0
Clinical Investigations: ASTHMA |

Effects of Itraconazole Therapy in Allergic Bronchopulmonary Aspergillosis* FREE TO VIEW

Fabienne Salez, MD; Anne Brichet, MD; Sophie Desurmont, MD; Jean-Marie Grosbois, MD; Benoit Wallaert, MD; André-Bernard Tonnel, MD
Author and Funding Information

*From the Clinique des Maladies Respiratoires, Hôpital Calmette (Drs. Salez, Brichet, Desurmont, Wallaert, and Tonnel), and the Clinique de la Louvière (Dr. Grosbois), Lille, France.

Correspondence to: Dr. André-Bernard Tonnel, Service de Pneumologie et Immuno-Allergologie, Hôpital Calmette, Bd du Prof. Leclerc, 59037 Lille Cedex, France



Chest. 1999;116(6):1665-1668. doi:10.1378/chest.116.6.1665
Text Size: A A A
Published online

Study objectives: Allergic bronchopulmonary aspergillosis (ABPA) is the result of an immune reaction to antigens of Aspergillus fumigatus, which colonizes the bronchial lumen of affected individuals. Presently, the recommended treatment of ABPA, mainly for acute episodes of exacerbations, is administration of glucocorticoids. We initiated this study to analyze the effects of itraconazole on the clinical, biological, and functional parameters in patients with ABPA.

Patients: in this report, we describe the follow-up of 14 asthmatic patients who presented with ABPA. During the 2-year reference period (a 2-year period before the introduction of itraconazole), 14 patients were treated with inhaled corticosteroids and 12 of the 14 received oral glucocorticoids. During the itraconazole treatment period, the patients were treated with oral itraconazole, 200 mg/d, for at least 12 months.

Results: During the 2-year reference period, no significant clinical, immunologic, and functional improvement was observed on a long-term basis. During the itraconazole treatment period, a clinical improvement was observed. Blood eosinophilia, serum total IgE levels, and serum precipitating antibodies against A fumigatus antigen significantly decreased. No decrease of specific IgE against A fumigatus spp was observed. All patients experienced a partial improvement in pulmonary function tests: FEV1 significantly increased from 1,433 ± 185 to 1,785 ± 246 mL/s (p < 0.01). All patients successfully lowered oral glucocorticoid dose when receiving itraconazole. In 7 of 14 patients receiving itraconazole, the removal of oral glucocorticoids was possible.

Conclusion: These results demonstrate the efficacy of itraconazole in ABPA in reducing or eliminating the need for glucocorticoid therapy, along with clinical, biological, and functional improvement.

Figures in this Article

Allergic bronchopulmonary aspergillosis (ABPA) is a complex hypersensitivity reaction related to the presence of Aspergillus fumigatus colonizing the bronchial tree. ABPA is a rare etiology of asthma, but it must be thought of in severe asthma or glucocorticoid-dependent asthma.14 Treatment still represents the dark area in our knowledge of ABPA. Although the efficacy of oral glucocorticoids in the acute phase or in exacerbations is well known, long-term treatment of the chronic form of the disease remains unclear.56 Most of the patients with ABPA require long-term oral glucocorticoid therapy, with severe side effects such as osteoporosis, mellitus diabetes, and weight gain. Because A fumigatus colonizes the bronchial tree, antifungal therapy might be useful. Some authors have studied the effects of amphotericin and ketoconazole in ABPA, but no significant improvement has been observed.7 Itraconazole is a triazol antifungal agent that is active against A fumigatus, notably in invasive aspergillosis.9 With this in mind, we report the effects of itraconazole on the clinical, biological, and functional parameters in 14 patients with ABPA. The patients were followed during a 2-year reference period before the introduction of itraconazole, and then during a 1-year itraconazole treatment period.

Patients

Fourteen patients were studied: 7 men and 7 women (mean age, 44.5 ± 3.1 years old; range, 26 to 67). All of them presented signs of ABPA as defined by the criteria of Rosenberg et al.6 The patients were considered to have ABPA if they had asthma, eosinophilia, immediate skin reaction to A fumigatus antigen, elevated total serum IgE (> 1,000 UI/mL), elevated serum specific IgE, serum precipitins to A fumigatus, transient pulmonary infiltrates, and central bronchiectasis.,6,10 The clinical characteristics of the patients before itraconazole treatment are summarized in Table 1 .

