Discussion

This UK Difficult Asthma Network aims to standardise clinical assessment across specialist centres and use a Registry to facilitate phenotypic characterisation and research in patients with ‘difficult asthma’. These specialist centres have established assessment protocols, ensuring subjects have well characterised refractory asthma. The numbers of subjects per centre provide further analytical strengths and, when data are consistent across three or four centres, we believe they are representative of the UK refractory asthma population. Between-centre differences are not explained by local referral patterns (60–75% tertiary referrals, the remainder coming from primary/non-specialist physicians); however, this cannot be entirely excluded.

Three other multicentre studies have collated data on ‘difficult asthma’ previously. The TENOR study was a large-scale US observational study (4756 patients, 3489 adults) of difficult asthma (≥2 unscheduled care visits or ≥2 oral steroid bursts plus high dose inhaled steroids)9; 51% were classified as severe asthma by the treating physician. The ENFUMOSA cross-sectional study (12 centres in nine European countries) recruited 163 patients with severe asthma (≥1 exacerbation in the previous year despite ≥1200 μg of BDP equivalent inhaled steroid).10 The SARP study included 204 subjects ≥12 years, fulfilling the ATS definition of refractory asthma (9 US and 1 UK centre).11 In these studies, group data only are presented, whereas our data additionally allow comparison between individual UK centres, which has demonstrated important differences.

Our data confirm the usual female preponderance which remains unexplained,9–11 though catamennial asthma was not a common exacerbating factor.

Age at first assessment was similar between centres, though age at asthma diagnosis was significantly lower in the Brompton cohort. Median body mass index (BMI) was in the non-obese range, and similar to that seen in TENOR (average BMI was 29.9),9 whereas the average BMI in ENFUMOSA was lower (male average 26.5, female average 27.2). Current smoking is infrequent, though 29.8% had previously been smokers, with no difference between centres; these smoking prevalence figures are similar to the TENOR cohort where 4.3% of ‘difficult to control’ adults were current smokers, 32% ex-smokers and 63.7% never smokers.9

In Leicester, more patients were in full-time employment, compared with 33–36% in other centres, but why asthma is less often volunteered as the reason for not working in Belfast remains unclear, though this would significantly impact on costing refractory asthma. Occupational asthma worsening was consistently uncommon, and only appears relevant to a minority of patients.

Three centres recorded a family history of asthma in 42–44%, but in Belfast this was 74%. Retrospective data checking confirmed that the ‘family history’ definition was applied consistently, and a family history appears more common in Northern Ireland, which has traditionally low levels of immigration. Recorded familial asthma death was low, suggesting it is an infrequent event, even in this refractory group; however, this was not well recorded and we cannot exclude that the familial asthma death rate may be higher.

This higher reported atopic prevalence in London was supported by allergen testing (table 3), as subjects were more likely to be allergen positive. The difference is particularly notable between London and Belfast, where all subjects were tested for similar allergens. In Leicester and Manchester, targeted allergen testing is performed, and reported allergen positivity may represent an underestimation. Interestingly, Apergillus sensitivity in Manchester (which is routinely tested) was ‘between’ that of London and Belfast. In SARP, 71% of those with severe asthma were skin prick positive to ≥1 of 14 allergens (85% and 87% for subjects with mild/moderate asthma, respectively).11 In ENFUMOSA, ∼58% of those with severe asthma had positivity ≥1 allergen, (well controlled asthmatics ∼76%), with individual allergen positivity in those with severe asthma varying between ∼10% and 35%.10 Individual centre data are not presented in these studies; however, our data suggest that individual allergen sensitisation appears to vary in different refractory asthma populations in UK specialist centres, possibly reflecting important regional differences even within the UK.

Oral steroid courses in the 12 months before referral were fewer in Manchester compared with other centres, where the median number of rescue steroids was 4–5 per annum; this difference may reflect patient recollection in Manchester, but the similarity in other centres supports significant rescue steroid use in this group. In SARP, 54% of those with severe asthma reported ≥3 steroid bursts per year11 and, in our cohort, 63% used ≥3 courses in the previous year. Unscheduled visits were more common in Belfast, although hospital admissions and ICU usage were higher in London, though they were uncommon events. In SARP, 54% reported ≥1 unscheduled care visit per year,11 whereas this was 86% for this UK cohort. It is unclear if differences are due to different healthcare delivery for exacerbation management, or to differences in exacerbation severity.

Almost twice as many patients in the Brompton were on maintenance steroids, compared with the other centres. Inhaled steroid dose at referral was also higher in the Brompton patients compared with all other centres. The UK cohort average inhaled steroid dose was similar to the ENFUMOSA severe asthma cohort (1676±667 μg BDP equivalent), but comparative data between centres were not presented. Our data suggest that in multicentre studies specifying a minimum steroid dose for inclusion, it is important to examine medication utilisation from individual centres.

Wide variation was noted in nebuliser usage, and patients in Belfast and Brompton were more likely to be on a theophylline and leukotriene receptor antagonist at referral. These differences presumably relate to local prescribing practice and referral pattern, but all patients were on multiple medications at referral. Few patients were on steroid-sparing medication or anti-IgE treatment at referral, suggesting that these medications are not widely used outside specialist centres.

