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Keywords:

  • aspergillus;
  • bronchiectasis;
  • high-resolution computed tomography;
  • severe asthma

Abstract

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusion
  7. Acknowledgments
  8. Conflict of interest
  9. References

To cite this article: Menzies D, Holmes L, McCumesky G, Prys-Picard C, Niven R. Aspergillus sensitization is associated with airflow limitation and bronchiectasis in severe asthma. Allergy 2011; 66: 679–685.

Abstract

Background:  Abnormalities, including bronchiectasis, that are detectable on high-resolution computed tomography (HRCT) have been associated with severe asthma. Bronchiectasis is associated with the diagnosis of allergic bronchopulmonary aspergillosis (ABPA), which also occurs in patients with severe asthma. We sought to determine the frequency and pattern of HRCT abnormality and the relationship with Aspergillus fumigatus sensitization in one severe asthma population.

Methods:  We examined our database of patients attending a supraregional severe asthma service (Manchester, UK). Clinical, physiological and immunological characteristics were compared between those with HRCT evidence of airway disease (specifically bronchiectasis) and those with no radiological abnormality.

Results:  Of 133 patients analysed, 111 (83.4%) had an abnormal HRCT with bronchial wall thickening (41.3%), bronchiectasis (35.3%), air trapping (20.3%) and bronchial dilatation (16.5%) occurring most frequently. Radiological evidence of airway disease was associated with more obstructive spirometry (postbronchodilator FEV1/FVC ratio 73.2%vs 64.8% [difference −8.5%, 95% CI −16.9 to −0.1, P = 0.048]). A. fumigatus sensitization was associated with a 2.01 increased hazard ratio of bronchiectasis (95% CI 1.26 to 3.22, P = 0.005), and more obstructive spirometry (postbronchodilator FEV1/FVC ratio 57.6 vs 70.3 [difference −12.8, 95% CI −19.8 to −5.7, P = 0.001]). Patients with A. fumigatus sensitization had variable clinical and radiological characteristics that frequently did not conform to the conventional diagnostic criteria for ABPA.

Conclusion:  Patients with severe asthma frequently have radiological abnormalities on HRCT. Sensitization to A. fumigatus is associated with bronchiectasis and greater airflow obstruction, even when diagnostic criteria for ABPA are not met.

Patients with severe asthma frequently have macroscopic anatomical abnormalities secondary to airway remodelling that are detectable with high-resolution computed tomography (HRCT) (1–5). Compared with healthy volunteers, patients with asthma have increased bronchial wall thickening on HRCT, and disease severity is a surrogate for demonstrable structural airway change (1, 2, 6–8). Bronchial wall thickening, luminal narrowing and air trapping seen on HRCT have been shown to correlate with airflow limitation, neutrophilic airway inflammation, bronchial epithelial thickness at biopsy, and also bronchodilator response in patients with severe asthma (1, 2, 8, 9). Other radiological features associated with severe asthma include mucus impaction, bronchial dilatation and bronchiectasis (6, 9–12). Despite these observations, the relative frequency of radiological abnormality in the severe asthma population is not well characterized, and the clinical implications of finding airway disease on HRCT are not yet fully defined.

Allergic bronchopulmonary aspergillosis (ABPA) occurs in patients with pre-existing lung disease and is characterized by a predominately Th2-mediated allergic response to Aspergillus colonizing the host airway (13). This leads to worsening of the underlying lung condition, and as such patients with ABPA are over-represented in the severe asthma population. Published case series estimates that 0.7–3.5% of the referred asthma population have ABPA, with the prevalence increasing to between 5% and 25% of patients regularly attending asthma clinics (13–20). In the asthma population, diagnostic criteria for ABPA include immediate cutaneous hyperreactivity to Aspergillus antigen, circulating immunoglobulin E (IgE) >1000 KIU/l and raised Aspergillus-specific IgE and/or IgG (21, 22). Further pointers to the diagnosis include expectoration of mucus plugs, positive identification of Aspergillus species in respiratory samples, elevated serum IgG precipitins and a positive delayed cutaneous hypersensitivity response. These criteria were first proposed in 1977 and codified later, but there is a considerable ongoing debate about the relative merits of the radiological, microbiological and immunological tests utilized, and how to best differentiate Aspergillus sensitization, Aspergillus colonization and ABPA as clinical entities (13, 16, 23). In particular, the precise cut-off value for total IgE and the method by which to demonstrate Aspergillus sensitization (cutaneous hyperreactivity or specific IgE) has been questioned. Division of ABPA into disease associated with central bronchiectasis (ABPA-CB) and that with serological evidence of sensitization only (ABPA-S) is also described (13, 16).

