Catherine M. Jackson

Allergic rhinitis and its impact on asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen)

J. Bousquet, N. Khaltaev, A. A. Cruz, J. Denburg, W. J. Fokkens, A. Togias, T. Zuberbier, C. E. Baena-Cagnani, G. W. Canonica, C. van Weel, I. Agache, N. A t-Khaled, C. Bachert, M. S. Blaiss, S. Bonini, L.-P. Boulet, P.-J. Bousquet, P. Camargos, K.-H. Carlsen, Y. Chen, A. Custovic, R. Dahl, P. Demoly, H. Douagui, S. R. Durham, R. Gerth van Wijk, O. Kalayci, M. A. Kaliner, Y.-Y. Kim, M. L. Kowalski, P. Kuna, L. T. T. Le, C. Lemiere, J. Li, R. F. Lockey, S. Mavale-Manuel , E. O. Meltzer, Y. Mohammad, J. Mullol, R. Naclerio, R. E. O Hehir, K. Ohta, S. Ouedraogo, S. Palkonen, N. Papadopoulos, G. Passalacqua, R. Pawankar, T. A. Popov, K. F. Rabe, J. Rosado-Pinto, G. K. Scadding, F. E. R. Simons, E. Toskala, E. Valovirta, P. van Cauwenberge, D.-Y. Wang, M. Wickman, B. P. Yawn, A. Yorgancioglu, O. M. Yusuf, H. Zar Review Group: I. Annesi-Maesano, E. D. Bateman, A. Ben Kheder, D. A. Boakye, J. Bouchard, P. Burney, W. W. Busse, M. Chan-Yeung, N. H. Chavannes, A. Chuchalin, W. K. Dolen, R. Emuzyte, L. Grouse, M. Humbert, C. Jackson, S. L. Johnston, P. K. Keith, J. P. Kemp, J.-M. Klossek, D. Larenas-Linnemann, B. Lipworth, J.-L. Malo, G. D. Marshall, C. Naspitz, K. Nekam, B. Niggemann, E. Nizankowska-Mogilnicka, Y. Okamoto, M. P. Orru, P. Potter, D. Price, S. W. Stoloff, O. Vandenplas, G. Viegi, D. Williams

Allergic Rhinitis and its Impact on Asthma (ARIA) 2008

J. Bousquet, N. Khaltaev, A. A. Cruz, J. Denburg, W. J. Fokkens, A. Togias, T. Zuberbier, C. E. Baena-Cagnani, G. W. Canonica, C. van Weel, I. Agache, N. A t-Khaled, C. Bachert, M. S. Blaiss, S. Bonini, L.-P. Boulet, P.-J. Bousquet, P. Camargos, K.-H. Carlsen, Y. Chen, A. Custovic, R. Dahl, P. Demoly, H. Douagui, S. R. Durham, R. Gerth van Wijk, O. Kalayci, M. A. Kaliner, Y.-Y. Kim, M. L. Kowalski, P. Kuna, L. T. T. Le, C. Lemiere, J. Li, R. F. Lockey, S. Mavale-Manuel , E. O. Meltzer, Y. Mohammad, J. Mullol, R. Naclerio, R. E. O Hehir, K. Ohta, S. Ouedraogo, S. Palkonen, N. Papadopoulos, G. Passalacqua, R. Pawankar, T. A. Popov, K. F. Rabe, J. Rosado-Pinto, G. K. Scadding, F. E. R. Simons, E. Toskala, E. Valovirta, P. van Cauwenberge, D.-Y. Wang, M. Wickman, B. P. Yawn, A. Yorgancioglu, O. M. Yusuf, H. Zar Review Group: I. Annesi-Maesano, E. D. Bateman, A. Ben Kheder, D. A. Boakye, J. Bouchard, P. Burney, W. W. Busse, M. Chan-Yeung, N. H. Chavannes, A. Chuchalin, W. K. Dolen, R. Emuzyte, L. Grouse, M. Humbert, C. Jackson, S. L. Johnston, P. K. Keith, J. P. Kemp, J.-M. Klossek, D. Larenas-Linnemann, B. Lipworth, J.-L. Malo, G. D. Marshall, C. Naspitz, K. Nekam, B. Niggemann, E. Nizankowska-Mogilnicka, Y. Okamoto, M. P. Orru, P. Potter, D. Price, S. W. Stoloff, O. Vandenplas, G. Viegi, D. Williams

Safety of inhaled and intranasal corticosteroids: lessons for the new millennium.