Study Design

During the initial 2-year reference period, the patients were treated with inhaled glucocorticoid and short actingβ 2-agonists; 12 out of 14 were taking long-term oral glucocorticoids (prednisolone). The oral glucocorticoids were adjusted to the lowest dose to obtain adequate clinical control, but they were reintroduced at a higher dose (1 mg/kg/d) when acute exacerbation occurred. Active treatment with itraconazole, 200 mg qd, was started after this 2-year reference period and was continued for 1 year. During the entire study, a clinical assessment of the patients was performed four times a year in the outpatient section. Lung function tests and chest radiographs were performed at least once a year and more often in cases with a suspicion of clinical exacerbation.

Clinical and Laboratory Assessments

Exacerbations of asthma were defined as periods of increased symptoms and reduced lung function that resulted in diminished ability to perform usual activities.11Exacerbation of ABPA was characterized by chest radiograph infiltrates (usually pulmonary infiltrations of the middle lobe or upper lobes),12 peripheral blood eosinophilia, and markedly elevated total serum IgE. Worsening of asthma was or was not associated with exacerbation of ABPA.5

A chest radiograph was performed in the posteroanterior projection once a year during the 2-year reference period and three times a year during the itraconazole period.

Pulmonary function tests were performed using in standard spirometry (model 1070; Medical Graphics; St. Paul, MN), and lung volumes were measured via body plethysmography (model 1085; Medical Graphics). Lung functions were performed once a year and more often in cases with a clinical suspicion of exacerbation.

Complete and differential blood counts were obtained. Total serum IgE was measured by fluoroenzymeimmunoanalysis (UniCAP; Pharmacia & Upjohn; Stockholm, Sweden). Specific IgE against A fumigatus antigen was measured by fluoroenzymeimmunoanalysis (UniCAP; Pharmacia & Upjohn). Precipitins against A fumigatus antigens were determined by the double gel diffusion technique of Ouchterlony using A fumigatus antigen.

The results were expressed as mean ± SEM. The Wilcoxon nonparametric procedure was used to compare differences between the reference period and the itraconazole period. Statistical significance was defined as p < 0.05.

During the first 2-year reference period, the number of exacerbations of ABPA per year was 2.4 ± 0.2. Four patients had three or more exacerbations per year. The values of FEV1, FVC, and forced expiratory flow after 25 to 75% of vital capacity has been expelled ( FEF25–75%) at the beginning of the study and at the end of this 2-year reference period are shown in Table 2 , as well as biological data.

All the 14 patients were treated with itraconazole for 1 year. Interestingly, itraconazole treatment was associated with a marked improvement of clinical symptoms: the number of acute exacerbations of ABPA significantly decreased from 2 ± 0.2 to 0.93 ± 0.4/yr (p < 0.01; Fig 1 ). In patient 9, more exacerbations were observed during the itraconazole treatment, but FEV1 showed an improvement (from 2,230 mL just before the introduction of itraconazole to 2,960 mL after 1 year of itraconazole). For patients 2, 12, and 13, no more exacerbations were observed during itraconazole treatment.

The mean oral glucocorticoid dosage decreased from 22 ± 3.3 to 6.5 ± 2.3 mg/d. Oral glucocorticoid therapy was stopped in 7 of 12 patients at the end of the itraconazole treatment period. It is worth noting that during the reference period, the mean oral glucocorticoid dosage did not decrease significantly (from 26.6 ± 6.2 to 22 ± 3.3 mg/d; Fig 2 ).

Despite the progressive decrease of oral glucocorticoids, lung function tests (FEV1 and FEF25–75%) significantly improved (Table 2). Blood eosinophilia, serum total IgE, and serum precipitin antibodies against A fumigatus antigen significantly decreased during itraconazole treatment. No decrease of A fumigatus-specific IgE was observed (Table 2).

Several parameters were analyzed at the beginning of and during itraconazole treatment (clinical side effects of itraconazole such as hallucinations13). In addition, because of its inhibitory effects on cytochrome P-450 enzymes, liver function tests, aspartate aminotransferase, and alanine aminotransferase were also measured. The follow-up of these biological parameters showed no significant changes.

