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Archives: Medical Journal Reviews

Medical Journal Review

Posted: April 2010

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

1. Maternal stress and disruption of immunity in utero.
Associations among prenatal maternal stress and cord blood mononuclear cell (CBMC) cytokine responses were prospectively examined in the Urban Environment and Childhood Asthma Study (N=557 families). Prenatal maternal stress included financial hardship, Difficult Life Circumstances, community violence, neighborhood/block and housing conditions. Factor analysis produced latent variables representing three contexts - individual stressors and ecological-level strains (housing and neighborhood problems) which were combined to create a composite cumulative stress indicator. CBMCs were incubated with innate [lipopolysaccharide, Poly I:C, CpG, peptidoglycan] and adaptive [tetanus, dust mite, cockroach] stimuli, RSV, phytohemagglutinin, or medium alone. Cytokines were measured using multiplex ELISAs. Using linear regression, associations among increasing cumulative stress and cytokine responses were examined. Mothers were primarily minorities [Black (71%), Latino (19%)] with an income <$15,000 (69%). Mothers with the highest cumulative stress were older and more likely to have asthma and deliver lower birth weight infants. Higher prenatal stress was related to increased IL-8 production after microbial (CpG, PIC, PG) stimuli and increased TNF-α to microbial stimuli (CpG, PIC). In the adaptive panel, higher stress was associated with increased IL-13 after dust mite stimulation and reduced PHA-induced IFN-γ. Prenatal stress was associated with altered innate and adaptive immune responses in CBMCs.
Editor's comment: Stress-induced perinatal immunomodulation may impact the expression of allergic disease.
Wright RJ , Visness CM, Calatroni A et al. Prenatal Maternal Stress and Cord Blood Innate and Adaptive Cytokine Responses in an Inner-city Cohort. American Journal of Respiratory and Critical Care Medicine [Published online ahead of print, March 1, 2010]

2. Early-life viral infections and asthma.
The authors reviewed recent studies that highlight a potential role for human rhinovirus as a risk factor for asthma. The links between early-life viral lower respiratory infections (LRIs) and subsequent asthma are generally via wheeze; however, the presence of wheeze does not give any information about why the child is wheezing. Wheeze in early life is, at best, a fuzzy phenotype and not specific for subsequent asthma. The risk of asthma after viral LRI is increased in the presence of allergic sensitization in early life and if the infection is more severe. Atopy-associated mechanisms also appear to be involved in viral-induced acute exacerbations of asthma, especially in prolonging symptoms after the virus has been cleared from the lungs. Breaking the nexus between viral respiratory infections and asthma may be possible with interventions designed to inhibit atopy-related effector mechanisms from participating in the host response to respiratory viral infections.
Editor's comment: The research on the interaction between viruses and the immune system is crucial for the development of preventive strategies
Sly PD, Kusel M, Holt PG. Do early-life viral infections cause asthma? The Journal of Allergy and Clinical Immunology [Articles in press, Corrected Proof, Published online 22 March 2010]