Our centre has recently recommended defining another category of patients labelled severe asthma with fungal sensitization (SAFS) (24). We postulated that these patients represent a group of severe asthmatics with circulating IgE and airway colonization by Aspergillus or other fungi at lower concentrations than that seen in ABPA. The resulting allergic response may be clinically important but below the arbitrary threshold for diagnosis of ABPA. Observational data demonstrate colonization of airways by Aspergillus fumigatus in patients with severe asthma is more frequent in patients with concomitant evidence of systemic sensitization and is also associated with bronchiectasis and greater impairment of lung function (25). Identification of such patients is also of value as a recent randomized placebo-controlled trial has shown clinical benefit in asthma outcomes in patients with SAFS treated for long periods with antifungal drugs (26).

We sought to determine the frequency of macroscopic airway abnormality on HRCT in our severe asthma population. In addition, we have examined the related features of bronchiectasis in association with severe asthma and associations between this radiological characteristic and A. fumigatus sensitization.

Methods

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusion
  7. Acknowledgments
  8. Conflict of interest
  9. References

Patients

Information about patients attending the Manchester severe asthma service is currently entered into a database, some of which is centrally collated along with that from other centres across the UK and forms part of a larger ongoing networked study (27). Patients are included in the Manchester database if they are >16 years, attend the supraregional dedicated severe asthma clinic and have given informed consent. For this study, we examined the Manchester severe asthma database of for patients in whom an HRCT scan had been performed, and the full report was available. Ethical approval was not required for this analysis.

CT scan reporting

High-resolution computed tomography images of all patients attending the severe asthma clinic are routinely reviewed for the following specific features of airway disease: bronchial wall thickening, bronchial dilatation, central bronchiectasis, peripheral bronchiectasis, air trapping, mucus plugging and ground-glass attenuation. A standard HRCT protocol is employed by our radiology department using a 16-slice Siemens scanner with 5-mm collimation and a scan time of 0.5 s per slice; the intra-operator reproducibility of HRCT reporting in patients with severe asthma within our department has previously been estimated as 95% (unpublished data).

Aspergillus sensitization and colonization

Allergic bronchopulmonary aspergillosis was defined as asthma, a total serum IgE >1000 KIU/l and an elevated A. fumigatus-specific IgE, which we use in lieu of immediate cutaneous hypersensitivity response to Aspergillus; subdivision into disease with and without the evidence of central bronchiectasis was then based on the associated HRCT report. Sensitization to A. fumigatus was defined as an elevated total and A. fumigatus-specific IgE but without the other features necessary for a diagnosis of ABPA. Patients were considered to have airway colonization if Aspergillus species were positively identified on direct staining and microscopy or growth in fungal media. Growth or sensitization to species other than A. fumigatus was not considered in this study. All microbiology samples were processed according to BSOP57, with the modification that 10 μl of processed sample was plated instead of 1 μl (28).

Statistical analysis

spss version 19 (SPSS Inc, Chicago, IL, USA) for Macintosh and Prism Version 4 (GraphPad Software Inc, La Jolla, CA, USA) for Macintosh were used to perform the analysis. Data were examined for normality using distribution plots and the Shapiro–Wilk test; non-Gaussian data (IgE and peripheral eosinophil count) were log transformed prior to analysis. Mean values and proportions between groups were compared using the unpaired Student’s t-test and Fisher’s exact test, respectively. Associations between variable were determined using Pearson’s correlation. Differences were considered significant at P ≤ 0.05 (two-tailed).

Results

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusion
  7. Acknowledgments
  8. Conflict of interest
  9. References

Data for 179 patients are currently entered in the Manchester severe asthma database of which 133 underwent HRCT and had the full report available. All patients met the American Thoracic Society criteria for refractory asthma (Table 1) (29). The majority of patients (n = 111, 83.4%) had features on HRCT consistent with airway disease, and 47 patients (35.3%) had evidence of bronchiectasis (Table 2). Similar numbers of those with bronchiectasis had a central (n = 21) or peripheral (n = 26) distribution of disease. In patients without bronchiectasis, the most common abnormality was bronchial wall thickening and bronchial dilatation. In a number of patients (26), clinically important unexpected radiological abnormalities were also detected including (n) the following: pulmonary nodules (4), consolidation (4), atelectasis and scarring (8), emphysema (3), parenchymal sarcoid (1), tracheomalacia (1), parenchymal cysts (1), adenopathy (3) and features of pulmonary hypertension (1).

