Bronchiectasis is defined as abnormal, irreversible thick-walled dilatation of the bronchi and represents the end stage of a variety of pathological processes. Caused by the inflammatory reaction of the bronchi and their frequent chronic bacterial colonization, bronchiectasis usually presents with recurrent lower respiratory tract infections and chronic mucopurulent sputum production.
Bronchiectasis often goes unrecognized, even when characteristic features are present and appropriate diagnostic techniques are readily available. In a recent study the etiology of the condition was identified in only 57% of patients [
Several studies have attempted to establish an association between asthma and bronchiectasis [
The aim of the present study was to compare the prevalence of bronchiectasis in a cohort of patients with severe steroid-dependent asthma (SDA) and in another with non-steroid-dependent asthma (NSDA), in order to establish whether the SDA group has an increased associated risk of developing bronchiectasis. We also determined the Ig and IgG subclass blood levels in an attempt to correlate them with the development of bronchiectasis in either group.
The study was performed between 2004 and 2011 at the Corporació Sanitària Universitària Parc Taulí, a 760-bed university hospital with a reference population of 400,000 inhabitants. The study design was a single-center, prospective case-control study. Each patient in the SDA group was matched for age and sex status with one in the NSDA group. Patients were consecutively recruited from our institution’s asthma out-patient clinic [
All patients were nonsmokers and were treated in accordance with the severity of their disease following international guidelines [
The maximum treatment received by NSDA patients was salmeterol 50
In addition to the treatment just described, SDA patients were also given oral steroids at least 7.5 mg/day of oral prednisone (or equivalent). No patient was receiving immunomodulatory treatment [
A stabilization period of three months was required before admission, during which the FEV1 did not change more than 5% and patients did not report any deterioration in their clinical symptoms. Failure in full-tapering of corticosteroids for at least three months was also required.
A general protocol was applied to the entire study population (general instrumentation) to establish the prevalence of bronchiectasis and, in a second step, a specific etiologic protocol to determinate the cause(s) of bronchiectasis in patients in which this entity was documented (specific instrumentation).
The following tests were performed in all patients. (a) Blood analysis was performed including red and white blood cell count, platelet count, renal, hepatic biochemical parameters, rheumatoid factor, autoantibody screening test and determination of IgG, IgM, and IgA by nephelometry, and IgE. IgG subclass levels were determined by radiated immunodiffusion. (b) Forced spirometry with bronchodilator test was performed in accordance with local guidelines [
This part of the protocol was only performed in patients who had shown radiological evidence of bronchiectasis ruling out other causes of the disease: (a) clinical assessment to detect chronic sputum production and remote infections in childhood or prior to the onset of asthma symptoms; (b) blood analysis: alpha-1-antitrypsin deficiency, precipitins for aspergillus, and genetic profile of cystic fibrosis; (c) sweat test; (d) nasal potential difference; (e) saccharin test; and (f) seminogram in males.
In patients with a diagnosis other than asthma, the bronchiectasis was attributed to this alternative diagnosis. These patients were classified as having non-asthma-related bronchiectasis and were excluded from the study. Bronchiectasis in patients without alternative etiological diagnosis was considered asthma to be related to. The alternative diagnostics were defined as follows: (a) alpha-1-antitrypsin deficiency was diagnosed if serum levels were below 80 m/dL; (b) common variable immunodeficiency: presence of IgG or subclass deficiency (below 700 mg/dL for total IgG, and 550, 130, 21 and 20 mg/dL for IgG1 to IgG4 subclasses, resp.) with IgA or IgM levels below normal lower limit (below 70 and 40 mg/dL, resp.); (c) adulthood cystic fibrosis: presence of a mutation associated in the literature with cystic fibrosis with altered sweat test; (d) bronchopulmonary allergic aspergillosis: central bronchiectasis plus positive precipitins for aspergillus; (e) postinfectious bronchiectasis: medical history of documented pulmonary infection (tuberculosis or not) in the site of bronchiectasis.
Since the only reliable data on the prevalence of bronchiectasis in steroid-dependent asthmatic patients were reported in our earlier pilot study [
Statistical Package for the Social Sciences (SPSS version 19.0) was used for data entry and analysis. The results are given as mean (SD) values. Statistical comparisons between groups were performed using the two-tailed unpaired Student’s
The protocol was approved by the Ethics Committee of our Institution, and informed consent was obtained from each participant.
Fifty patients were included in the SDA group and 50 age- and sex-matched controls in the NSDA. None of them had a history of tobacco exposure. No differences in age (
As stated in Table
Spirometric and Ig/IgG subclass plasmatic values in SDA and NSDA patients.