Our study demonstrates that itraconazole is an effective treatment of ABPA, allowing a significant improvement of clinical symptoms, a reduction of the mean dose of oral glucocorticoids, and a partial but significant improvement of pulmonary function tests.

Because ABPA is a rare and chronic disease that spreads its course over many years, it is difficult to perform a prospective, randomized, placebo-controlled study; therefore, we chose to use a methodology in which the same patients were used as controls. We retrospectively evaluated 14 patients who were regularly followed up at the outpatient section; all of the patients received in the previous 2 years drugs that are usually employed in ABPA according to the severity of asthma and/or the occurrence of acute episodes of exacerbations. In these 14 patients for whom we had adequate information on chest radiograph, pulmonary function tests, and biological data, treatment with itraconazole was begun and was followed for 12 months.

Associated with A fumigatus bronchial colonization, ABPA represents a lung disorder for which antifungal therapy may be potentially useful. Stark14described a case of ABPA that was successfully treated with inhalation of nystatin. Shale and colleagues15 studied the use of ketoconazole in six patients and demonstrated efficiency in ABPA, but no respiratory function improvement was observed. This study was abandoned due to the report of liver alterations and other side effects associated with ketoconazole.

Recently, a new triazole antifungal agent, itraconazole, was evaluated in the treatment of aspergillosis: itraconazole may be effective in 55 to 80% of patients with invasive aspergillosis, this being similar to amphotericin B.9,1617 Denning et al18have reported improvement in clinical, serologic, and pulmonary function status with itraconazole treatment in six patients with ABPA (three of the six patients had underlying cystic fibrosis); unfortunately, no statistical analysis was performed due to the small number of patients. Nepomuceno et al19also recently reported the efficacy of itraconazole in 16 patients with cystic fibrosis and ABPA, as judged by fewer acute episodes of ABPA despite a reduction in the average daily oral steroid dose. Germaud et al20 noted the advantage of associating itraconazole with corticosteroid treatment in six patients with ABPA, and the efficiency of itraconazole alone in six other patients. However pulmonary function tests were not performed, which did not allow for any significant conclusion. In our study, it is of importance to emphasize the fact that 12 patients had severe asthma and initially required oral glucocorticoids.

Surprisingly, while itraconazole induced a significant decrease in total IgE levels, treatment did not modify specific IgE antibodies against A fumigatus. This has also been reported by Denning et al18 and Germaud et al.20

The mechanisms by which itraconazole improves lung function remain controversial. The fact that precipitins decrease suggests that itraconazole acts as an antifungal treatment.2122 However, we cannot exclude the fact that itraconazole exerts anti-inflammatory properties. Linthoudt et al23 hypothesize that the interaction between itraconazole and exogenous glucocorticoids may explain the ability to reduce the glucocorticoid dose; however, in our study, glucocorticoid therapy was stopped in seven patients, suggesting another mechanism.

In conclusion, our results confirm the reports of Denning et al,18 Germaud et al,20 and Pacheco et al22 in support of the hypothesis that itraconazole is useful in the prevention of recurrent acute episodes and exacerbations of ABPA. Oral itraconazole allowed the reduction or elimination of the use of oral corticosteroids in the management of ABPA. However, randomized, controlled studies are required to determine the role of itraconazole in the long-term management of ABPA and the duration of itraconazole treatment to control ABPA and to avoid relapse.

Abbreviations: ABPA = allergic bronchopulmonary aspergillosis; FEF25–75% = forced expiratory flow after 25 to 75% of vital capacity has been expelled

Table Graphic Jump Location
Table 1. Clinical Characteristics of the 14 Patients at the Beginning of the Study*
* 

Data are presented as mean ± SEM or No., unless otherwise noted.

Table Graphic Jump Location
Table 2. Evolution of Laboratory Data and Pulmonary Function Tests*
* 

Data are expressed as mean ± SEM.

 

p < 0.05 significantly different from eosinophilia at the end of the 2-year reference period.

 

p < 0.05 significantly different from the other values.

§ 

p < 0.005 significantly different from the other values.