Table 1.   Patient characteristics
CharacteristicValue
  1. BDP, beclometasone diproprionate; ICS, inhaled corticosteroids; FEV1, forced expiratory volume in first second; FVC, forced vital capacity.

  2. All values expressed as mean (standard error of mean) except: *median (interquartile range).

Age – years47.2 (1.2)
Male/Female –n42/91
Atopic/Nonatopic –n62/71
Disease duration – years27.5 (1.5)
Postbronchodilator FEV1–% predicted75.3 (2.7)
Postbronchodilator FEV1/FVC ratio65.9 (1.7)
ICS dose –μg BDP equivalent*1800 (1000–2000)
Maintenance oral steroids –n12
Table 2.   Frequency of abnormal findings on thoracic high-resolution computed tomography in patients with severe asthma
Findings on CT, n = 133n (%)
  1. Numbers do not add up as some patients had more than one abnormal feature.

Normal22 (16.5)
Bronchiectasis
 Any47 (35.3)
 Central21 (15.8)
 Peripheral26 (19.5)
Airway disease (no bronchiectasis)
 Any62 (46.6)
 Bronchial wall thickening55 (41.3)
 Bronchial dilatation22 (16.5)
 Air trapping27 (20.3)
 Mucus plugging15 (11.3)
Ground-glass changes only2 (1.5)

Excluding those with bronchiectasis, severe asthma patients with radiological features of airway disease on HRCT had more obstructive pre- and postbronchodilator spirometry than those in which radiological abnormalities were absent (Table 3). There were no other differences between these groups including age, disease duration, circulating IgE level or A. fumigatus sensitization. In contrast, patients with severe asthma and concomitant bronchiectasis had less response to inhaled bronchodilator (mean difference −6.0 ml [95% CI −10.9 to −1.1, P = 0.017]), and there was a trend towards longer disease duration (mean difference −6.1 years [95% CI −12.3 to 0.1, P = 0.055]) than those severe asthmatics without bronchiectasis (Table 4). A. fumigatus sensitization occurred frequently (36.2% of those tested) and was associated with a 2.01-fold (95% CI 1.26 to 3.22, P = 0.005) increased risk of having bronchiectasis in our severe asthma population. The pre- and postbronchodilator FEV1/FVC ratio (SEM) in patients sensitized to A. fumigatus was 54.0 (2.3) and 57.6 (2.4) compared with 68.0 (1.8) and 70.3 (2.3) in those without evidence of sensitization, giving a mean difference of −13.9 (95% CI −19.7 to −8.1, P < 0.001) and −12.8 (95% CI −19.8 to −5.7, P = 0.001), respectively. Although the pre- and postbronchodilator FEV1 was also lower in those sensitized to A. fumigatus compared to those without sensitization (61.7% predicted vs 70.5% predicted, and 69.9% predicted vs 80.1% predicted), the difference between the means failed to reach statistical significance (P = 0.108 and P = 0.082, respectively).

Table 3.   Comparison of severe asthma patients with and without features of airway disease on high-resolution computed tomography
CharacteristicNormal CT (n = 22)Features of airway disease on CT (n = 62)Difference (95% CI)P value
  1. BD, bronchodilator; FEV1, forced expiratory volume in first second; FVC, forced vital capacity; KIU/l, thousand international units per litre; IgE, immunoglobulin E.

  2. All data as mean (standard error of mean) except:

  3. *Geometric mean (standard error geometric mean) and difference expressed as fold change.