Although inhaled and intranasal corticosteroids are first-line therapy for asthma and allergic rhinitis, there has recently been an increasing awareness of their propensity to produce systemic adverse effects. The availability of more potent and lipophilic corticosteroids and new chlorofluorocarbon (CFC)-free formulations has focused attention on these safety issues.The main determinant of systemic bioavailability of these drugs is direct absorption from the lung or nose, where there is no first-pass inactivation. Consequently, the systemic bioavailability of inhaled corticosteroids is greatly influenced by the efficiency of the inhaler device. Thus, when comparing different inhaled corticosteroids it is imperative to consider the unique drug/device interaction.The pharmacokinetic profile is important in determining the systemic bioactivity of inhaled and intranasal corticosteroids. For highly lipophilic drugs, such as fluticasone propionate or mometasone furoate, there is preferential partitioning into the systemic tissue compartment, and consequently a large volume of distribution at steady state. In contrast, drugs with lower lipophilicity, such as triamcinolone acetonide or budesonide, have a smaller volume of distribution. The systemic tissue compartment may act as a slow release reservoir, resulting in a long elimination half-life for the lipophilic drugs.For intranasal corticosteroids, a high degree of lipophilicity diminishes water solubility in mucosa and therefore increases the amount of drug swept away by mucociliary clearance before it can gain access to tissue receptor sites. This may reduce the anti-inflammatory efficacy in the nose, but might also reduce the propensity for direct systemic absorption from the nasal cavity.The hydrofluoroalkane (HFA) formulations of beclomethasone dipropionate are solutions and exhibit a much higher respirable fine particle dose than do the CFC formulations. Dose-response studies with one of the HFA formulations have shown therapeutic equivalence at half the dosage, with little evidence of adrenal suppression at dosages up to 800 μg/day. A lack of similar studies for another of the available HFA formulations has led to a discrepancy in the recommendations for equivalence. Although in vitro studies have pointed to a similar fine particle distribution for the HFA and CFC formulations of fluticasone propionate, this is not supported by in vivo data for lung bioavailability, suggesting that care will be required when switching these formulations.Prescribers of inhaled and intranasal corticosteroids should be aware of the potential for long term systemic effects. The safest way to use these drugs is to ‘step-down’ to achieve the lowest possible effective maintenance dosage.

Effect of five genetic variants associated with lung function on the risk of chronic obstructive lung disease, and their joint effects on lung function

RATIONALE Genomic loci are associated with FEV1 or the ratio of FEV1 to FVC in population samples, but their association with chronic obstructive pulmonary disease (COPD) has not yet been proven, nor have their combined effects on lung function and COPD been studied. OBJECTIVES To test association with COPD of variants at five loci (TNS1, GSTCD, HTR4, AGER, and THSD4) and to evaluate joint effects on lung function and COPD of these single-nucleotide polymorphisms (SNPs), and variants at the previously reported locus near HHIP. METHODS By sampling from 12 population-based studies (n = 31,422), we obtained genotype data on 3,284 COPD case subjects and 17,538 control subjects for sentinel SNPs in TNS1, GSTCD, HTR4, AGER, and THSD4. In 24,648 individuals (including 2,890 COPD case subjects and 13,862 control subjects), we additionally obtained genotypes for rs12504628 near HHIP. Each allele associated with lung function decline at these six SNPs contributed to a risk score. We studied the association of the risk score to lung function and COPD. MEASUREMENTS AND MAIN RESULTS Association with COPD was significant for three loci (TNS1, GSTCD, and HTR4) and the previously reported HHIP locus, and suggestive and directionally consistent for AGER and TSHD4. Compared with the baseline group (7 risk alleles), carrying 10-12 risk alleles was associated with a reduction in FEV1 (β = -72.21 ml, P = 3.90 × 10(-4)) and FEV1/FVC (β = -1.53%, P = 6.35 × 10(-6)), and with COPD (odds ratio = 1.63, P = 1.46 × 10(-5)). CONCLUSIONS Variants in TNS1, GSTCD, and HTR4 are associated with COPD. Our highest risk score category was associated with a 1.6-fold higher COPD risk than the population average score.

A randomized primary care trial of steroid titration against mannitol in persistent asthma: STAMINA trial.

