Medical Journal Review
Posted: January 2010
Reviewed by Juan Carlos Ivancevich, MD, in collaboration with Phil Lieberman, MD.
1. Thirteen-year follow-up of early intervention with an inhaled corticosteroid (ICS) in patients with asthma.
To evaluate the long-term effects of early diagnosis and treatment of asthma, the researchers studied data on 103 adult patients with newly-diagnosed asthma who participated in the START (Inhaled Steroid Treatment as Regular Therapy in Early Asthma) study. Half of the patients (n=50) were assigned to receive high-dose budesonide (600 µg twice daily) within 12 months of symptom development (early therapy), and the other half (n=53) were assigned to receive initial terbutaline treatment followed by budesonide (375 µg twice daily) after 2 years (delayed therapy). All the patients had their medications individually adjusted after 3 years. Ten years later, the researchers found that there were no statistically significant differences in clinical or functional variables. However, patients in the delayed therapy group had a higher neutrophil count, and higher concentrations of eosinophilic cationic protein and myeloperoxidase in induced sputum, and they also had used more asthma medications and visited the hospital more often at follow-up.
Editor's comment: Early ICS treatment seems to improve asthma control.
Haatela T, Tamminen K, Kava T et al, Thirteen-year follow-up of early intervention with an inhaled corticosteroid in patients with asthma. Journal of Allergy and Clinical Immunology 2009; 124(6):1180-1185.
2. Childhood immunization and atopic disease into middle-age - a prospective cohort study.
To address possible associations between childhood immunizations and asthma and allergies in middle-aged adults, the researchers assessed data from the Tasmanian Longitudinal Health Study on 5,729 participants who were followed-up from ages 7 to 44. Most of the participants (up to 90.7%) had undergone childhood immunization against diphtheria, tetanus, pertussis, polio, and/or smallpox. By the age of 44 years, 11.2% of the participants had been diagnosed with asthma; 11.1% had at least one food allergy; 37.0% had eczema; and 50.3% had hayfever. After accounting for confounders, multivariable regression analysis revealed no significant associations between any childhood immunization and asthma (odds ratios [ORs] ranging from 0.87 to 1.17), eczema (ORs=0.99-1.07), food allergy (ORs=0.97-1.11), and hayfever (ORs=1.02-1.05) at age 44 years. Cox regression analysis also revealed no significant associations between any childhood immunization and incident asthma after the age of 7 years (ORs=1.03-1.21).
Editor's comment: Childhood immunization could not be linked to asthma in adulthood.
Matheson MC, Walters EH, Burgess JA et al, Childhood immunization and atopic disease into middle-age - a prospective cohort study. Pediatric Allergy and Immunology, Early View - online in advance of print 7 December 2009.
3. Alternaria and Cladosporium fungal allergen epitopes are denatured by sodium hypochlorite.
To investigate removal of environmental allergenic material derived from Alternaria and Cladosporium using sodium hypochlorite in vivo and in vitro, the authors used freeze dried allergen extract from Alternaria alternata and Cladosporium herbarum treated with hypochlorite concentrations of 322, 88, 38, 16, 3, 0.3, and 0 mM, respectively. They quantified remaining native allergenic material using enzyme immunoassay and evaluated remaining viable fungal material. The results of treating Alternaria or Cladosporium extract with sodium hypochlorite were immediate and obvious. Concentrations greater than 100 mM removed color and concentrations between 100 and 38 mM partially uncolored the extract. Immunoassay for total antigenic and allergenic material remaining after treatment with sodium hypochlorite, including 2 concentrations recommended for killing fungus, confirmed a general destruction of antigenic and allergenic material at concentrations of 38 mM or greater. Destruction of recognized antigenic and allergenic epitopes occurred at hypochlorite concentrations commonly used for household cleaning.
Editor's comment: This work confirms the ability of solutions of sodium hypochlorite to denature fungal allergenic material from common outdoor and indoor fungi.
Barnes C, Pacheco F, Dhar M et al, Alternaria and Cladosporium fungal allergen epitopes are denatured by sodium hypochlorite. World Allergy Organization Journal, 2(12):296-302.