  4. Ratio (percentage) and difference expressed as hazards ratio.

Age – years44.5 (3.5)46.9 (1.4)−2.3 (−8.7 to 4.0)0.467
Disease duration – years23.7 (3.5)25.5 (2.2)−1.8 (−10.2 to 6.5)0.685
Pre-BD FEV1–% predicted71.1 (6.7)63.3 (2.4)−7.8 (−20.0 to 4.4)0.213
Pre-BD FEV1/FVC ratio70.9 (2.9)60.9 (1.3)−10.1 (−16.6 to −3.5)0.003
Post-BD FEV1–% predicted83.2 (6.6)74.7 (2.2)−8.5 (−21.5 to 4.6)0.201
Post-BD FEV1/FVC ratio73.2 (3.4)64.8 (1.5)−8.5 (−16.9 to −0.1)0.048
BD response –% FEV116.6 (3.5)13.5 (2.2)−3.1 (−9.5 to 3.4)0.343
Residual volume –% predicted118.9 (8.8)125.1 (3.7)6.1 (−14.9 to 27.2)0.564
Total lung capacity –% predicted103.1 (3.2)100.2 (1.5)−2.9 (−11.0 to 5.2)0.478
Peripheral eosinophils × 109/l*0.14 (0.11–0.19)0.19 (0.16–0.23)0.76 (0.38–1.54)0.444
Total IgE – KIU/l*123 (79–191)195 (158–239)0.62 (0.27–1.46)0.269
Nasal Polyps –n (%)†6/22 (27.2)8/51 (13.6)0.50 (0.20–1.27)0.188
Aspergillus sensitization –n (%)†6/21 (28.6)14/52 (26.9)0.94 (0.42–2.12)>0.99
Table 4.   Comparison of severe asthma patients with and without bronchiectasis on high-resolution computed tomography
CharacteristicNo bronchiectasis (n = 86)Bronchiectasis (n = 47)Difference (95% CI)P value
  1. BD, bronchodilator; FEV1, forced expiratory volume in first second; FVC, forced vital capacity; KIU/l, thousand international units per litre; IgE, immunoglobulin E.

  2. All data as mean (standard error of mean) except:

  3. *Geometric mean (standard error geometric mean) and difference expressed as fold change.

  4. Ratio (percentage) and difference expressed as hazards ratio.

Age – years46.3 (1.4)50.0 (2.0)−3.7 (−8.4 to 0.9)0.119
Disease duration – years25.4 (1.8)31.5 (2.7)−6.1 (−12.3 to 0.1)0.055
Pre-BD FEV1–% predicted64.3 (4.5)67.7 (4.5)−3.3 (−13.5 to 7.2)0.536
Pre-BD FEV1/FVC ratio63.5 (1.6)63.0 (2.6)0.5 (−5.2 to 6.2)0.871
Post-BD FEV1–% predicted76.8 (2.8)74.7 (5.6)2.0 (−9.3 to 13.3)0.723
Post-BD FEV1/FVC ratio66.7 (1.8)64.0 (4.0)2.6 (−4.6 to 9.8)0.472
BD response –% FEV114.2 (1.4)8.2 (1.7)−6.0 (−10.9 to −1.1)0.017
Residual volume –% predicted124.0 (4.4)110.9 (5.3)13.2 (−0.7 to 27.0)0.062
Total lung capacity –% predicted100.9 (1.7)97.3 (2.4)3.6 (−2.2 to 9.4)0.219
Peripheral eosinophils × 109/l*0.23 (0.19–0.29)0.17 (0.15–0.20)0.73 (0.45–1.18)0.198
Total IgE – KIU/l*166 (138–200)229 (173–302)0.72 (0.38–1.38)0.328
Nasal Polyps –n (%)†15/82 (9.8)7/43 (16.3)1.8 (0.6–5.35)0.583
Aspergillus sensitization –n (%)†20/75 (26.7)22/41 (53.7)2.01 (1.26 to 3.22)0.005

Details of the patients with Aspergillus sensitization (including ABPA) and bronchiectasis are summarized in Table 5. Seven of the 22 patients with bronchiectasis (31.8%) met the conventional criteria for ABPA, but only three had central bronchiectasis, and the remainder had a peripheral distribution of airway disease. Although the remaining Aspergillus-sensitized patients also had severe asthma and bronchiectasis (often associated with fungal colonization, significantly elevated Aspergillus IgE or marked peripheral eosinophila), the total IgE precluded a diagnosis of ABPA. The overall prevalence of ABPA in our severe asthma population was 13/133 (9.0%), which included five patients with no evidence of bronchiectasis in any distribution. There was no association between the degree of A. fumigatus sensitization (Aspergillus-specific IgE) and any other marker of disease severity or indeed total circulating IgE (Fig. 1).