3. IL-13 Gene polymorphisms in rhinosinusitis and eosinophilic Inflammation in aspirin intolerant asthma (AIA).
AIA is characterized by moderate to severe asthma aggravated by aspirin or NSAIs . Affected patients frequently have chronic rhinosinusitis (RS) and nasal polyposis with persistent upper and lower airway inflammation with marked eosinophilia. IL-13 plays a crucial role in the development of allergic asthma inducing airway eosinophilia and hyperreactivity, and it has been correlated with an increased eosinophil count. The authors studied two promoter polymorphisms of the IL-13 gene (-1510 A>C and -1055C>T) and one coding nonsynonymus Arg110Gln (110G>A) polymorphism. They were genotyped using primer extension methods in 162 patients with AIA, 301 patients with aspirin-tolerant asthma (ATA), and 430 normal healthy controls (NC). There was no significant difference in the genotype, allele, and haplotype frequencies of the three polymorphisms among the three groups. AIA patients with the AA genotype -1510A>C (P=0.012) and CC genotype -1055C>T (P<0.001) had a significantly higher frequency of RS than those with the minor alleles of these two SNPs. AIA patients with the GG genotype had higher peripheral eosinophils (P=0.025) and higher serum eotaxin-1 (P=0.044), as compared to patients with the AA genotype IL-13 Arg110Gln (110G>A). IL-13 Arg110Gln may be associated with increased eosinophils and eotaxin-1 and could increase eosinophilic inflammation in the upper and lower airways of patients with AIA.
Editor's comment: These findings suggest that the IL-13 polymorphisms at -1510A>C and 1055C>T are associated with the development of RS in AIA patients.
Palikhe NS, Kim SH, Cho BYet al, IL-13 Gene Polymorphisms are Associated With Rhinosinusitis and Eosinophilic Inflammation in Aspirin Intolerant Asthma. Allergy Asthma and Immunology Research 2010; 2(2);134-140.
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4. Cellular therapy approach to suppress allergic responses.
Bone marrow stromal cells [BMSCs; also known as mesenchymal stem cells (MSCs)] effectively suppress inflammatory responses in acute graft-versus-host disease in humans and in disease models in mice. Using a ragweed induced mouse asthma model, the authors studied if BMSCs could be beneficial in an allergic, Th2-dominant environment. When BMSCs were injected i.v. at the time of the antigen challenge, they protected the animals from asthma-specific pathological changes, including inhibition of eosinophil infiltration and excess mucus production, decreased levels of Th2 cytokines (IL-4, IL-5, and IL-13) in bronchial lavage, and lowered serum levels of Th2 immunoglobulins (IgG1 and IgE). To explore the mechanism of the effect the authors used BMSCs isolated from a variety of knockout mice, performed in vivo blocking of cytokines and studied the effect of asthmatic serum and bronchoalveolar lavage from ragweed challenged animals on the BMSCs in vitro. Their results suggest that IL-4 and/or IL-13 activate the STAT6 pathway in the BMSCs resulting in an increase of their TGF-β production, which seems to mediate the beneficial effect, either alone, or together with regulatory T cells.
Editor's comment: Allergic conditions-specifically therapy resistant asthma-might be a likely target of the recently discovered cellular therapy approach using BMSCs.
Nemeth K , Keane-Myers A, Brown JM et al, Bone marrow stromal cells use TGF-β to suppress allergic responses in a mouse model of ragweed-induced asthma. Proceedings of the National Academy of Sciences (PNAS) [Published online before print March 15, 2010]

5. Association of polymorphims in human histamine receptor H4 gene with atopic dermatitis (AD).
A strong connection between genetic factors and AD has been described and the histamine receptor H4 (HRH4) has been shown to be related to different kinds of allergic and autoimmune disorders. The authors examine a possible association between HRH4 and AD by extraction of genomic DNA from 301 patients with AD and 313 healthy controls. Three exons of HRH4 were sequenced. They found three new single nucleotide polymorphisms (SNPs) in HRH4 significantly associated with AD: ss142022671 (OR 1·87, 95% CI 1·24-2·81; P = 0·002), ss142022677 (OR 4·40, 95% CI 2·42-8·00; P = 1·5 × 10-7) and ss142022679 (OR 4·26, 95% CI 2·38-7·61; P = 1·3 × 10-7. Two-SNP haplotype analysis (ss142022677 and ss142022679) showed that the major AA haplotype was protective against AD (OR 0·22, 95% CI 0·12-0·40; P = 3·1 × 10-8) and the minor TT haplotype was significantly associated with AD (OR 4·13, 95% CI 2·27-7·54; P = 6·6 × 10-7).
Editor's comment: This could be one of the genetic connections between AD and allergy.
Yu B, Shao Y, Zhang J et al, Polymorphisms in the human histamine receptor H4 gene are associated with atopic dermatitis. British Journal of Dermatology [Early View, Articles online in advance of print, 1 March 2010]