We observed a low prevalence of aspirin/non-steroidal anti-inflammatory drug (NSAID) sensitivity and, while different definitions of aspirin sensitivity probably affect reported prevalence,12 our data are notably different from those of ENFUMOSA, which suggested an association between asthma severity and self-reported aspirin exacerbation.10 Our data are similarly based on self-reported increased asthma symptoms after aspirin/NSAID ingestion, and the difference may reflect differences between the UK and a European population.

Spirometry for the UK group was lower than for the ENFUMOSA study (FEV₁ % predicted 71.8% rising to 80.9% postbronchodilator), though it was similar to SARP (FEV₁ % predicted 62±22%), consistent with a patient population with more severe asthma. Consistent with better spirometry in ENFUMOSA, total lung capacity in the UK cohort was higher (134.7±42.3%), compared with ENFUMOSA (104.4±15.2%). Of note, K_CO was normal and similar in all centres despite the high prevalence of ex-smoking in the UK cohort, though we demonstrated a relationship between K_CO and prior smoking. The normal percentage K_CO is again different from ENFUMOSA, where K_CO was 90.6±19% predicted; the authors suggested that abnormal gas exchange and parenchymal injury may be a feature of severe asthma. However, our data suggest that in a well characterised population with refractory asthma, the transfer factor is well preserved, and any reductions relate to prior smoking history.

Interesting differences between UK centres are seen for spirometry. Prebronchodilator and postbronchodilator spirometry and degree of airflow obstruction were better in Leicester compared with other centres. Allied with other indices—for example, increased numbers in full-time work—it suggests less severe disease in the Leicester cohort compared with other centres. This is despite the fact that all of these patients fulfilled the same definition of refractory asthma, suggesting a spectrum of severity using the ATS definition. Prospective analysis of patient outcome and treatment requirements, which is facilitated by the UK Registry, will help address this issue further. Residual volume % predicted and total lung capacity were significantly greater in the London cohort compared with Belfast and Manchester; however, the absolute differences are small.

Peripheral blood eosinophil count was highest in Belfast, but there was no significant difference in sputum eosinophilia or FeNO between centres. In SARP, FeNO data were available on 135 subjects with severe asthma and FeNO was 40±38 ppb, which is similar to this UK cohort. Mean IgE in ENFUMOSA was 109 (95% CI 85 to 139), and in SARP 100±5.75. We have presented IgE as median (IQR) as this is not normally distributed in this cohort, but our median value of 130 is comparable with other published cohorts. In subjects who had bone density measurements, 18 (10.6%) subjects had either a spinal or femoral neck bone density T score less than or equal to −2.5 (osteoporosis) and 58 (34.3%) subjects had a T score less than or equal to −1.0 (osteopenia). Bone density measurements were not done in all subjects and there may be some selection bias; however, these data are consistent with a significant morbidity in this group.

Important clinical outcomes in this group are unscheduled healthcare visits, rescue steroid use, hospital admission and ICU admission. Hierarchical regression modelling supported important between-centre differences, as this remained a significant factor in the final model for three of the four tested dependent variables (table 7). It is important to note that if this patient group was treated as a homogeneous study population, different regression models were obtained, with other additional significant associations, which were not demonstrated when centre was included as a factor (data not shown). Importantly, however, the factors which remained in our regression models with clinical centre included as a random factor also remained in each regression model, independent of whether centre was included or not.

The association between peripheral blood eosinophils and both steroid exposure and unscheduled visits in this refractory patient group is consistent with other studies which have demonstrated a relationship between blood and/or sputum eosinophilia and asthma exacerbation and loss of asthma control.13–15 Patients who were younger at the time of assessment at the Difficult Asthma Service had higher levels of both unscheduled visits and hospital admissions in the respective models. The association between total number of prior ICU admissions and hospital admission is perhaps not surprising as prior severe asthmatic events are associated with increased risk of asthma death.16 17 Home nebuliser usage and theophylline prescription may also be markers of severity and thus related to increased rescue steroid exposure and unscheduled visits, respectively. The association with female gender and unscheduled visits is interesting, particularly as this gender effect is not translated into either more steroid exposure or hospital admission, and might suggest a lower threshold for healthcare contact in females. The association between dose of inhaled steroids and ICU admission is interesting, particularly as this has previously been shown to be a predictor of treatment-resistant asthma5 and is presumably an index of longer term severity with increasing doses of inhaled steroid over time. The association with age of asthma diagnosis may reflect ICU admission in childhood but, even if this is the case, it does suggest that severe asthma in this group is present from an early stage after the initial diagnosis.

In summary, this paper presents for the first time demographic, physiological and immunological data from a well characterised UK population of subjects with refractory asthma. While similarities exist to other comparable published cohorts, there are also differences which may reflect different patient populations (difficult to control vs refractory vs different levels of asthma severity), and again argues for the production and application of precise definitions for this population of subjects with asthma. In addition, important population characteristics are different between UK specialist centres, suggesting that ‘grouping’ multicentre data (even centres in the same country) may miss important differences and potentially confound attempts to phenotype refractory asthma, giving rise to so-called ‘ecological fallacy’. The differences identified between UK centres warrant further study, but suggest refractory asthma may be more heterogeneous within an individual country than previously known.