inversely associated with asthma symptoms and sensitization to inhalant allergens, with each one consumption-day per week associated with a 10.0% reduced risk for either outcome. Similarly, each one consumption-day per week of fruit at 2-3 years of age was associated with a 7.0% reduced risk for asthma symptoms. However, fruit consumption at 7-8 years of age was not associated with asthma symptoms or sensitization to inhalant allergens. There were no significant associations between increased consumption of any of the other foods and risk for asthma symptoms or atopy. The authors concluded that the results of this study indicate no consistent effects of increased early or late consumption, or increased long-term intake of certain foods or food groups on asthma and allergy outcomes in 8-year-old children, with a possible exception for fruit.
Editor's comment: Future prospective studies should use more detailed dietary data to better assess nutrient or food specific effects on asthma and sensitization to inhalant allergens.
Willers SM, Wijga AH, Brunekreef B et al. Childhood diet and asthma and atopy at 8 years of age: the PIAMA birth cohort study. European Respiratory Journal November 25, 2010 [Published online before print. doi: 10.1183/09031936.00106109]

4. Practical recommendations for safety considerations of omalizumab.
This excellent review provides a summary of the epidemiologic research carried out to date and presents a concise, practical set of recommendations for the prevention, monitoring and management of omalizumab-associated anaphylaxis. Omalizumab has demonstrated efficacy among patients with moderate to severe persistent allergic asthma, whose symptoms are inadequately controlled with other controller agents. This therapy is generally well tolerated, but there are some safety considerations, the most important of which is the rare, but potentially life-threatening, occurrence of omalizumab-associated anaphylaxis. In Canada, data from the manufacturer indicate that the frequency of anaphylaxis attributed to omalizumab in post-marketing use is approximately 0.2%. Other researchers, including the American Omalizumab Joint Task Force (OJTF), have suggested a lower overall frequency of 0.09%. Prevention tips include advice on patient education measures, concomitant medications and optimal administration. For the first three injections, the recommendation is to monitor in clinic for two hours after the omalizumab injection; for subsequent injections, the monitoring period should be 30 minutes or an appropriate time agreed upon by the individual patient and healthcare professional. In the event that a patient does experience omalizumab-associated anaphylaxis, the paper provides recommendations for handling the situation in-clinic and recommendations on how to counsel patients to recognize the potential signs and symptoms in the community and react appropriately.
Editor's comment: While the adverse effects of omalizumab-related anaphylaxis are rare, we should be familiar with its presentation and management.
Kim HL , Leigh R and Becker A. Omalizumab: Practical Considerations Regarding the Risk of Anaphylaxis. Allergy, Asthma & Clinical Immunology 2010; 6: 32.
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5. Endotoxin and tobacco smoke exposure on wheeze and diurnal peak expiratory flow variability in children and adolescents.
To study the relationship between endotoxin exposure and asthma severity (wheeze and airways obstruction), the effects of endotoxin and tobacco smoke exposure on self-reported wheeze and diurnal Peak Expiratory Flow variability (DV-PEF) were examined in children aged 6-18 years with asthma or wheeze in a cross-sectional study performed in a rural area. Children who reported wheeze in the previous 12 months or a physician diagnosis of asthma (n= 98) were selected for a case-control study. These cases, who were the basis for the present analysis, completed a) a home environmental assessment, including dust collection to measure endotoxin levels, b) a clinic visit, including saliva collection to measure cotinine levels, and c) two-week monitoring of twice daily symptom records, including wheeze, and PEF to calculate DV-PEF. Among these children, 22.4% reported wheeze during the monitoring period. Greater DV-PEF was associated with higher endotoxin loads in play areas. The association between salivary cotinine levels and high DV-PEF was modified by gender. In females, higher cotinine levels were associated with an increased risk of high DV-PEF compared with lower cotinine levels, but this was not observed among males. The authors concluded that higher endotoxin exposure was associated with greater DV-PEF among children with asthma or wheeze. Individuals with asthma should avoid high exposure levels of endotoxin to limit exacerbations. The effect of tobacco smoke exposure on lung health may differ between male and female children.
Editor's comment: Among children and adolescents with asthma or wheeze, exposure to endotoxin may influence asthma symptoms or result in exacerbations.
Lawson JA, Dosman JA, Rennie DC et al. Relationship of endotoxin and tobacco smoke exposure to wheeze and diurnal peak expiratory flow variability in children and adolescents. Respirology 2010 [Accepted article; published online for future issues. doi: 1440-1843.2010.01911.x/abstract]

