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Archives: Medical Journal Reviews

Medical Journal Review

Posted: December 2010

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

1. Thymic stromal lymphopoietin (TSLP) gene variants linked to asthma.
To investigate if sex might modify the role thymic stromal lymphopoietin (TSLP) plays in asthma, the authors studied DNA samples collected from 417 Costa Rican children with asthma and their families. Significant associations were then validated in genetic data collected from 470 white and African-American asthmatic participants in the Childhood Asthma Management Program; 2,772 white and Hispanic participants (1,206 asthmatics) in the Children's Health Study; 935 African-Americans (464 asthmatics) in the Genomic Research on Asthma in the African Diaspora study; and 7,477 white participants (961 asthmatics) in the Framingham Heart Study. Using pooled data from all cohorts, the researchers found that two single nucleotide polymorphisms (SNPs) (rs1837253 and rs2289276) in TSLP were significantly associated with a reduced risk for asthma. Further analysis by gender revealed that the T allele of rs1837253 was significantly associated with a reduced risk (up to 16%) for asthma in males only, while the T allele of rs2289276 was significantly associated with a reduced risk (up to 13%) for the condition in females only. The authors concluded that they have identified a sex-specific association between two polymorphisms in the genomic region of TSLP and asthma. This work provides support to the growing body of evidence that TSLP plays an important role in the pathogenesis of asthma and the relation between sex and asthma.
Editor's comment: Two single nucleotide polymorphisms (SNPs) in the thymic stromal lymphopoietin gene (TSLP) are associated with a gender-specific reduced risk for asthma.
Hunninghake GM, Soto-Quirós ME, Avila L et al. TSLP polymorphisms are associated with asthma in a sex-specific fashion. Allergy 2010; 65(12): 1398-9995.

2. Optimum duration of dust mite sublingual immunotherapy (SLIT).
To investigate the long-term effects of SLIT, and the optimal duration of treatment, the researchers studied 78 patients aged 18-65 years, with allergic rhinitis (with or without asthma), who were monosensitized to dust mites. The participants were divided into four groups to receive mite-specific SLIT plus drug therapy for 3 (n=19), 4 (n=21), or 5 years (n=17), or drug therapy alone (controls; n=21). Clinical benefit, based on the frequency and severity of symptoms, were assessed every year during the winter months over a follow-up period of 15 years. During this time, 10 patients receiving SLIT and nine controls dropped out of the study. There was no significant change in clinical scores among the 12 controls. In patients receiving SLIT, a significant clinical benefit was observed after just 1 year, which persisted for 7 years among patients who received SLIT for 3 years, and 8 years among those who received SLIT for 4 or 5 years. After loss of clinical benefit, patients in the SLIT groups received a second course of treatment, and this induced a benefit more rapidly than the first course. All patients in the control group developed a new skin sensitization during the follow-up period compared with just 21%, 12%, and 11% of patients who received SLIT for 3, 4, and 5 years, respectively. They concluded that under the present conditions, it can be suggested that a 4-year duration of SLIT is the optimal choice because it induces a long-lasting clinical improvement similar to that seen with a 5-year course and greater than that of a 3-year vaccination.
Editor's comment: A 4-year course of sublingual immunotherapy (SLIT) would be the optimum duration for allergic rhinitis patients sensitized to dust mite allergens.
Marogna M, Spadolini I, Massolo A et al. Long-lasting effects of sublingual immunotherapy according to its duration: A 15-year prospective study. Journal of Allergy and Clinical Immunology 2010; 126(5): 969-975.