4. Interferon-γ (INF-γ) release test can detect cutaneous adverse effects to statins.
An increasing number of cutaneous adverse effects to statins are being reported. The authors conducted a study to establish the relationship between statins and cutaneous reactions by the in vitro INF-γ release test. They incubated lymphocytes of 20 patients with suspected drug-induced skin reactions with and without the drug, and measured the increase of INF-γ by enzyme-linked immunosorbent assay (ELISA). Response was positive in 27 (21.43%) of the 126 drugs tested. Statins were the only drugs with a positive response in 80% of those cases. 9 of 20 patients (45.0%) had complete resolution after discontinuation; 6 (30.0%) who replaced one statin by another had partial or no resolution; and 5 (20.0%) had no resolution despite cessation of statins.
Editor's comment: The INF-γ release test can be useful in establishing statins as the cause of skin reactions.
Goldberg I, Isman G, Shirazi I et al, Interferon-γ (INF-γ) release test can detect cutaneous adverse effects to statins. International Journal of Dermatology 2009; 48(12):1370-1375(6).
5. Influence of early gut microbiota on the maturation of childhood mucosal and systemic immune responses.
Previous studies have shown that infants with high levels of salivary SIgA are less likely to develop allergic symptoms perhaps because they are more likely to be colonized with gut bacteria which may protect against the development of allergic disease. The purpose of the present study was to determine if early colonization with certain gut microbiota species, e.g. Lactobacilli and Bifidobacterium (B. fragilis), might exert immune effects protective for the development of allergy and if these effects could be correlated with levels of SIgA. To accomplish this, the authors collected fecal samples and saliva from 64 infants at 1 week, 1 month, and 2 months after birth to analyze fecal bacterial DNA and measure salivary SIgA. They followed the children for 5 years. At 6 months, the number of B. fragilis species in fecal samples correlated significantly with the total levels of salivary SIgA. Peripheral blood mononuclear cells from infants colonized early with high amounts of B. fragilis expressed lower levels of TLR4 mRNA. Lipopolysaccharide (LPS)-induced production of IL -6 and CCL4 was inversely correlated with the levels of B. fragilis.
Editor's comment: The study suggests that bifidobacterial diversity might enhance the maturation of the immune system.
Sjögren YM, Tomicic S, Lundberg A et al, Influence of early gut microbiota on the maturation of childhood mucosal and systemic immune responses: Gut microbiota and immune responses. Clinical & Experimental Allergy, 2009; 39(12):1842-1851.
6. Increased levels of outdoor air pollutants are associated with reduced bronchodilation in children with asthma.
Increased outdoor air pollution levels are associated with more frequent use of short-acting β-agonists (SABAs) in subjects with asthma. To explain this phenomenon the researchers studied 85 children (ages 7-12 years) living in Mexico City with mild-to-moderate asthma. They compared fluctuations in outdoor levels of nitrogen dioxide (NO2), ozone (O3), and fine particulate matter (PM2.5) near the children's homes with changes in their FEV1 after treatment with SABAs. Analysis revealed that a same-day interquartile increase of 10 ppb in NO2 concentration was associated with an average 15% reduction in FEV1 response to SABA therapy. An interquartile increase of 16 ppb in O3 concentration was associated with an 11% reduction in FEV1 response to SABA therapy 5 days later. They found no significant reductions in response to SABA therapy associated with same-day or lag-time increases in PM2.5.
Editor's comment: An Increase in air pollution is associated with reductions in bronchodilator response in children with asthma.
Hernández-Cadena L, Holguin F, Barraza-Villareal A, Increased levels of outdoor air pollutants are associated with reduced bronchodilation in children with asthma. Chest 2009; 136(6):1529-1536.
7. Predicting short term response to anti-inflammatory therapy in young children with asthma.
To evaluate potential biomarkers of predicting short-term (6-week) response to inhaled corticosteroids (ICS) and leukotriene receptor antagonist (LTRA) in children with asthma, 102 children (4-7 years) with episodic asthma were enrolled in an open labeled single-center study. Biomarkers and asthma characteristics were evaluated as predictors of treatment. Of 102 children, 45 became symptomatic during observation and were randomized to treatment either with montelukast or fluticasone for 6 weeks. As the authors stated, "Forced Expiratory Volume in one second (FEV1) increased with both treatments: FEV1 at randomisation was 90.2% and after therapy 106.8% with fluticasone vs. 90.8% and 103.7% for montelukast, respectively, showing that montelukast and fluticasone were equally effective in this age group (p = 0.44)." Strong correlations to a favorable treatment response were pre-bronchodilatory FEV1 (p < 0.001) and airway reversibility (p = 0.04) at time of randomization. None of the other biomarkers (methacholine, exhaled nitric oxide [eNO], allergy, total IgE, cumulative specific IgE, eosinophils and parental smoking) were predictive.