Table 5.   Characteristic features of patients with bronchiectasis and Aspergillus sensitization
Gender/age (years)Second line therapy (mg/day)FEV1 (% predicted)Eosinophil count (×109/l)Total IgE (KIU/l)Aspergillus-specific IgE (KIU/l)Aspergillus precipitantsAspergillus colonizationPattern of bronchiectasisMeets criteria for ABPA
  1. ABPA, allergic bronchopulmonary aspergillosis; BDP, beclometasone diproprionate; CB, central bronchiectasis; F, female; FEV1, forced expiratory volume in first second; ICS, inhaled corticosteroids; I, itraconazole; IgE, immunoglobulin E; IgG, immunoglobulin G; KIU/l, thousand international units per litre; M, male; P, prednisilone; S, serology; IgE, immunoglobulin E.

F/58I820.3732003.5NegativePositive (sputum)Lower lobe CentralYes (CB)
M/60I430.61280023.7NegativeNegative (sputum)Multilobed CentralYes (CB)
M/58I531.2816001.4NegativeNegative (sputum/BAL)Multilobed PeripheralYes (S)
M/60I500.34290011.2PositiveNegative (Sputum)Multilobed PeripheralYes (S)
F/40P (30) I290.2811002.0Not availableUnknownMultilobar CentralYes (CB)
M/57I781.04150016.5PositivePositive (Sputum)Upper lobe PeripheralYes (S)
F/52P (10) I450.51480048.6NegativeUnknownLower lobe PeripheralYes (S)
M/43P (35) I500.152300.5Not availableUnknownUpper lobe PeripheralNo
F/67I780.8899018.4NegativeUnknownUpper lobe PeripheralNo
F/43I720.5149013.5PositiveUnknownDiffuse PeripheralNo
M/54Nil1000.4615050.0NegativeNegative (sputum)Multilobed CentralNo
F/43I800.707000.5PositiveNegative (Sputum)Upper lobe PeripheralNo
M/55P (30)310.251108.0Not availableUnknownMultilobed CentralNo
M/65P (10)460.425408.7Not availableUnknownMultilobed PeripheralNo
M/58Nil390.282602.8Not availableUnknownLower lobe PeripheralNo
M/38I691.03550.8Not availableUnknownMultilobar PeripheralNo
F/59I700.7129620.8NegativeNegative (Sputum)Lower lobe PeripheralNo
F/44P (5)740.752603.4Not availableNegative (Sputum)Upper lobe PeripheralNo
M/42Nil290.55871.2NegativePositive (BAL)Multilobar CentralNo
F/18Nil1120.184003.5Not availableUnknownMultilobar CentralNo
M/40I1061.192300.6Not availableUnknownMultilobar CentralNo
F/89Nil1040.132200.9Not availableUnknownMultilobar CentralNo
image

Figure 1.  Lack of correlation between Aspergillus sensitization and alternative surrogate markers of disease severity in patients with severe asthma. FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; IgE, immunoglobulin E; KIU/l, thousand international units per litre.

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Discussion

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusion
  7. Acknowledgments
  8. Conflict of interest
  9. References

Study limitations

Our study has a number of possible shortcomings. This is a group of patients attending a single severe asthma centre. Respiratory specialists referred the patients who had already been established on a variety of anti-asthma treatments that would influence some of the measured variables (e.g. lung function and blood eosinophilia). There may also be a degree of referral bias that is difficult to quantify, as local respiratory physicians would be aware of the research and clinical activity at our centre. We have used peripheral blood A. fumigatus-specific IgE only as a marker of sensitization, but not other immunological techniques or the cutaneous hypersensitivity response. Opinion is conflicting as to the utility of each of these indices for determining sensitization, and published evidence suggests a degree of discordance exists between different surrogate measures (30, 31). Until recently, our current practice was only to test for Aspergillus-specific IgE in the majority of cases, and the retrospective nature of this study precluded acquisition of information about the cutaneous response to allergen. It is possible that we have underestimated the prevalence of Aspergillus sensitization or ABPA as a result. The HRCT scans had not all been reported by a single radiologist, and interpretation of the scans has been restricted to extraction of specific information against standardized criteria from the radiologist’s report. While potentially introducing a degree of error related to interoperator variability, this approach has been adopted to enable uniformity of data interpretation.