BACKGROUND We compared titrating inhaled corticosteroid (ICS) against mannitol airway hyperresponsiveness (AHR) or a reference strategy (control) based on symptoms, reliever use, and lung function in primary care. METHODS One hundred sixty-four patients with persistent asthma were randomized in parallel group fashion following an initial ICS tapering. Subsequent ICS doses (as ciclesonide) were titrated against either the provocative dose of mannitol causing a 10% fall in FEV(1) (PD(10)) (AHR strategy) or a control group (reference strategy) over a 1-year period. RESULTS One hundred nineteen participants (n = 61 AHR, n = 58 control) completed the study. Time to first mild exacerbation was not significantly different: hazard ratio, 1.29; 95% CI, 0.716-2.31; P = .40. Although there were 27% fewer total number of mild exacerbations over 12 months in AHR vs control groups (n = 84 vs n = 115, P = .03), there was no difference in severe exacerbations (n = 12 vs n = 13). No other significant differences were seen between groups with the exception of mannitol PD(10) and ICS dose. There was a 1.52 (95% CI, 0.61-2.42; P = .001) doubling dose difference in mannitol PD(10) between AHR vs control groups. The final mean daily ciclesonide dose was higher (P < .0001) in AHR vs control groups (514 μg vs 208 μg), with no associated significant suppression of overnight urinary cortisol/creatinine. Significant improvements were seen within the AHR group but not the control group for the provocative concentration of methacholine causing a 20% fall in FEV(1) (P < .05), salivary eosinophilic cationic protein (P < .05), exhaled nitric oxide (P < .05), symptoms (P < .005), and reliever use (P < .001). CONCLUSIONS Mannitol challenge was well tolerated in a primary care setting. Using mannitol resulted in exposure to a higher dose of ciclesonide, which was associated with equivocal effects on exacerbations without associated adrenal suppression. Large-scale trials using mannitol in patients with more severe disease may now be warranted to further define its role. TRIAL REGISTRATION ClinicalTrials.gov; No.: NCT01216579; URL: www.clinicaltrials.gov.

Butterbur, a herbal remedy, attenuates adenosine monophosphate induced nasal responsiveness in seasonal allergic rhinitis.

Background Butterbur (BB) or Petasites hybridus, a herbal remedy, exhibits in vitro inhibition of cysteinyl leukotriene biosynthesis. However, no placebo‐controlled studies have been performed to evaluate the effectiveness of BB on objective outcomes such as nasal provocation testing in seasonal allergic rhinitis (SAR).

Benefit-risk assessment of long-acting β2-Agonists in asthma

The use of a regular long-acting β2-adrenoceptor agonists (β2-agonists; LABA) is now established in asthma guidelines as the preferred option for second-line controller therapy in addition to inhaled corticosteroids. This has been driven by data showing beneficial effects of LABAs on exacerbation rates, in turn suggesting a putative corticosteroid-sparing effect. As LABAs are devoid of any clinically meaningful anti-inflammatory activity in vivo, their effects on exacerbations are presumably due to a diurnal stabilising effect on airway smooth muscle.LABAs have marked effects on symptoms and lung function, and this may make it difficult to assess anti-inflammatory control with inhaled corticosteroids when used in a combination inhaler such as fluticasone propionate/salmeterol or budesonide/formoterol. The use of fixed-dose combination inhalers is in many respects counter-intuitive to conventional teaching regarding flexible dosage titration with inhaled corticosteroids. It would therefore seem prudent first to gain optimal control of inflammation with inhaled corticosteroids before considering adding a LABA. Increasing the dosage of inhaled corticosteroids will have a relatively greater effect on exacerbations than on symptoms and lung function, whereas the converse applies when adding a LABA. Another option is to add a leukotriene receptor antagonist, which confers additional anti-inflammatory activity and is as effective on exacerbations as adding a LABA.Despite in vitro and ex vivo data showing a ligand-independent effect of LABAs on glucocorticoid receptor activation, clinical data do not indicate any relevant synergy between LABAs and inhaled corticosteroids when used together in the same inhaler. In particular, there is no evidence of potentiation by LABAs of the in vivo anti-inflammatory activity of inhaled corticosteroids that would suggest any genuine corticosteroid-sparing activity. Nonetheless, the data support the additive effects of inhaled corticosteroids and LABAs when used together due to their separate effects on inflammation and smooth muscle, respectively.Tolerance with LABAs is a predictable pharmacological phenomenon that occurs despite concomitant therapy with inhaled corticosteroids. Moreover, cross-tolerance also develops to short-acting β2-agonists used for protection against bronchoconstrictor stimuli as a result of LABA-induced down-regulation, desensitisation and prolonged occupancy of β2-adrenoceptors. The exact role of β2-adrenoceptor polymorphism in determining tolerance with LABAs requires further prospective clinical studies evaluating long-term effects on outcomes such as exacerbations in patients with relevant genotypes and haplotypes.The next decade will provide challenging issues for clinicians with respect to defining further the role of LABAs as add-on controller therapy, particularly in evaluating the long-term effects of combination inhalers on inflammatory outcomes and airway remodelling.