6. Inhaled insulin absorption in asthmatics and the effects of bronchodilators.
People with mild and moderate asthma have been shown to absorb less inhaled insulin than healthy subjects. The authors investigated the effect of prior administration of a bronchodilator on the absorption of inhaled insulin in people with asthma treated with inhaled corticosteroids (ICs). A single-centre, randomized, open-label, two-period cross-over trial was carried out in 41 nondiabetic subjects with asthma treated with ICs, with reversible bronchoconstriction (RB) (Rev+; n= 25) or without RB (Rev-; n= 16). A dose of 0.10 U kg(-1) inhaled human insulin was administered on each dosing day with or without prior administration of terbutaline (in random order). Prior administration of terbutaline led to a 44% increase in absorption of insulin over 6 h for the Rev+ group compared with no prior administration, whereas no effect was seen for the Rev- or the whole group. The authors concluded that in asthmatics with RB, the administration of a bronchodilator prior to inhaled insulin led to increased absorption of insulin, whereas no effect on insulin absorption could be detected in subjects without significant reversibility.
Editor's comment: This study shows that reduction of bronchoconstriction in asthmatics leads to increased absorption of inhaled insulin.
Petersen AH, Korsatko S, Köhler G et al, The effect of terbutaline on the absorption of pulmonary administered insulin in subjects with asthma. British Journal of Clinical Pharmacology 2010; 69(3):271-8.

7. Predictors of oral tolerance/outgrowing of soy allergy.
The authors reviewed the records of patients with soy allergy seen in a tertiary referral clinic to describe the natural history of soy allergy and identify predictors of oral tolerance/outgrowing. The data collected included soy allergy-related symptoms, history of other food allergies and atopic diseases, soy-specific IgE levels, peanut-specific IgE levels, and food challenge results. One hundred thirty-three patients were studied (96 male and 37 female). Eighty-five (64%) had asthma, 95 (71%) had allergic rhinitis, and 108 (85%) had atopic dermatitis. Eighty-eight percent had concomitant peanut allergy. The median age at the initial visit was 1 year (range, 2 months to 17.5 years); the median duration of follow-up was 5 years (range, 1-19 years). Kaplan-Meier analysis predicted resolution of soy allergy in 25% by age 4 , 45% by age 6, and 69% by age 10. By age 6, 59% of children with soy IgE level of less than 5 kU/L, 53% of children with s-IgE level of 5 to 9.9 kU/L, 45% of children with s-IgE level of 10 to 49.9 kU/L, and 18% of children with s-IgE level greater than 50 kU/L had outgrown soy allergy (P < .01 for trend).
Editor's comment: 50% of children with soy allergy outgrew their allergy by age 7. Absolute soy IgE levels were useful predictors of outgrowing soy allergy.
Savage JH, Kaeding AJ, Matsui EC, et al. The natural history of soy allergy. Journal of Allergy and Clinical Immunology 2010; 125(3):683-6.