SDA | NSDA |
| ||
---|---|---|---|---|
Forced spirometry | FEV1 L (%) |
|
|
0.01 |
FVC L (%) |
|
|
Ns | |
FEV1/FVC % |
|
|
<0.01 | |
| ||||
Ig (mg/dL) |
IgA ( |
|
|
0.03 |
IgM (40–230) |
|
|
ns | |
IgG (700–1600) |
|
|
<0.001 | |
| ||||
IgG subclass (mg/dL) | IgG1 ( |
|
|
0.01 |
IgG2 ( |
|
|
0.01 | |
IgG3 ( |
|
|
0.01 | |
IgG4 ( |
|
|
ns |
Mean values of IgA, IgG, and IgG subclasses 1, 2, and 3 were lower in the SDA group. We did not detect combined deficiency of IgG (or subclasses) with low IgA or IgM values corresponding to a common variable immunodeficiency (Table
Twelve out of 50 patients in the SDA group were diagnosed with bronchiectasis by the HRCT scan. Severity of the condition according to the classification of Reiff et al. [
Applying the etiology study protocol, an alternative diagnostic etiology was found in six cases: two of them in the SDA group (both adult cystic fibrosis) and four in the NSDA group (one tuberculosis, one bronchiectasis postpneumonia, and two cases of adult cystic fibrosis). After ruling out those cases with a definitive etiology of bronchiectasis, the prevalence of asthma-associated bronchiectasis was 10/50 (20%) in the SDA group and 2/50 (4%) in the NSDA group (
Table
Comparison of demographic conditions, spirometric values, and plasmatic values of Ig and IgG subclass in patients with and without asthma-associated bronchiectasis.
Asthma-associated bronchiectasis |
Non-asthma-associated bronchiectasis |
|
||
---|---|---|---|---|
Baseline conditions | Age |
|
|
<0.05 |
Time from diagnosis (yr) |
|
|
<0.05 | |
| ||||
Spirometric values | FEV1 (L) |
|
|
<0.05 |
FEV1 % |
|
|
ns | |
FVC (L) |
|
|
ns | |
FVC % |
|
|
ns | |
FEV1/FVC |
|
|
0.01 | |
| ||||
Ig (mg/dL) | IgA |
|
|
ns |
IgM |
|
|
<0.01 | |
IgG |
|
|
ns | |
| ||||
IgG subclass (mg/dL) | IgG1 |
|
|
ns |
IgG2 |
|
|
ns | |
IgG3 |
|
|
ns | |
IgG4 |
|
|
ns |
Finally, after adjusting for immunoglobulin levels, a stepwise regression logistic analysis showed that only age (aOR 1.08, 95% CI: 1.01–1.16) and steroid dependence (aOR 6.9, 95% CI: 1.35–35.09) were associated with the presence of asthma-related bronchiectasis.
To establish the prevalence of a pathology, a preliminary appraisal using a cross-sectional study is required. Patient selection and sample size estimation must be performed with care. Given the lack of reliable data in the literature, we based our calculations of the sample size on our earlier pilot study [
From the point of view of the methodology used to diagnose bronchiectasis and its causes, our study presents two innovative features. First, we established the diagnosis using a HRCT scan in stable patients. The original CT scans designed to assess airway structure involved thin-slice images (typically 1-2 mm axial), which were acquired using a “stop and shoot” protocol and were reconstructed using an edge-enhancing algorithm. Conversely, the high-resolution CT (HRCT) protocol allows the measurement of the airways in true cross section at any location, using retrospective reconstruction of the images to achieve a cross-sectional image of the airway [
Second, after confirming the diagnosis, we performed an etiological diagnosis of bronchiectasis applying our pneumology service’s protocol which includes innovative techniques for screening infrequent illnesses [
To evaluate bronchiectasis severity, we used the easily reproducible CT grading system described by Reiff and coworkers [
The literature review takes us back to the 1960s, when Dunnill’s autopsy findings recorded the presence of bronchiectasis in 4/20 (25%) asthmatic subjects [
Though some of these studies used HRCT scan, the method and/or the moment used for accepting the diagnosis of bronchiectasis were often inadequate, or no etiological differential diagnosis of bronchiectasis was performed. Consequently a wide range of prevalence results have been found. Paganin et al. [
In a recent study, Anwar et al. [
Regarding the PFT results, we observed that the degree of airway obstruction was more severe in SDA than in NSDA. Asthma and bronchiectasis coexist in many patients, and it has been shown that bronchiectasis can contribute to severe and difficult-to-control asthma with pulmonary complications [
In patients with asthma, especially in those with severe disease, several studies have reported a high incidence of Ig and IgG subclass deficiency and suggest that this may play a role in the pathogenesis of the disease [
The prevalence of bronchiectasis is statistically higher in SDA than in NSDA. Steroid dependency is associated with a higher risk of developing bronchiectasis, and the development of the condition is not due to the circulating levels of immunoglobulins. So it seems logical to attribute this increased risk to the evolution of steroid-dependent asthma, with higher levels of inflammation and bronchial remodeling, higher levels of formation of thick, difficult-to-clear mucous plugs, and progressive obstruction of the airway with a low degree of reversibility.
The study has several limitations. The first is the fact that we do not know the prevalence of bronchiectasis in the general nonsmoking population and in NSDA. For this reason we assumed a high prevalence (4%), to be sure that the calculation of the sample size was sufficient. The second is the selection bias in patient recruitment. The SDA patients were recruited from the study of difficult-to-control asthma carried out at our hospital [
Therefore, after having ruled out other potential causative factors, we believe that our results show a clear association between SDA and bronchiectasis that is related not to the immunological situation of the patient but probably to the disease itself. Future studies should explore whether the risk of infection and colonization by germs that are more frequent in patients with bronchiectasis than in patients with asthma is higher in SDA patients.
The study was partially supported by Grant: CIR-FPT (Fundació Parc Taulí) in 2001.