Some information that is necessary to fully characterize the patients with respect to Aspergillus was absent (e.g. not every patient had respiratory samples cultured Aspergillus spp. or underwent testing for Aspergillus precipitins). This reflects varying practice among our clinicians and also how easy it was for patients to expectorate in clinic, and in this regard highlights the disparity in opinion about the relative significance of markers used for the evaluation of patients with Aspergillus sensitization and possible ABPA. For the purpose of this analysis, we have not considered potential concomitant sensitization to other fungal allergens (largely as numbers would be too small to derive any meaningful interpretation), which may be important, although we have described the presence of such sensitization within this population previously (24, 26).

HRCT abnormalities and Aspergillus sensitization

The majority of our patients had an abnormal HRCT and radiological evidence of airway disease on HRCT translated into a greater degree of airflow limitation, which is consistent with findings from other similar studies (2, 9, 11). This appears biologically plausible as asthma-related pathological change in the airways (mucus hypersecretion, increased bronchial wall thickening, and increased bronchial tone) proportionate to disease severity could conceivably lead to macroscopic change and more profound airflow limitation. Imaging and lung function appear to be alternate-modality surrogates of this same process.

Although an association between bronchiectasis and asthma has been noted previously, this relationship has infrequently been examined specifically in the severe asthma population or in relation to other disease characteristics particularly Aspergillus sensitization. The frequency of bronchiectasis (35.3%) and Aspergillus sensitization (36.2%) in our severe asthma population is comparable with that reported elsewhere (10, 14, 32). It is impossible to determine the mechanism that underpins bronchiectasis in asthma or to ascribe causality based on the current retrospective observational data; however, it is noteworthy that A. fumigatus sensitization was a statistically significant risk factor for this complication but not for other features of asthma-related radiological abnormality (Tables 3 and 4). Fairs et al. (25) recently reported data from 79 prospectively recruited patients with asthma attending another UK asthma clinic (the majority of which had severe disease) and showed a significant reduction in postbronchodilator FEV1 in those patients with Aspergillus sensitization (68% predicted vs 88%), which is comparable with the values obtained from our patients (69.9% predicted and 80.1% predicted, respectively). In the same study, the frequency of bronchiectasis was approximately twofold higher in patients with Aspergillus sensitization (68%vs 35%), which is also comparable with our data (53.7%vs 26.7%).

In our population of severe asthmatics with associated A. fumigatus sensitization, the pattern of bronchiectasis was manifest with a high degree of variability: peripheral, central, localized and multifocal changes were noted (Table 5). There was also variability in other markers traditionally regarded as important when considering a diagnosis of ABPA, in particular peripheral eosinophil count, total IgE and positive microbiological identification. As such, this process is likely to represent a continuum, with Aspergillus sensitization leading to progressive allergic airway inflammation, remodelling and ultimately bronchiectasis. It remains unclear whether there are factors that may predetermine or increase the risk of certain individuals becoming sensitized to Aspergillus to begin with and how that sensitization will be expressed as either altered asthma severity or macroscopic airway damage. There appears to be a disconnect between the degree of allergic sensitization (i.e. Aspergillus-specific IgE) and other markers of disease severity, specifically spirometric indices, total IgE, radiological abnormality and eosinophil count (Fig. 1 and Table 5). Possible mechanisms for this include a differential response to concomitant asthma therapy, variable host immunity and a potential interaction between other aspects of pre-existing airway disease (e.g. co-sensitization to alternate allergens or fungi) (33). Measuring A. fumigatus-specific IgE only quantifies one part of the exaggerated host response to fungal colonization and does not take account of any direct injury caused by this airborne fungus, cell-mediated immunity or the airway eosinophil tracking, which characterizes ABPA. Given that fundamental aspects of this complex interaction are missing from the way we describe and label Aspergillus sensitization in the asthma population, the lack of association between surrogate markers is therefore unsurprising. This study supports the growing body of evidence that clinical manifestations of airway disease, host response to Aspergillus colonization, airway remodelling and the effect of therapeutic intervention is a highly heterogeneous and continuous process. Diagnostic subdivision of asthma associated with Aspergillus into sensitization, ABPA-S and ABPA-CB appears arbitrary and fails to encapsulate this phenomenon in a biologically complete or clinically applicable way.

