Medical Journal Review
Posted: November 2008
Reviewed by Prof. Richard F. Lockey, MD, WAO Web Editor-in-Chief, and Guest Editor Mark Glaum, MD PhD
1. EFFECT OF PHARMACOTHERAPY ON RATE OF DECLINE OF LUNG FUNCTION IN COPD - RESULTS FROM THE TORCH STUDY
This study investigates the effects of combined salmeterol (S) 50 μg plus fluticasone propionate (F) 500 μg (SF), either S or F alone or placebo (P), on the rate of post-bronchodilator FEV1 decline in patients with moderate or severe COPD. 5,343 of 6,112 patients in the TORCH Study were included in the analysis of randomized, DBPC data. Spirometry was measured every 24 weeks for three years and there were 26,539 on-treatment observations. The adjusted rate of decline in FEV1 was 55 ml/year for P, 42 ml/year for S, 42 ml/year for F, and 39 ml/year for SF (95% confidence interval, 7-25; P <0.001). Rates of decline were similar among the active treatment arms. Decline rates were the greatest in current smokers and patients with a lower body mass index. Treatment with SF or S or F reduces the rate of decline in FEV1 in patients with moderate to severe COPD. Editor's comment: Treatment with S, F, or SF decreases the decline in FEV1 in COPD. Celli BR, et al., Am J Respir Crit Care Med 2008;178:332. (editorial: a Suissa, pp. 322)
2. A 4-YEAR TRIAL OF TIOTROPIUM (T) IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)
This randomized, DBPC trial compared four yrs of therapy with either T or placebo (P) in patients with COPD permitted to use all respiratory medications except inhaled anticholinergic agents. A total of 5993 patients (mean age, 65±8 yrs) with a mean FEV1 of 1.32±0.44 liters after bronchodilation (48% of predicted value) participated. 2987 were assigned to T and 3006 to P. Mean absolute improvements in FEV1 in the T group were maintained compared to P (P <0.001). After day 30, the differences between the two groups in the rate of decline in the mean FEV01 before and after bronchodilation were not significant. The mean absolute total score on the St. George's Respiratory Questionnaire (SGRQ) was lower in the T group at each time point throughout four yrs. At four yrs and 30 days, T was associated with a reduction in the risks of exacerbations, related hospitalizations and respiratory failure. The authors conclude that T is associated with improvements in lung function, quality-of-life (QOL), and exacerbations during a four yr period but does not reduce the rate of decline in FEV1. Editor's comment: T is an excellent medication to treat COPD. Tashkin DP, et al., N Engl J Med 2008;359:1543.
3. ALLERGEN IMMUNOTHERAPY (AI): WHAT CAN AND CANNOT BE MIXED?
Grass pollen allergens are most susceptible to proteases. Fungal and insect allergenic extracts contain the highest levels of proteases and should be separated from pollen extracts, particularly grass extracts, unless otherwise indicated by the manufacturer. Grass allergens can be mixed with U.S. manufactured dust mite extracts at concentrations for optimal therapeutic outcomes. These mite extracts contain relatively low protease content since they are derived from 99% pure mite bodies as compared to European extracts which contain higher levels of protease because they are derived from spent cultures. An AAAAI committee investigated the stability of an extract containing standardized dust mite, cat hair, short ragweed pollen, and timothy grass pollen. The optimal concentration for immunotherapy retained potency for up to one year when stored at 2ºC to 8ºC. A figure is included indicating which extracts should or should not be mixed with others. Editor's comment: This is a short, easily understood treatise on allergen extracts and compatibility in a mixed vaccine. Esch RE, J Allergy Clin Immunol 2008;122:659.
4. WHEEZING RHINOVIRUS (RV) ILLNESSES IN EARLY LIFE PREDICT ASTHMA (A) DEVELOPMENT IN HIGH-RISK CHILDREN
259 children (one parent was required to have a positive aeroallergen skin test and A) were followed prospectively from birth to six years of age during which time the etiology and timing of specific viral wheezing respiratory illnesses were assessed using nasal lavage, culture, and multiplex reverse transcriptase-polymerase chain reaction. Viral etiologies were identified in 90% of wheezing illnesses. From birth to age three yrs, respiratory syncytial virus (RSV) (OR, 2.6), RV (OR, 9.8), or both, (OR, 10) were associated with increased A risk at six yrs. In year one, both RV wheezing (OR, 2.8) and aeroallergen sensitization (OR, 3.6) independently increased A risk at age six yrs. By age three yrs, wheezing with RV (OR, 25.6) was more strongly associated with A at age six yrs than aeroallergen sensitization (OR, 3.4). Nearly 90% (26 of 30) of children who wheezed with RV in year three had A at six yrs of age. Wheezing in infancy and early childhood associated with RV infections are the most significant predictors of subsequent A at age six in a high-risk birth cohort. Editor's comment: RV infection in early life is associated with a risk for asthma. Jackson DJ, et al., Am J Respir Crit Care Med 2008;178:667.