6. The influenza A virus (H3N1) and a novel pathway that can regulate airway hyperreactivity (AHR).
To improve the understanding of the role of respiratory viral infection in children in the development of asthma, the authors studied a mouse model of asthma in which suckling mice were infected with the influenza A virus (H3N1), and were subsequently studied as adults for susceptibility to allergen-induced AHR. The results showed that infection of suckling mice with influenza A virus protected the mice as adults against allergen-induced AHR. The protective effect was associated with the preferential expansion of CD4-CD8-, but not CD4+, NKT cells. Adoptive transfer of this cell population into allergen-sensitized adult mice suppressed the development of allergen-induced AHR, an effect associated with expansion of the allergen-specific forkhead box p3+ (Foxp3+) Treg cell population. Influenza-induced protection was mimicked by treating suckling mice with a glycolipid derived from Helicobacter pylori (a bacterium associated with protection against asthma) that activated NKT cells in a CD1d-restricted fashion. These findings suggest a novel pathway that can regulate AHR, and a new therapeutic strategy (treatment with glycolipid activators of this NKT cell population) for asthma.
Editor's comment: The role of viral infection in modulating the development of asthma is particularly complex because many different viruses affect the respiratory tract, some appearing to enhance and some to protect against the development of asthma.
Chang YJ, Kim HY, Albacker LA et al. Influenza infection in suckling mice expands an NKT cell subset that protects against airway hyperreactivity. The Journal of Clinical Investigation 2011; 124(1): 57-69.
Full text, open access

7. Relationship between low levels of serum vitamin D and reduced lung function exercise-induced bronchoconstriction in asthmatic children.
To study the relationship between vitamin D levels and exercise-induced bronchoconstriction in asthmatic children, the researchers studied 45 children with intermittent asthma who attended the outpatient department at the University of Verona hospital. Blood samples were collected from the children and assessed for vitamin D levels (25 hydroxyvitamin D), which were categorized as sufficient (>e;30 ng/ml), insufficient (20-30 ng/ml), or deficient (<20 ng/ml). The children were also assessed for FEV1, forced vital capacity (FVC), and percentage fall in FEV1 after a standardized exercise challenge. Overall, just 11.1% (n=5) of children had sufficient vitamin D levels, while 37.8% (n=17) had insufficient levels, and the remaining 51.1% (n=23) had deficient levels. The researchers found a significant positive correlation between vitamin D levels and both FEV1 and FVC. Furthermore, children with a FEV1 value that fell by 10% or more after the exercise challenge had significantly lower mean vitamin D levels than those who experienced no significant fall in FEV1, at 16.2 versus 23.4 ng/ml. The authors concluded that their results indicate that hypovitaminosis D is frequent in asthmatic children who live in a Mediterranean country. In those children, lower levels of vitamin D are associated with reduced lung function and with increased reactivity to exercise.
Editor's comment: Low serum levels of vitamin D are common in children with asthma and are associated with reduced lung function and exercise-induced bronchoconstriction.
Chinellato I,Piazza M, Sandri M et al. Vitamin D serum levels and exercise-induced bronchoconstriction in children with asthma. European Respiratory Journal November 11, 2010 [Published online ahead of print. doi: 10.1183/09031936.00044710]

8. Implication of CPI-17 (protein-kinase C-potentiated myosin phosphatase inhibitor) in asthma.
To study the effects of CRBM-0244, a newly synthesized DHA (docosahexaenoic acid) derivative on lung inflammation and airway hyperresponsiveness the authors used an in vitro model of TNF-stimulated human bronchi as well as in an in vivo model of allergic asthma. Mechanical tension measurements revealed that CRBM-0244 prevented bronchial hyperresponsiveness in TNF-pretreated human bronchi. Moreover, CRBM-0244 treatments resulted in a decrease in NF?B activation and COX2 over-expression triggered by TNF. CRBM-0244 reduced Ca2+ sensitivity of bronchial smooth muscle through a decrease in CPI-17 phosphorylation and expression level. Results also revealed an over-expression of CPI-17 protein in lung biopsies derived from asthmatic patients. Furthermore, the presence of specialized enzymes such as 5- and 15-Lipoxygenases in the lung may convert CRBM-0244 in active mediators leading to resolution of inflammation. In vivo anti-inflammatory properties of CRBM-0244 were also investigated in a guinea pig model of allergic asthma. After oral CRBM-0244 administration, airway leukocyte recruitment, airway mucus, ovalbumin-specific IgE and pro-inflammatory markers such as TNF and COX2 were markedly reduced. Hence, CRBM-0244 treatment prevents airway hyperresponsiveness, Ca2+ hypersensitivity and CPI-17 over-expression in lung tissues.
Editor's comment: These findings provide key evidence regarding the mode of action of CRBM-0244 in lung and point to new therapeutic strategies for modulating inflammation in asthmatic patients.
Morin C, Fortin S, Cantin AM et al. DHA Derivative Prevents Inflammation and Hyperreactivity in Lung: Implication of CPI-17 in Asthma. American Journal of Respiratory Cell and Molecular Biology November 5, 2010 [Published online ahead of print. doi: 10.1165/rcmb.2010-0156OC]