Conclusion

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusion
  7. Acknowledgments
  8. Conflict of interest
  9. References

The majority of patients with severe asthma have features of airway disease on HRCT, which in turn is associated with more obstructive spirometry. Bronchiectasis also occurs frequently in this group of patients, and Aspergillus sensitization is associated with an increased risk for this complication. There is a high degree of immunological, radiological and physiological variability among patients with severe asthma, bronchiectasis and Aspergillus sensitization. Defining ABPA based on the established historical criteria may therefore be unhelpful. In patients with severe asthma, clinicians should retain a low threshold for undertaking HRCT specifically to look for evidence of bronchiectasis, particularly in those sensitized to Aspergillus.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusion
  7. Acknowledgments
  8. Conflict of interest
  9. References

LH and GM were responsible for clinical and radiological data acquisition from the clinical record and entry of this information into the database. DM was responsible for data analysis and manuscript preparation and takes responsibility for the integrity of the results presented. RM undertook study design, oversaw the study and assisted with preparation of the manuscript. RCC undertook clinical data acquisition and assisted with preparation of the manuscript. There were no specific external funding sources, but DM received financial assistance from Novartis and from the Scadding-Morriston Davies clinical fellowship during the time the study was undertaken.

The authors thank Professor David Denning (Director, National Aspergillosis Centre, Manchester, UK) for internal review of the manuscript.

Conflict of interest

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusion
  7. Acknowledgments
  8. Conflict of interest
  9. References

No author has any conflict of interest to declare.