5. BODY MASS AND GLUCOCORTICOID (GC) RESPONSE IN ASTHMA (A)
45 non-smoking adults, 33 with and 12 without A underwent characterization of lung function, BMI, and spirometric response to prednisone. Dexamethasone (DEX, 10-6 M) -induced mitogen-activated protein kinase phosphatase-1 (MKP-1) and baseline tumor necrosis factor (TNF)-α expression were evaluated by PCR in peripheral blood mononuclear cells (PBMCs) and bronchoalveolar lavage cells. DEX-induced PBMC MKP-1 expression was reduced in overweight/obese vs lean patients with A (P = 0.01). PBMC TNF-α; expression increased as BMI increased in A (P = 0.01). The PBMC log (TNF-α):DEX-induced MKP-1 ratio also increased as BMI increased in A (P =0.004). In bronchoalveolar lavage cells, DEX-induced MKP-1 expression was also reduced in overweight/obese versus lean patients with A (P = 0.05). Similar findings were not observed in control subjects. The authors conclude that in vitro biomarkers of GC insensitivity increase in both the lung and peripheral blood as body mass increases in A. Editor's comment: Obesity may lead to reduce efficacy of GC in A subjects. Sutherland ER, et al., Am J Respir Crit Care Med 2008;178:682.
6. ARG 1 IS A NOVEL BRONCHODILATOR RESPONSE GENE
The authors genotyped 844 single nucleotide polymorphisms (SNPs) in 111 candidate genes in 209 children and their parents participating in the Childhood Asthma (A) Management Program. The association of these SNPs with acute response to inhaled β-agonists (bronchodilator response [BDR]) was screened using a novel technique. Genes that had SNPs with median power in the highest quartile were then taken for replication analyses in three other asthma cohorts. Evidence for association from the four A cohorts was combined, and SNPs from ARG 1 were significantly associated with BDR. The authors conclude that ARG 1 is a novel gene for acute BDR in both children and adults with A. Editor's comment: The arginase 1 gene (ARG1) is a potential β-agonist response gene. Litonjua AA, et al., Am J Respir Crit Care Med 2008;178:688.
7. EFFECTS OF DOG OWNERSHIP IN EARLY CHILDHOOD ON IMMUNE DEVELOPMENT AND ATOPIC DISEASES
275 children at increased risk of developing allergic diseases were evaluated to age three yrs for pet ownership, blood cell cytokine responses, and atopy. Can f 1, Fel d 1, endotoxin, ergosterol, and muramic acid were measured in settled dust from 101 homes. Dog exposure at birth was associated with decreased atopic dermatitis (AD) (P = 0.004) and wheezing (W) (P = 0.005) in year three. The rates of AD and W in year three were relatively high in children who acquired dogs after birth. The prevalence of dog sensitization between the two groups did not vary according to dog exposure. Can f 1 levels in bedroom dust were positively associated with IL-10 (P =0.01), IL-5 (P< 0.001), and IL-13 (P =0.0004) responses at age one and IL-5 (P=0.022) and IL-13 (P=0.015) responses at age three. Endotoxin was associated with IFN-γ (P=0.002) and IL-13 (P=0.01) responses at age three but not at age one, and similar relationships were found for muramic acid. Exposure to dogs in infancy, and especially around the time of birth, is associated with changes in immune development. Reductions in W and atopy are not explained by exposure to endotoxin, ergosterol, or muramic acid. Editor's comment: The means by which dog ownership at birth may prevent atopic disease remains an enigma. Bufford JD, et al., Clin Exp Allergy 2008;38:1635.
8. SUBLINGUAL IMMUNOTHERAPY (SLIT) IN YOUNGSTERS: ADHERENCE IN A RANDOMIZED CLINICAL TRIAL
204 youngsters (6-18 yrs) with hayfever participated in a SLIT randomized controlled trial with grass pollen extract or placebo for two yrs. The primary outcome, i.e., change in mean daily total rhinoconjunctivitis symptom score in the second grass pollen season was negative. Adherence to medication intake was assessed by weighing the study medication. Participants who completed the follow-up and used ≥80% of the prescribed medication were considered adherent. 154 youngsters completed the study. The number and reasons for drop-outs did not differ between treatment groups. Drop-out was affected by age, evaluation of the treatment effect and medication instructions. Non-adherence to medication intake was influenced by the severity of the disease before the trial. However, the ineffectiveness of SLIT could not be explained by non-adherence. Editor's comment: Non-adherence to the study protocol did not explain the outcome in this negative SLIT study. Röder E, et al., Clin Exp Allergy 2008;38:1659.