Editor's comment: Pre-bronchodilator FEV1 and airway reversibility seem to be good indicators of short-term anti-inflammatory therapy in young children with asthma.
Zielen S, Christmann M, Kloska M et al, Predicting short term response to anti-inflammatory therapy in young children with asthma. Current Medical Research and Opinion. Epub ahead of print, posted online 14 Dec 2009.
8. Variants of DENND1B associated with asthma in children.
A genome-wide association study involving children with asthma included 793 North American children of European ancestry with persistent asthma who required daily inhaled glucocorticoid therapy and 1988 matched controls (the discovery set). Researchers also tested for genome-wide association in an independent cohort of 917 persons of European ancestry who had asthma and 1,546 matched controls (the replication set). Finally, they tested for an association between 20 single-nucleotide polymorphisms (SNPs) at chromosome 1q31 and asthma in 1,667 North American children of African ancestry who had asthma, and 2,045 ancestrally matched controls. In the meta-analysis of all samples from persons of European ancestry, they observed an association, with genome-wide significance, between asthma and SNPs at the previously reported locus on 17q21 and an additional eight SNPs at a novel locus on 1q31. The SNP most strongly associated with asthma was rs2786098 (P=8.55x10-9). They observed replication of the association of asthma with SNP rs2786098 in the independent series of persons of European ancestry (combined P=9.3x10-11). The alternative allele of each of the eight SNPs on chromosome 1q31 was strongly associated with asthma in the children of African ancestry (P=1.6x10-13 for the comparison across all samples). The 1q31 locus contains DENND1B, which is a gene that is expressed by natural killer cells and dendritic cells and that encodes a protein that interacts with the tumor necrosis factor α receptor.
Editor's comment: A locus containing DENND1B on chromosome 1q31.3 is associated with susceptibility to asthma.
Sleiman PMA, Flory J, Imielinski M et al, Variants of DENND1B associated with asthma in children. New England Journal of Medicine, Epub ahead of print 23 Dec 2009.
9. Gaps in anaphylaxis management at the level of physicians, patients, and the community: a systematic review of the literature.
The search included MEDLINE, EMBASE, CINAHL, and Evidence-Based Medicine Reviews. Studies were included if they addressed an outcome describing gaps in anaphylaxis knowledge, education, anaphylaxis management, and quality of life (QOL). Populations of interest were health care professionals involved in the care of patients at risk for anaphylaxis, and patients of any age, their parents, caregivers, and teachers in primary care, hospital or community settings. Of 5014 citations that were identified, the final 59 studies (selected from 75 full-text articles) met the inclusion criteria. 202 gaps were identified and classified according to major themes: gaps in knowledge and anaphylaxis management (physicians and patients); gaps in follow-up care (physicians); and QOL of patients and caregivers. Findings from this systematic review revealed gaps in anaphylaxis management at the level of physicians, patients, and the community.
Editor's comment: Findings provide a basis for developing interventional strategies to help address these deficiencies.
Kastner M, Harada L and Waserman S, Gaps in anaphylaxis management at the level of physicians, patients, and the community: a systematic review of the literature. Allergy, online in advance of print, posted 21 Dec 2009.
10. The effect of oral steroids with and without vitamin D3 on early efficacy of immunotherapy in asthmatic children.
In this randomized, DBPC study, 54 children allergic to house dust mites received a single 20-mg dose of prednisone, with or without vitamin D3, or placebo on the day of the buildup phase of subcutaneous immunotherapy (SIT). After 12 months of SIT, the median daily inhaled corticosteroid (ICS) dose, which controls the symptoms of asthma, was reduced by 25% in the steroid group. However, a 50% reduction of the median daily ICS dose was observed in the control group. The clinical effects of SIT were not affected in the steroid+D3 group. The intervention with prednisone significantly impaired the induction of T regulatory lymphocytes. The clinical and immunological effects of SIT were not affected by intervention with steroids administered with vitamin D3.
Editor's comment: The mechanism of this protective effect of vitamin D3 is still unknown.
Majak P, Rychlik B and Stelmach I, The effect of oral steroids with and without vitamin D3 on early efficacy of immunotherapy in asthmatic children. Clinical and Experimental Allergy 2009; 39(12):1830-1841.
