Medical Journal Review
Posted: August 2010
Reviewed by Juan Carlos Ivancevich, MD, in collaboration with Phil Lieberman, MD.
1. Recommendations for the assessment in allergic rhinitis and asthma: a GA²LEN taskforce position paper.
The expression, "Patient-Reported Outcomes" (PROs), which came into frequent use only in the last decade, refers to "any report coming from patients about a health condition and its treatment", as opposed to data provided by other sources (clinical and instrumental tests, providers and caregivers). PROs are gaining increasing awareness and emphasis in clinical research and by regulatory bodies because of their relevance in the overall treatment efficacy assessment. Among PROs, Health-Related Quality of Life (HRQoL) and patient-reported symptoms have been extensively evaluated in rhinitis and asthma, but unexplored areas and methodological limits have recently been identified and discussed. This approach enables us to better understand patient-related factors influencing clinical trials and real-life management outcomes, to identify patients subgroups that can benefit from specific treatment and management plans and to tailor treatment to address PROs (not only physician-defined targets) to improve asthma and rhinitis management.
Editor's comment: PROs are gaining increasing awareness and emphasis because of their relevance in the overall treatment efficacy assessment.
Braido F, Bousquet PJ, Brzoza Z et al. Specific recommendations for PROs and HRQoL assessment in allergic rhinitis and/or asthma: A GA²LEN taskforce position paper. Allergy 2010; 65(8): 959-968.
2. Efficacy of allergen-specific immunotherapy as a steroid-sparing agent in children with allergic asthma.
The aim of this study was to investigate the efficacy of an allergen-specific immunotherapy with a high-dose hypoallergenic mite preparation (allergoid) as a steroid-sparing agent in children with allergic asthma. Sixty-five children with asthma (Global Initiative for Asthma treatment levels II and III; 6-17 years old), after reaching asthma control with inhaled steroids during a 5-month baseline period, were randomized to receive subcutaneous mite allergoid immunotherapy (SCIT) plus fluticasone propionate (FP), or FP therapy alone for 2 years. During 2 subsequent 5-month winter periods, steroid therapy was adjusted according to predefined dose steps, determining and comparing the changes in FP dosages and the lowest FP dose sufficient to maintain asthma control. Immunologic and functional investigations were also carried out. Children treated with house dust mite SCIT plus FP were able to significantly reduce the FP dose by more steps (P < .05), compared to the group on FP alone. The mean daily dose in the immunotherapy group decreased from 330.3 µg in the baseline period to 151.5 µg after 2 treatment years, whereas in the control group the dose decreased from 290.6 µg to 206.3 µg. Compared with the control group, significant improvement was also observed in morning peak expiratory flow (P = .0315). Significantly increased levels of specific IgG(1) (P = .0001) and IgG(4) (P < .0001) were also observed. The authors concluded that adding mite allergoid SCIT to pharmacologic treatment is an effective and safe strategy to reduce corticosteroid doses while maintaining disease control in children with mite-induced allergic asthma.
Editor's comment: Specific immunotherapy in allergy induced asthma should not be an alternative but a complementary treatment to drug treatment.
Zielen S, Kardos P, and Madonini E. Steroid-sparing effects with allergen-specific immunotherapy in children with asthma: A randomized controlled trial. Journal of Allergy and Clinical Immunology 2010; in press [published online ahead of print 12 July 2010]
3. Cigarette smoke induced inflammation in upper and lower airways.
Cigarette smoke (CS) is known to initiate a cascade of mediator release and accumulation of immune and inflammatory cells in the lower airways. The authors investigated and compared the effects of CS on upper and lower airways in a mouse model of subacute and chronic CS exposure. C57BL/6 mice were whole-body exposed to mainstream CS or air, for 2, 4 and 24 weeks. Bronchoalveolar lavage fluid (BAL) was obtained and tissue cryosections from nasal turbinates were stained for neutrophils and T cells. Furthermore the investigators evaluated GCP-2, KC, MCP-1, MIP-3alpha, RORc, IL-17, FoxP3, and TGF-beta1 in nasal turbinates and lungs by RT-PCR. In both upper and lower airways, subacute CS-exposure induced the expression of GCP-2, MCP-1, MIP-3alpha and resulted in a neutrophilic influx. However, after chronic CS-exposure, there was a significant downregulation of inflammation in the upper airways, while on the contrary, lower airway inflammation remained present. Whereas nasal FoxP3 mRNA levels increased after 2 weeks, lung FoxP3 mRNA increased only after 4 weeks, suggesting that mechanisms to suppress inflammation occur earlier and are more efficient in the nose than in the lung. Altogether, these data demonstrate that CS induced inflammation may be differently regulated in the upper versus lower airways in mice. Furthermore, these data may help to identify new therapeutic targets in this disease model.