3. CX3CR1 and CX3CL1 are interesting therapeutic targets in allergic asthma.
CX3CL1 is upregulated upon inflammation. It has been proposed to contribute to inflammatory diseases by promoting the transmigration of CX3CR1-expressing cells to inflamed tissues. The authors investigated the role of CX3CR1 and CX3CL1 in the development of allergic airway inflammation in mice and found that untreated CX3CR1-deficient mice or wild-type (WT) mice treated with CX3CR1-blocking reagents show reduced lung disease upon allergen sensitization and challenge. Transfer of WT CD4(+) T cells into CX3CR1-deficient mice restored the cardinal features of asthma, and CX3CR1-blocking reagents prevented airway inflammation in CX3CR1-deficient recipients injected with WT T(H)2 cells. CX3CR1 signaling promoted T(H)2 survival in the inflamed lungs, and injection of B cell leukemia/lymphoma-2 protein (BCl-2)-transduced CX3CR1-deficient T(H)2 cells into CX3CR1-deficient mice restored asthma. CX3CR1-induced survival was also observed for T(H)1 cells upon airway inflammation but not under homeostatic conditions or upon peripheral inflammation. Therefore, CX3CR1 and CX3CL1 may represent attractive therapeutic targets in asthma.
Editor's comment: Blocking CX3CR1 signaling may represent a promising alternative therapy in allergic asthma.
Mionnet C, Buatois V, Kanda A et al. CX3CR1 is required for airway inflammation by promoting T helper cell survival and maintenance in inflamed lung. Nature Medicine 2010; 16(11): 1305-1312.

4. Viruses and bacteria in acute asthma exacerbations.
The authors reviewed systematically the current knowledge and developments in infection epidemiology of acute asthma in children and adults, describing the known impact for each individual agent and highlighting knowledge gaps. Exacerbations of asthma have been strongly and consistently associated with respiratory infections. Respiratory viruses and bacteria are therefore possible treatment targets. Among infectious agents, human rhinoviruses are the most prevalent in regard to asthma exacerbations. The newly identified type-C rhinoviruses may prove to be particularly relevant. Respiratory syncytial virus and metapneumovirus are important in infants, while influenza viruses seem to induce severe exacerbations mostly in adults. Other agents are relatively less or not clearly associated. Mycoplasma and Chlamydophila pneumoniae seem to be involved more with asthma persistence rather than with disease exacerbations. Recent data suggest that common bacteria may also be involved, but this should be confirmed.
Editor's comment: This is a very interesting update on the role of infections on asthma exacerbations.
Papadopoulos NG, Christodoulou I, Rohde G et al. Viruses and bacteria in acute asthma exacerbations - A GA2LEN-DARE* systematic review. Allergy, November 2010 [Published online ahead of print. doi: 10.1111/j.1398-9995.2010.02505.x]

5. T Helper 17-Associated Cytokines IL-17A and IL-17F in Asthma and COPD.
The T helper (Th) 17 cytokines IL-17A and IL-17F have been implicated in the development of neutrophilic airway inflammation, but their expression in asthma and COPD was uncertain.The authors assessed IL-17A and IL-17F expression in the bronchial submucosa from 30 subjects with asthma, 10 ex-smokers with mild to moderate COPD, and 27 nonsmoking and 14 smoking control subjects. IL-17A was increased in mild to moderate asthma compared with healthy control subjects but not in severe asthma. In COPD, IL-17A was increased compared with nonsmoking control subjects but not compared with smoking control subjects. IL-17F was increased in severe asthma and mild to moderate asthma compared with healthy controls subjects but was not increased in subjects with COPD. IL-17A and IL-17F were not associated with increased neutrophilic inflammation, but IL-17F was correlated with the submucosal eosinophil count. The sputum IL-17 concentration in COPD was increased compared with asthma and was correlated with post-bronchodilator FEV1% predicted and FEV1/FVC. These findings support a potential role for the Th17 cytokines IL-17A and IL-17F in asthma and COPD, but do not demonstrate a relationship with neutrophilic inflammation.
Editor's comment: IL-17A and IL-17F do not appear to be associated with neutrophilic inflammation in asthma and COPD.
Doe C, Bafadhel M, Siddiqui S et al. Expression of the T Helper 17-Associated Cytokines IL-17A and IL-17F in Asthma and COPD. Chest 2010; 138(5): 1140-1147.