9. ARE FISH OIL SUPPLEMENTS SAFE IN FINNED FISH (FF)-ALLERGIC PATIENTS?
Many manufacturers label fish oil supplements with the warning "avoid this product if you are allergic to fish". Six FF-sensitive subjects, as determined by a positive history and skin tests, were selected. They were skin tested with two different fish oil supplements and given an oral challenge of each supplement one hour apart. All patients with positive skin tests to at least one FF had negative skin tests to both fish oil supplements. All tolerated the fish oil challenge. This pilot study indicates that FF-sensitive patients tolerate fish oil supplements. Editor's comment: These data indicate that food labeling for FF-allergic subjects is not necessarily accurate. Mark BJ, et al., Allergy and Asthma Proc 2008:29:528.
10. GOOD PROGNOSIS, CLINICAL FEATURES, AND CIRCUMSTANCES OF PEANUT AND TREE NUT REACTIONS (PTNR) IN CHILDREN TREATED BY A SPECIALIST ALLERGY CENTER
785 children were followed for 3640 patient-years for PTNR. The prognosis for children with PTNR is good with a low frequency and severity of subsequent reactions and need for epinephrine (E). School age children are at highest risk for a recurrent reaction, which occurs most commonly at home. The fact that few reactions occur in school is attributed to informed school training by professionals with expertise in food allergy. Contact PTNR were always mild. A three-fold reduction in the use of E in subsequent vs the index reaction is reported. Index reactions were mild in 66% (516), moderate in 29% (224) and severe in 5% (45). Ninety percent had the same/reduced severity grade on follow-up reactions. Editor's comment: Education is the primary means to control PTNR. By doing so, accidental reactions are uncommon and when they do occur, they are usually mild requiring little or no treatment. Clark AT, et al., J Allergy Clin Immunol 2008;122:286.
11. REVIEW ARTICLES ON EXERCISE-INDUCED ASTHMA (EIA)
The August J Allergy Clin Immunol contains five articles on EIA, "Airway injury as a mechanism for exercise-induced bronchoconstriction in elite athletes" (Anderson SD, et al., p225); "Exercise and other indirect challenges to demonstrate asthma or exercise-induced bronchoconstriction in athletes" (Rundell KW, et al., p238); "The elite athlete: Yes, with allergy we can" (Bonini S, et al., p249); "Long-acting β-agonists and exercise" (Weinberger M, p251); "Asthma and the elite athlete: Summary of the International Olympic Committee's Consensus Conference, Lausanne, Switzerland, January 22-24, 2008" (Fitch KD, et al., p254). EIA is caused by evaporative water loss resulting in cooling and dehydration of the airway surface. The release of mediators is also implicated. These reviews outline the pathophysiology of EIB and how to diagnose and treat it even in elite athletes compelled to follow international guidelines required by the World Anti-Doping Agency. Editor's comment: Great review articles on EIA. J Allergy Clin Immunol 2008;122. Anderson; Rundell; Bonini; Weinberger; Fitch
12. NEURO-MEDIATORS AS PREDICTORS OF PAEDIATRIC ATOPIC DERMATITIS (AD)
40 AD cases were matched with 80 unaffected controls from the prospective Taiwan birth panel cohort study. Concentrations of IgE, nerve growth factor (NGF), and vaso-active intestinal peptide (VIP) in cord and maternal plasma were performed by ELISA. The NGF levels were significantly higher in AD patients vs controls (mean ± SD: 65.47 ± 44.45 vs 49.21 ± 12.18 pg/mL for cord plasma and 89.68 ± 41.04 vs 66.96 ± 23.05 pg/mL for maternal plasma) (P < 0.05). Comparative VIP levels were not significantly different from controls. NGF was a better biomarker than IgE to detect both intrinsic and extrinsic pediatric AD. The authors conclude that NGF is a good alternative biomarker to predict childhood AD. Editor's comment: NGF should be investigated as a biomarker for other atopic diseases. Wang IJ, et al., Clin Exp Allergy 2008;38:1302.
13. WHEEZING (W) IN CHILDHOOD: INCIDENCE, LONGITUDINAL PATTERNS AND FACTORS PREDICTING PERSISTENCE
This study investigates the incidence and natural course of W over the first 13 yrs of life and risk factors which predict W at 11-13 yrs. The Multicentre Allergy Study, a German birth cohort, recruited 1,314 children in 1990. History and physical examinations, immunoglobulin(Ig) E, and lung function tests were performed up to 13 yrs of age. Complete data on 441 children indicate that W declined with age. The first W episode was reported by 29%, 9% and 9% of participants at <3 yrs (early W), 3-6 yrs (late W), and >6 yrs (very late W) of age, respectively. W at age 13 was associated with parental atopy, with positive in vitro IgE tests, elevated IgE, and exposure to high levels of indoor allergens in early life. All associations were stronger among early W vs nonwheezers. The authors conclude that the early expression of atopy as a predictor of W at age 13 declines with increasing age of W onset. Editor's comment: Parental atopy, positive in vitro IgE tests, elevated IgE, and high levels of indoor allergens in early life are associated with higher incidence of W at age 13 in children. Matricardi PM, et al., Eur Respir J 2008;32:585.