Editor's comment: CS induced inflammation may be differently regulated in the upper versus lower airways in mice.
Huvenne W, Pérez-Novo CA, Derycke L et al. Different regulation of cigarette smoke induced inflammation in upper versus lower airway. Respiratory Research 2010;
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4. Theophylline: A new way to overcome corticosteroid resistance?
Theophylline, when used at bronchodilator doses, is difficult to monitor due to its interaction with various drugs and its narrow therapeutic index. However, when theophylline is used at low doses it has anti-inflammatory properties and may enhance the activity of a key corticosteroid-associated corepressor protein, histone deacetylase (HDAC), which is reduced in COPD. Therefore, inhaled corticosteroids and low-dose theophylline may not only independently reduce airway inflammation in COPD, but they may act synergistically. In a study to test the hypothesis that the combination of inhaled corticosteroids and theophylline has a greater therapeutic effect than theophylline alone, 30 patients with COPD discontinued any treatments with inhaled corticosteroids (ICS) and underwent a run-in period of 2 weeks. They were then randomized to two treatment arms. Subjects in Arm 1 were given inhalation placebo and placebo theophylline capsules for the first four-week period, and those in Arm 2 were given inhaled fluticasone propionate (FP, 500 µg bid) and placebo theophylline capsules. After a two-week washout period, subjects in Arm 1 were given inhalation placebo plus active theophylline (250 mg bid) for a second four-week period, and subjects in Arm 2 received FP plus active theophylline. Subsequently, the trial was extended with an open-label repeat of Arm 2 and included seven subjects from the original trial. The researchers found that the combination treatment with fluticasone and theophylline significantly reduced total sputum eosinophils. In addition, they showed that the FEV1 % predicted significantly increased with the fluticasone-theophylline combination. The combination of FP plus theophylline increased forced mid-expiratory flow rate from 470 mL/s to 555 mL/s.
Editor's comment: Combination therapy with an inhaled corticosteroid and low-dose theophylline may be helpful in treating airway inflammation in COPD patients.
Ford PA, Durham AK, Russell REK et al. Treatment effects of low-dose theophylline combined with an inhaled corticosteroid inCOPD. Chest 2010; 137(6): 1338-1344.
5. Study suggests the protein interferon (IFN) blocks Th2 cells and might be valuable for asthma patients.
This study found that type I IFN (IFN-/β) blocked human Th2 development and inhibited cytokine secretion from committed Th2 cells. This negative regulatory pathway was operative in human but not mouse CD4+ T cells and was selective to type I IFN, as neither IFN- nor IL-12 mediated such inhibition. IFN-/β blocked Th2 cytokine secretion through the inhibition of GATA3 during Th2 development and in fully committed Th2 cells. Ectopic expression of GATA3 via retrovirus did not overcome IFN-/β-mediated inhibition of Th2 commitment. The next step is to study whether interferon will prevent Th2 cells, that have been taken straight from asthma patients, from secreting the chemicals known to induce asthma. If interferon works against these cells, that would be an excellent basis for beginning a clinical trial and treating asthma patients.
Editor's comment: The findings provide proof-of-principle that targeting this particular group of cells with interferon might be an effective therapy for asthma patients.
Huber JP, Ramos HJ, Gill MA et al. Type I IFN reverses human Th2 commitment and stability by suppressing GATA3. Journal of Immunology 2010; 185(2): 813-817.