6. Objective Airway Monitoring Improves Asthma Control.
The authors evaluated the impact of an intervention to facilitate communication about the therapeutic plan, with a focus on improving inhaled corticosteriod (ICS) adherence, asthma control, and outcomes. In total, 139 asthma patients were enrolled. Of these, 68 patients being treated by 22 clinicians were assigned to the intervention group and 71 patients being treated by 21 clinicians were assigned to the control group. Both patient groups were similar in terms of age, gender, race, ethnicity, age at diagnosis, and lung function. Patients in the intervention group attended monthly clinician appointments to discuss peak flow data, while those in the control group received standard care. The researchers found that significantly fewer patients in the intervention group required courses of oral steroids during winter (9% vs 23%) and spring (3% vs 17%) than those in the control group. Furthermore, significantly fewer patients in the intervention group reported periods of worsening symptoms (65% vs 89%) and urgent care visits (10% vs 23%) during winter. The day-to-day peak flow variability fell consistently among patients in the intervention group, from an average of 32% at baseline to 23% at the end of the study period, indicating reduced airway reactivity over time. Post hoc analysis revealed that patients in the intervention group had greater adherence to ICS medication during winter. The authors concluded that their findings suggest that interpreted PFM may be beneficial to people with asthma during the seasons of greatest vulnerability.
Editor's comment: The peak flow information apparently led to improvements in ICS adherence resulting in less need for prednisone rescue medication and fewer episodes of worsening symptoms.
Janson SL, McGrath KW, Covington JK et al. Objective Airway Monitoring Improves Asthma Control in the Cold and Flu Season: A Cluster Randomized Trial. Chest 2010; 138(5): 1148-1155.

7. Raman spectroscopy permits stratification of filaggrin-associated atopic dermatitis (AD).
The authors determined whether specific Raman microspectroscopic natural moisturizing factor (NMF) signatures of the stratum corneum could be used as markers of filaggrin (FLG) genotype in patients with moderate-to-severe AD. Raman microspectroscopy uses the scattering of monochromic light by molecular vibrations to provide a noninvasive, real-time picture of disturbances in skin at the molecular level. In AD, it can detect abnormal filaggrin and thereby identify individuals carrying filaggrin mutations. Investigators monitored the composition and function of skin in 132 patients with moderate-to-severe AD. The use of Raman microspectroscopy to distinguish patients with one or more gene mutations from those with normal filaggrin genotypes had a sensitivity of 99% and a specificity of 87%. Functional measurements of transepidermal water loss, on the other hand, were not very helpful.
Editor's comment: In patients with AD, noninvasive Raman microspectroscopy can reveal disturbances in skin barrier function at the molecular level.
O'Regan GM, Kemperman PM, Sandilandset A al. Raman profiles of the stratum corneum define 3 filaggrin genotype-determined atopic dermatitis endophenotypes. Journal of Allergy and Clinical Immunology 2010; 126(3): 574-580.
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8. Meloxicam in patients with non-steroidal anti-inflammatory drug (NSAID)-induced urticaria (UR)/angioedema (AE).
The authors investigated the safety of preferential COX-2 inhibitor meloxicam in subjects with UR or AE type intolerance reaction to classical NSAIDs. Subjects with reliable or documented history of UR/AE due to classical NSAIDs underwent a single-blinded, placebo-controlled oral challenge with a cumulative dose of 7.5 mg meloxicam on 2 separate days. One-quarter and three-quarter divided doses of meloxicam or placebo were given at 1-h intervals. 116 patients (86 women and 30 men, mean age 39.6 ± 12.7 years) were enrolled to the study. The rate of atopy was 25.9%. Mean duration of drug reaction was 87.4 ± 110.8 (1-720) months. Almost half of the patients were multi-reactors. The most comorbid disease was asthma and the two most frequent NSAIDs inducing UR/AE were paracetamol (19. 6%) and aspirin (19%). Ten out of 116 patients (8.6%) developed mild UR/AE, or only erythema and pruritus at a one-quarter or cumulative dose of 7.5 mg of meloxicam. The remaining subjects (91.4%) tolerated perfectly meloxicam challenge. No reaction to placebo was observed. This study indicates that 7.5 mg meloxicam is a safe alternative for NSAID-intolerant UR/AE patients.
Editor's comment: Preferential COX-2 inhibitors may be a useful alternative in patients with NSAID-induced urticaria/angioedema.
Göksel O, Aydin O, Misirligil Z et al. Safety of meloxicam in patients with aspirin/non-steroidal anti-inflammatory drug-induced urticaria and angioedema. The Journal of Dermatology 2010; 37(11): 973-979.