References

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusion
  7. Acknowledgments
  8. Conflict of interest
  9. References
  • 1
    Aysola RS, Hoffman EA, Gierada D, Wenzel S, Cook-Granroth J, Tarsi J et al. Airway remodeling measured by multidetector CT is increased in severe asthma and correlates with pathology. Chest 2008;134:11831191.
  • 2
    Gupta S, Siddiqui S, Haldar P, Entwisle JJ, Mawby D, Wardlaw AJ et al. Quantitative analysis of high-resolution computed tomography scans in severe asthma subphenotypes. Thorax 2010;65:775781.
  • 3
    Siddiqui S, Gupta S, Cruse G, Haldar P, Entwisle J, McDonald S et al. Airway wall geometry in asthma and nonasthmatic eosinophilic bronchitis. Allergy 2009;64:951958.
  • 4
    Simpson JL, Milne DG, Gibson PG. Neutrophilic asthma has different radiographic features to COPD and smokers. Respir Med 2009;103:881887.
  • 5
    Takemura M, Niimi A, Minakuchi M, Matsumoto H, Ueda T, Chin K et al. Bronchial dilatation in asthma: relation to clinical and sputum indices. Chest 2004;125:13521358.
  • 6
    Busacker A, Newell JD Jr, Keefe T, Hoffman EA, Granroth JC, Castro M et al. A multivariate analysis of risk factors for the air-trapping asthmatic phenotype as measured by quantitative CT analysis. Chest 2009;135:4856.
  • 7
    Lee YM, Park JS, Hwang JH, Park SW, Uh ST, Kim YH et al. High-resolution CT findings in patients with near-fatal asthma: comparison of patients with mild-to-severe asthma and normal control subjects and changes in airway abnormalities following steroid treatment. Chest 2004;126:18401848.
  • 8
    Harmanci E, Kebapci M, Metintas M, Ozkan R. High-resolution computed tomography findings are correlated with disease severity in asthma. Respiration 2002;69:420426.
  • 9
    Gono H, Fujimoto K, Kawakami S, Kubo K. Evaluation of airway wall thickness and air trapping by HRCT in asymptomatic asthma. Eur Respir J 2003;22:965971.
  • 10
    Grenier P, Mourey-Gerosa I, Benali K, Brauner MW, Leung AN, Lenoir S et al. Abnormalities of the airways and lung parenchyma in asthmatics: CT observations in 50 patients and inter- and intraobserver variability. Eur Radiol 1996;6:199206.
  • 11
    Gupta S, Siddiqui S, Haldar P, Raj JV, Entwisle JJ, Wardlaw AJ et al. Qualitative analysis of high-resolution CT scans in severe asthma. Chest 2009;136:15211528.
  • 12
    Kurt E, Ozkan R, Orman A, Calisir C, Metintas M. Irreversiblity of remodeled features on high-resolution computerized tomography scans of asthmatic patients on conventional therapy: a 6-year longitudinal study. J Asthma 2009;46:300307.
  • 13
    Agarwal R. Allergic bronchopulmonary aspergillosis. Chest 2009;135:805826.
  • 14
    Agarwal R, Aggarwal AN, Gupta D, Jindal SK. Aspergillus hypersensitivity and allergic bronchopulmonary aspergillosis in patients with bronchial asthma: systematic review and meta-analysis. Int J Tuberc Lung Dis 2009;13:936944.
  • 15
    Agarwal R, Gupta D, Aggarwal AN, Saxena AK, Chakrabarti A, Jindal SK. Clinical significance of hyperattenuating mucoid impaction in allergic bronchopulmonary aspergillosis: an analysis of 155 patients. Chest 2007;132:11831190.
  • 16
    Greenberger PA. Allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol 2002;110:685692.
  • 17
    Maurya V, Gugnani HC, Sarma PU, Madan T, Shah A. Sensitization to Aspergillus antigens and occurrence of allergic bronchopulmonary aspergillosis in patients with asthma. Chest 2005;127:12521259.
  • 18
    Schwartz HJ, Greenberger PA. The prevalence of allergic bronchopulmonary aspergillosis in patients with asthma, determined by serologic and radiologic criteria in patients at risk. J Lab Clin Med 1991;117:138142.
  • 19
    Donnelly SC, McLaughlin H, Bredin CP. Period prevalence of allergic bronchopulmonary mycosis in a regional hospital outpatient population in Ireland 1985-88. Ir J Med Sci 1991;160:288290.
  • 20
    Eaton T, Garrett J, Milne D, Frankel A, Wells AU. Allergic bronchopulmonary aspergillosis in the asthma clinic. A prospective evaluation of CT in the diagnostic algorithm. Chest 2000;118:6672.
  • 21
    Patterson R, Greenberger PA, Harris KE. Allergic bronchopulmonary aspergillosis. Chest 2000;118:78.
  • 22
    Ricketti AJ, Greenberger PA, Mintzer RA, Patterson R. Allergic bronchopulmonary aspergillosis. Arch Intern Med 1983;143:15531557.
  • 23
    Rosenberg M, Patterson R, Mintzer R, Cooper BJ, Roberts M, Harris KE. Clinical and immunologic criteria for the diagnosis of allergic bronchopulmonary aspergillosis. Ann Intern Med 1977;86:405414.
  • 24
    Denning DW, O’Driscoll BR, Hogaboam CM, Bowyer P, Niven RM. The link between fungi and severe asthma: a summary of the evidence. Eur Respir J 2006;27:615626.
  • 25
    Fairs A, Agbetile J, Hargadon B, Bourne M, Monteiro WR, Brightling CE et al. IgE Sensitisation to Aspergillus fumigatus is Associated with Reduced Lung Function in Asthma. Am J Respir Crit Care Med 2010;182:13621368.
  • 26
    Denning DW, O’Driscoll BR, Powell G, Chew F, Atherton GT, Vyas A et al. Randomized controlled trial of oral antifungal treatment for severe asthma with fungal sensitization: the Fungal Asthma Sensitization Trial (FAST) study. Am J Respir Crit Care Med 2009;179:1118.
  • 27
    Heaney LG, Brightling CE, Menzies-Gow A, Stevenson M, Niven RM. Refractory asthma in the UK: cross-sectional findings from a UK multicentre registry. Thorax 2010;65:787794.
  • 28
    Investigation of bronchoalveolar lavage, sputum and associated specimens. In: National Standard Method BSOP 57 Issue 2.3: Health Protection Agency; 2009.
  • 29
    Proceedings of the ATS workshop on refractory asthma: current understanding, recommendations, and unanswered questions. American Thoracic Society. Am J Respir Crit Care Med 2000;162:23412351.
  • 30
    Clarke CW, Mitchell J, Nunn AJ, Pepys J. Reproducibility of prick skin tests to five allergens. Clin Allergy 1982;12:18.
  • 31
    O’Driscoll BR, Powell G, Chew F, Niven RM, Miles JF, Vyas A et al. Comparison of skin prick tests with specific serum immunoglobulin E in the diagnosis of fungal sensitization in patients with severe asthma. Clin Exp Allergy 2009;39:16771683.
  • 32
    Heaney LG, Conway E, Kelly C, Johnston BT, English C, Stevenson M et al. Predictors of therapy resistant asthma: outcome of a systematic evaluation protocol. Thorax 2003;58:561566.
  • 33
    Fukushima C, Matsuse H, Fukahori S, Tsuchida T, Kawano T, Senjyu H et al. Aspergillus fumigatus synergistically enhances mite-induced allergic airway inflammation. Med Sci Monit 2010;16:BR197BR202.