11. Time trends in asthma and wheeze in Swedish children 1996-2006: prevalence and risk factors by sex.
To investigate whether the prevalence of childhood wheezing is no longer rising in Sweden, the researchers assessed asthma and allergy questionnaires completed by the parents of 3,430 children in 1996 and 2,585 children in 2006. The age of the children was 7-8 years, and they came from the same towns in Sweden. Subsets of 2,148 children in 1996 and 1,700 in 2006 underwent skin prick tests. They found an increase in the overall prevalence of allergic sensitization, from 20.6% to 29.9%, with no significant increase in the overall prevalence of current wheeze, which rose slightly from 11.7% to 13.0%; allergic rhinitis, which increased marginally from 14.0% to 15.2%; or eczema, which fell from 27.2% to 25.8%. However, analysis by gender indicated a significant increase in the prevalence of current wheeze (12.9% to 16.4%) and physician-diagnosed asthma (7.1% to 9.3%) in boys, whereas the prevalence decreased in girls.
Editor's comment: Childhood wheezing rates overall are no longer increasing in Sweden and may have reached a plateau.
Bjerg A, Sandström T, Lundbäck B et al, Time trends in asthma and wheeze in Swedish children 1996-2006: prevalence and risk factors by sex. Allergy 2009; 65(1):48-55.
12. Mortality from pandemic A/H1N1 2009 influenza in England: public health surveillance study.
After the announcement of the swine flu pandemic by the World Health Organization (WHO) on 11 June 2009, all primary care trusts and acute hospitals in England were required to collate data on individuals who were believed to have died from the disease. Examination of these data shows that by November 8 2009, 138 people had died from swine flu out of an estimated 540,000 people with symptomatic H1N1 infection. The researchers calculate that the case fatality rate was 26 per 100,000 - a death rate of 0.026%. The rate was lowest in children aged 5-14 years and highest in those aged 65 years and older. The average age of those who died from swine flu was 39 years. The overall fatality rate of 0.026% is significantly lower than those from previous flu pandemics; the rate for the 1918 Spanish flu pandemic was 2-3%, and subsequent pandemics in 1957-1958 and 1967-1968 had rates of around 0.2%.
Editor's comment: Swine flu fatalities lower than expected.
Donaldson LJ, Rutter PD, Ellis BM et al, Mortality from pandemic A/H1N1 2009 influenza in England: public health surveillance study. BMJ 2009; 339:b5213.
13. Physical inactivity and obesity: Relation to asthma and chronic obstructive pulmonary disease?
Physical inactivity and obesity both are associated with a low-grade systemic inflammation in the general population. Because high C-reactive protein levels in young healthy adults are associated with a faster decline in lung function, the question arises whether physical inactivity and obesity are independent risk factors for the induction and clinical expression of asthma and COPD. Adult asthma and COPD patients demonstrate a higher prevalence of physical inactivity, obesity, and low-grade systemic inflammation; however, the exact interaction of these factors has not been studied and is unclear. Interventions that improve physical inactivity and reduce obesity may unravel a possible causal relationship between physical inactivity- and/or obesity-induced systemic inflammation and subsequent decline in lung function. Importantly, such studies should use performance-based instruments to assess physical inactivity.
Editor's comment: A very interesting review in linking physical inactivity and obesity to asthma and COPD.
ten Hacken, NHT, Physical inactivity and obesity: Relation to asthma and chronic obstructive pulmonary disease? Proceedings of the American Thoracic Society 2009; 6:663-667.
14. Epidemiology of the origins of airflow limitation in asthma.
There is now conclusive evidence that subjects with asthma, as a group, have lower levels of lung function as compared with their peers and that a significant proportion of subjects with persistent asthma are at risk of developing non-fully reversible airflow limitation. Although at the population level the most conspicuous form of airflow limitation in asthma seems to be that of subjects who wheeze during the first years of life and whose symptoms persist into adult life, asthma-related lung deficits can be related to both acquired deficits in growth of lung function in childhood and steeper decline of lung function in adult life. These trajectories of lung function are likely to differ across subgroups of individuals with asthma, suggesting that different windows of opportunity may exist to modify the natural course of the disease before irreversible deficits are established. These observations indicate the importance of identifying biomarkers that can be used to target children and adults with asthma at increased risk for airflow limitation and determining whether pharmacological interventions can protect these patients from the development of COPD.
Editor's comment: Another interesting review about the practical usefulness of knowledge of the epidemiology of asthma.
Guerra S and Martinez FD, Epidemiology of the origins of airflow limitation in asthma. Proceedings of the American Thoracic Society 2009; 6:707-711