9. Osteopontin (OPN) is not directly involved in the pathogenesis of allergic rhinitis (AR).
The aim of the authors was to determine the level and tissue distribution of OPN expression in the nasal mucosa of patients with AR and to determine whether OPN expression is affected by allergen exposure during a grass pollen season in allergic individuals, and if a nasal glucocorticoid affected local OPN expression. Subjects with AR were randomised to receive treatment with fluticasone propionate (FP) (n = 12) or placebo (n = 16) over the grass pollen season and nasal biopsies were taken prior to, and during the season. OPN expression in the nasal mucosa was examined with immunohistochemistry. Healthy non-AR controls (n = 5) were used as controls. OPN expression was detected in epithelial cells, subepithelial infiltrating/inflammatory cells and cells lining the vessels and glands of all subjects. Comparison of the pre- and peak-pollen season biopsy sections in placebo treated patients revealed no increase in OPN expression during the grass pollen season. Treatment with a local glucocorticosteroid did not alter the expression of OPN during pollen exposure. The authors concluded that OPN expression in the nasal mucosa of AR patients is not significantly affected by allergen exposure and is comparable to that of the healthy controls, suggesting that intracellular OPN is not directly involved in the pathogenesis of allergic rhinitis.
Editor's comment: Although OPN has been increasingly associated with the pathogenesis of various Th2-mediated diseases, it seems that it´s not involved in allergic rhinitis.
O'Neil SE, Malmhäll C, Samitas K et al. Quantitative expression of osteopontin in nasal mucosa of patients with allergic rhinitis: effects of pollen exposure and nasal glucocorticoid treatment. Allergy, Asthma & Clinical Immunology 2010; 6:28
Full Text, Open Access

10. Peach-induced contact urticaria is associated with lipid transfer protein sensitization.
The present study focused on peach-induced contact urticaria and aimed to investigate its prevalence and whether one particular main peach allergen is associated with this symptom.. Ninety-two peach-allergic subjects were studied. Patients were diagnosed as being sensitized to lipid transfer protein (LTP; Pru p 3) or as having a pollen-food allergy syndrome induced by Pru p 1 and/or profilin, Pru p 4, on the basis of the results of a skin prick test containing these allergenic proteins in an isolated form. Overall, contact urticaria was present in 21% of patients; the peach contact skin test was positive in all cases. Contact urticaria was significantly more frequent in patients hypersensitive to LTP (63%) than in subjects with pollen-food allergy syndrome (6%) and was not associated with a higher level of peach-specific IgE. In several cases, contact urticaria preceded the onset of food allergy by years. The contact test with nectarine scored negative in 5/5 cases. The negative clinical history and contact test with nectarine along with the well-known high concentration of LTP in peach fuzz suggest that peach fuzz plays a role in the pathogenesis of contact urticaria.
Editor's comment: LTP released from peach fuzz might play a relevant role in the pathogenesis of contact urticaria.
Asero R. Peach-induced contact urticaria is associated with lipid transfer protein sensitization. International Archives of Allergy and Immunology 2010; 154(4): 345-348.

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