6. Improvement in the management of atopic dermatitis (AD) influences the appearance of respiratory allergic diseases.
The study included 176 children affected by atopic dermatitis (AD) and previously evaluated between 1993 and 2002 at the age of 9-16 months, who underwent a telephonic interview by means of a semi-structured, pre-formed questionnaire after a mean follow-up time of 8 years. According to the SCORAD (scoring atopic dermatitis), at first evaluation children had mild AD in 23% of cases, moderate in 62%, severe in 15%. AD disappeared in 92 cases (52%), asthma appeared in 30 (17%) and rhinoconjunctivitis in 48 (27%). The factors significantly related to the appearance of asthma were: sensitization to food allergens with sIgE > 2 KU/L (cow's milk and hen's egg; P < 0.05) or to inhalant allergens with sIgE > 0.35 KU/L (P < 0.05). Logistic regression analysis showed that inhalant sensitization was positively related to the occurrence of asthma (OR = 4.219). While AD showed similar rates of disappearance to those of a previously published study performed by the same investigators, the incidence of asthma was reduced, at the same follow-up time, from 29% to 15% (P = 0.002), and the incidence of rhinoconjunctivitis from 35% to 24% (P = 0.02). Integrated management of AD does not seem to influence its natural course. Nevertheless, the decrease in the percentage of children evolving towards respiratory allergic disease stresses the importance of early diagnosis and improvement in management carried out by specialist centers. The presence of allergic sensitization at one year of age might predict the development of respiratory allergy.
Editor's comment: This study is further proof of the allergic march.
Ricci G, Patrizi A, Giannetti A et al. Does improvement management of atopic dermatitis influence the appearance of respiratory allergic diseases? A follow-up study. Clinical and Molecular Allergy 2010; 8(8).
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7. Validation of the Asthma Control Questionnaire (ACQ) in children.
This study evaluated the validity, measurement properties and interpretability of the ACQ in children 6-16 yrs. 35 children attended clinic on 3 occasions (0,1 & 4 wks) and completed the ACQ, Mini Paediatric Asthma Quality of Life Questionnaire and Royal College of Physicians Questionnaire. Parents completed the Paediatric Asthma Caregivers Quality of Life Questionnaire. Between visits children completed the Asthma Control Diary and measured PEF. At weeks 1& 4, clinicians and parents completed global rating of change questionnaires. All patients completed the study. 19 children were stable between two assessments and provided evidence of good test-retest reliability (Intraclass Correlation Coefficient=0.79). The ACQ was responsive to change in asthma control (p=0.026) and the Minimal Important Difference was 0.52±0.45. Both cross-sectional and longitudinal correlations between the ACQ and the other outcomes were close to predicted and provided evidence that the ACQ measures asthma control in children. The ACQ has strong measurement properties and is valid for use in children 6-16 yrs.
Editor's comment: The ACQ has been validated in adults but requires careful validation in pediatric asthma.
Juniper EF, Gruffydd-Jones K, Ward S et al. Asthma control questionnaire in children validation, measurement properties, interpretation. European Respiratory Journal 2010 [published online before print 7 June 2010].
8. Comparison of paranasal (PS) involvement with use of low-dose computed tomography (CT) and plain radiographs in allergic asthmatic patients with rhinitis.
Patients underwent paranasal (PS) radiography in the frontal and mentonian positions and low-dose computed tomography (CT) consisting of six to eight coronal scans performed on the central region of the sphenoidal, ethmoidal, maxillary, and frontal sinuses. Possible results for each sinus were a normal evaluation or the presence of mucosal thickening, opacification, and/or air-fluid level. Eighty-five (93.4%) of 91 study patients had radiological changes on radiography or CT. In only six (6.6%) were both tests normal. The maxillary was the most involved sinus by both methods. Simultaneous PS abnormalities were observed in 40.5% on X-ray and 56.7% on CT. For the frontal, ethmoidal, and sphenoidal sinuses, the proportion of normal results differed significantly between X-ray and CT: 80.2% versus 89%, 76.9% versus 63.7% and 96.7% versus 70.3%, respectively (P <.05). Agreement was over 70% for the maxillary and frontal sinuses. CT also provided a better diagnosis of air-fluid level changes than X-ray. Low-dose CT significantly showed larger number of normal PS results and diagnosed more severe PS lesions.
Editor's comment: Low-dose CT may replace PS plain X-ray and conventional CT to support better clinical decisions.
Stelmach R, Azevedo Dias Junior S, Figueiredo CM et al. Chronic rhinosinusitis in allergic asthmatic patients: Radiography versus low-dose computed tomography evaluation. Journal of Asthma 2010; 47(6): 599-603.