Twelve tips for developing and maintaining a simulated patient bank

Simulated patients have become almost indispensable in the education and training of health care professionals. Their contribution to the creation of a safe, yet realistic, learner centred environment is invaluable. Their support in enabling learners at all stages of their professional careers to develop both competence and confidence through repeated practice helps to ensure that learning from real patients can be maximized. A simulated patient bank can enable tracking and training of simulated patients to be coordinated in an effective and efficient way both for patients and learners. This paper shares experiences of developing a simulated patient bank against the background of changes in health care delivery and education and training. Twelve tips to developing and maintaining a simulated patient bank have been identified. The tips focus on the needs of the simulated patient bank and ensure that training is at an appropriate level for the learners, patient care is not compromised and simulated patients feel they are valued members of the educational team.

Does Bronchial Hyperresponsiveness in Asthma Matter

Bronchial hyperresponsiveness is a fundamental component of the asthmatic inflammatory process causing airway narrowing on exposure to a bronchoconstrictor stimulus. This in turn causes patients to experience symptoms of breathlessness, chest tightness, cough and wheeze. Bronchial challenge tests can be performed in the laboratory to establish the degree of bronchial hyperresponsiveness to both direct and indirect stimuli. The extent to which asthma pharmacotherapy attenuates bronchial hyperresponsiveness is therefore an important measure of efficacy. This review article discusses the effects of inhaled and oral asthma treatment upon bronchial hyperresponsiveness and highlights how, in conjunction with conventional measures of asthma control, it can be used as an aid to optimally manage patients.

Fair access to medicine? Retrospective analysis of UK medical schools application data 2009-2012 using three measures of socioeconomic status.

BackgroundMedical students have historically largely come from more affluent parts of society, leading many countries to seek to broaden access to medical careers on the grounds of social justice and the perceived benefits of greater workforce diversity. The aim of this study was to examine variation in socioeconomic status (SES) of applicants to study medicine and applicants with an accepted offer from a medical school, comparing the four UK countries and individual medical schools.MethodsRetrospective analysis of application data for 22 UK medical schools 2009/10-2011/12. Data were analysed for all 32,964 UK-domiciled applicants aged <20 years to 22 non-graduate medical schools requiring applicants to sit the United Kingdom Clinical Aptitude Test (UKCAT). Rates of applicants and accepted offers were compared using three measures of SES: (1) Postcode-assigned Index of Multiple Deprivation score (IMD); (2) School type; (3) Parental occupation measured by the National Statistics Socio Economic Classification (NS-SEC).ResultsThere is a marked social gradient of applicants and applicants with accepted offers with, depending on UK country of residence, 19.7–34.5 % of applicants living in the most affluent tenth of postcodes vs 1.8–5.7 % in the least affluent tenth. However, the majority of applicants in all postcodes had parents in the highest SES occupational group (NS-SEC1). Applicants resident in the most deprived postcodes, with parents from lower SES occupational groups (NS-SEC4/5) and attending non-selective state schools were less likely to obtain an accepted offer of a place at medical school further steepening the observed social gradient. Medical schools varied significantly in the percentage of individuals from NS-SEC 4/5 applying (2.3 %–8.4 %) and gaining an accepted offer (1.2 %–7.7 %).ConclusionRegardless of the measure, those from less affluent backgrounds are less likely to apply and less likely to gain an accepted offer to study medicine. Postcode-based measures such as IMD may be misleading, but individual measures like NS-SEC can be gamed by applicants. The previously unreported variation between UK countries and between medical schools warrants further investigation as it implies solutions are available but inconsistently applied.