9. Brain-derived neurotrophic factor (BDNF) as severity marker in childhood asthma.
To address the role of BDNF (a member of the neurotrophin family) in pediatric asthma the authors studied 57 children with persistent mild (n=19), moderate (n=24), and severe (n=14) asthma, aged an average of 10.0 years, and 18 healthy children without the condition who were aged an average of 9.3 years. Blood samples were collected from the children and assessed for BDNF levels using an enzyme-linked immunosorbent assay. They were also assessed for levels of various inflammatory markers including the chemokines CCL3, CCL11, CCL22, CCL24, CXCL8, CXCL9, CXCL10, and soluble tumor necrosis factor (TNF) receptors 1 and 2. Analysis revealed that BDNF levels varied significantly across all groups. Specifically, BDNF plasma levels were significantly higher in children with moderate and severe asthma than in those with mild asthma and controls. Children with mild asthma had similar BDNF levels to those of healthy children. There were no significant differences among the groups regarding levels of chemokines and soluble TNF receptors. The authors concluded that their findings suggest that BDNF, a neurotrophin currently shown to be involved in the pathophysiology of adult asthma, may also play a role as a biomarker for clinical severity in childhood asthma.
Editor's comment: Future studies should disentangle the role of intervenient variables (eg, stress factors, medication) that may change neurotrophin levels.
Müller GC, Pitrez PM, Teixeira AL et al. Plasma brain-derived neurotrophic factor levels are associated with clinical severity in school age children with asthma. Clinical and Experimental Allergy 2010; 40(12): 1755-1759.

10. Protozoa in sputum and asthma.
To evaluate if the protozoa observed in several respiratory case series are more common in patients with asthma than healthy controls, the authors investigated the prevalence of flagellated protozoa in the sputum of asthma patients. The team enrolled 54 asthmatics and 42 nonatopic, non-smoking controls aged between 21 and 62 years. The presence of flagellated protozoa in sputum was assessed using a novel set of morphological and staining criteria, which is able to distinguish protozoa from ciliated epithelial cells. The participants also completed questionnaires detailing asthma severity, the use of steroid inhalers, and housing conditions. Sputum samples from a total of 30 asthma patients and 13 controls were included in the final analysis, of which 66.7% and 30.8%, respectively, tested positive for protozoa (relative risk=1.58). Among patients with asthma, there were no significant differences between those who tested positive and negative for protozoa regarding the use of steroid inhalers in the preceding 2 weeks or the proportion of individuals who lived in damp homes. This case-control study demonstrates an association between flagellated protozoa in sputum and asthma. It is now necessary to confirm and characterize the protozoa using genetic techniques based on 18S ribosomal RNA. Once this is established, it would be worthwhile to determine if asthma symptoms improve when treated by anti-protozoal agents.
Editor's comment: This hypothesis requires further exploration to determine whether these organisms are playing any primary or secondary pathogenic role, or whether their presence is merely an incidental finding.
van Woerden HC, Ratier-Cruz A, Aleshinloye OB et al. Association between protozoa in sputum and asthma: A case-control study. Respiratory Medicine 2010; in press [doi: 10.1016/j.rmed.2010.11.016]

11. Perioperative Management of Obstructive Sleep Apnea (OSA).
Obstructive sleep apnea (OSA) is the most common breathing disorder, with a high prevalence in both the general and surgical populations. OSA is frequently undiagnosed, and the initial recognition often occurs during medical evaluation undertaken to prepare for surgery. Adverse respiratory and cardiovascular outcomes are associated with OSA in the perioperative period; therefore, it is imperative to identify and treat patients at high risk for the disease. The aim of this review was to discuss the available epidemiologic data about OSA in the surgical population and provide a better understanding of the impact of anesthetics on the pathophysiology of upper airway resistance. The authors also explore the usefulness of various questionnaires used to identify individuals most at risk for OSA and suggest intraoperative and postoperative treatment regimens. Additionally, the role of continuous positive airway pressure in perioperative management of OSA and a brief discussion of ambulatory surgery in patients with OSA is provided. An algorithm is provided to simplify the management and, it is hoped, diminish the perioperative risks of these complex patients.
Editor's comment: It has been estimated that up to 80% of patients with OSA in the general population are undiagnosed and therefore untreated.
Adesanya AO, Lee W, Greilich NB et al. Perioperative Management of Obstructive Sleep Apnea. Chest 2010; 138(6): 1489-1498.

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