8. Hypersensitivity of the respiratory tract to budesonide.
The authors describe two cases. Firstly, a 37- year-old atopic woman who developed labial angioedema and nasal itching after the use of budesonide nasal spray. A month later, after the first puffs of a formoterol/budesonide spray prescribed for asthma, she noticed symptoms of tongue and oropharyngeal itching and redness with subsequent dysphagia, labial and tongue angioedema, and facial oedema. The second is a 15-year-old non-atopic woman who reported pruritic eruptions around the nostrils after using a budesonide nasal spray. A year later she presented nasal pruritus with intense congestion and labial and facial oedema after using the same spray. Both patients were evaluated with patch-tests using the commercial T.R.U.E. test®, a budesonide solution, and corticosteroid creams. Test evaluation was performed at 48 and 96 hours. In both patients, patch tests were positive to budesonide (++) on the second day. The first patient also had a positive (+) reaction to tixocortol-21-pivalate. All the other patch tests were negative.
Editor's comment: Respiratory type-IV hypersensitivity reactions due to corticosteroids is a rare phenomenon but clinicians should be aware that hypersensitivity reactions may occur during the use of nasal or orally inhaled corticosteroids.
Pitsios C, Stefanaki EC, Helbling A, Type IV delayed-type hypersensitivity of the respiratory tract due to budesonide use: report of two cases and a literature review. Primary Care Respiratory Journal 2009; 18 [Ahead of print, Article in press]
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9. Antitussive effects of leukotriene receptor antagonists.
To evaluate the antitussive effect of montelukast in cough variant asthma (CVA) and atopic cough (AC), seventy-five patients with chronic cough received diagnostic bronchodilator therapy with oral clenbuterol hydrochloride for 6 days. Of the 75 patients, 48 and 27 met the simplified diagnostic criteria for CVA and AC, respectively. Patients with CVA were randomly divided into 3 groups: montelukast, clenbuterol, and montelukast plus clenbuterol. Patients with AC were randomly divided into 2 groups: montelukast and placebo. The efficacy of cough treatment was assessed with a subjective cough symptom scale (0 meant "no cough" and 10 denoted "cough as bad as at first visit"). The cough scale, pulmonary function test, and peak expiratory flow rate (PEF) were evaluated before and after 2 weeks of treatment. In patients with CVA, 2-week treatment with montelukast, clenbuterol, and montelukast plus clenbuterol all significantly decreased cough scores and treatment with montelukast plus clenbuterol was superior to treatment with montelukast alone. In the montelukast plus clenbuterol group, PEF values in the morning and evening significantly increased after 2 weeks compared with values before treatment. In patients with AC, scores on the cough scale did not differ significantly between the montelukast group and the placebo group.
Editor's comment: Montelukast suppress chronic cough in CVA, but it was not effective in AC.
Kita T, Fujimura M, Ogawa H et al, Antitussive Effects of the Leukotriene Receptor Antagonist Montelukast in Patients with Cough Variant Asthma and Atopic Cough. Allergology International 2010;59(2) [Article in press]
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10. Reviewing the phenotypes of atopic dermatitis.
The author does a thorough review of various aspects of atopic dermatitis (AD). AD can be categorized into the extrinsic and intrinsic types. Extrinsic or allergic AD shows high total serum IgE levels and the presence of specific IgE for environmental and food allergens, whereas intrinsic or non-allergic AD exhibits normal total IgE values and the absence of specific IgE. While extrinsic AD is the classical type with high prevalence, the incidence of intrinsic AD is approximately 20% with a female predominance. The clinical features of intrinsic AD include relative late onset, milder severity, and Dennie-Morgan folds, but no ichthyosis vulgaris or palmar hyperlinearity. The skin barrier is perturbed in the extrinsic, but not intrinsic type. Filaggrin gene mutations are not a feature of intrinsic AD. The intrinsic type is immunologically characterized by the lower expression of interleukin (IL) -4, IL-5, and IL-13, and the higher expression of interferon-γ. It is suggested that intrinsic AD patients are not sensitized with protein allergens, which induce Th2 responses, but with other antigens, and metals might be one of the candidates of such antigens.
Editor's comment: Excellent review that clarifies important aspects of this difficult pathology.
Tokura Y, Extrinsic and intrinsic types of atopic dermatitis. Journal of Dermatological Science 2010; 58(1):1-7.

11. Assessment of inhaled corticosteroid treatment response in asthma.
Measuring cough response during bronchial provocation tests may offer an effective method for assessing treatment response in patients such as the elderly and children, who find spirometry difficult. The authors studied 16 steroid-naïve asthma patients and 10 non-asthmatic controls with respiratory symptoms, aged 20-66, who were asked to take beclomethasone 800 µg via a dry powder inhaler each day for 8 weeks. All the participants underwent inhalation challenge with hypertonic histamine solution before and after the treatment. Airway challenge responsiveness was expressed as the cumulative number of coughs divided by the final histamine concentration (coughs/concentration ratio [CCR]), and as the concentration of histamine used to induce a 20% fall in FEV1 (PC20). Analysis revealed that among asthma patients, the mean CCR fell from 494 coughs per mg/ml before to 73.6 coughs per mg/ml after 8 weeks of beclomethasone treatment. In addition, PC20 levels among the patients increased from 1.31 mg/ml before to 1.91 mg/ml after treatment. There were no significant changes in CCR, PC20, or symptoms among the non-asthmatic controls over the study period. The authors conclude that hypertonic histamine challenge-induced cough and PC20 are sensitive measures in assessing the treatment effect in asthma.
Editor's comment: The cough response may be especially useful in subjects who cannot perform spirometry reliably.
Purokivi M, Koskela H Koistinen T et al., Assessment of inhaled corticosteroid treatment response in asthma using hypertonic histamine challenge-induced cough. The Clinical Respiratory Journal 2010; 4(2):67-73.

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