Figure Jump LinkFigure 1. The number of clinical exacerbations in 14 patients and the comparison of the 2-year reference period to the 1-year itraconazole treatment period.Grahic Jump Location
Figure Jump LinkFigure 2. The evolution of daily glucocorticoid treatment.Grahic Jump Location
Basich, JE, Graves, TS, Baz, MN, et al (1981) Allergic bronchopulmonary aspergillosis in cortico-dependent asthmatics.J Allergy Clin Immunol68,98-102. [PubMed] [CrossRef]
 
Clayton, DE, Busse, WW Development of allergic bronchopulmonary aspergillosis during treatment of severe asthma with systemic corticosteroids.J Allergy Clin Immunol1981;67,243-246. [PubMed]
 
Nichols, D, Dopico, GA, Braun, S, et al Acute and chronic pulmonary function changes in allergic bronchopulmonary aspergillosis.Am J Med1979;67,631-637. [PubMed]
 
Backman, KS, Greenberger, PA, Patterson, R Airways obstruction in patients with long-term asthma consistent with “irreversible asthma.”Chest1997;112,1234-1240. [PubMed]
 
Greenberger, PA Diagnosis and management of allergic bronchopulmonary aspergillosis.Allergy Proc1994;15,335-339. [PubMed]
 
Rosenberg, M, Patterson, R, Roberts, M, et al The assessment of immunologic and clinical changes occurring during corticosteroid therapy for allergic bronchopulmonary aspergillosis.Am J Med1978;64,599-606. [PubMed]
 
Fournier, EC Trial of ketoconazole in allergic bronchopulmonary aspergillosis [letter]. Thorax. 1987;;42 ,.:831
 
Ellis, ME, Halim, MA, Spence, D, et al Systemic amphoterin B versus fluconazole in the management of antibiotic resistant neutropenic fever: preliminary observations from a pilot, exploratory study.J Infect1995;30,141-146. [PubMed]
 
Jennings, TS, Hardin, TC Treatment of aspergillosis with itraconazole.Ann Pharmacother1993;27,1206-1211. [PubMed]
 
Greenberger, PA, Miller, TP, Roberts, M, et al Allergic bronchopulmonary aspergillosis in patients with and without evidence of bronchiectasis.Ann Allergy1993;70,333-338. [PubMed]
 
National Heart, Lung, and Blood Institute. Asthma management and prevention: guidelines for the diagnosis and management of asthma. Bethesda, MD: National Institutes of Health, April 1997; Publication No. 98–4051.
 
Thompson, BH, Stanford, W, Galvin, JR, et al Varied radiologic appearances of pulmonary aspergillosis.Radiographics1995;15,1273-1284. [PubMed]
 
Cleveland, KO, Campbell, JW Hallucinations associated with itraconazole [letter]. Clin Infect Dis. 1995;;21 ,.:456. [PubMed]
 
Stark, JE Allergic pulmonary aspergillosis successfully treated with inhalations of nystatin: report of a case.Dis Chest1967;51,96-99. [PubMed]
 
Shale, DJ, Faux, JA, Lane, DJ Trial of ketoconazole in non-invasive pulmonary aspergillosis.Thorax1987;42,26-31. [PubMed]
 
Pannelier, C, Vienet, A, Chwetzoff, E Itraconazole in systemic aspergillosis: experience in 22 cases [abstract]. Chemotherapy. 1992;;38(suppl 1) ,.:54
 
Kane, GC, Salazar, A, Israel, HL Aspergillosis: expanding spectrum of pulmonary disease.Clin Pulm Med1998;5,151-157
 
Denning, DW, Van Wye, JF, Lewiston, NJ, et al Adjunctive therapy of allergic bronchopulmonary aspergillosis with itraconazole.Chest1991;100,813-819. [PubMed]
 
Nepomuceno, BIB, Esrig, S, Moos, RB Allergic bronchopulmonary aspergillosis in cystic fibrosis: role of atopy and response to itraconazole.Chest1999;115,364-370. [PubMed]
 
Germaud, P, Tuchais, E, Canfrere, I, et al Therapy of allergic bronchopulmonary aspergillosis with itraconazole [abstract]. Am Rev Respir Dis. 1992;;145 ,.:A736
 
Spencer, DA, John, P, Ferryman, SR, et al Successful treatment of invasive pulmonary aspergillosis in chronic granulomatous disease with orally administered itraconazole suspension.Am J Respir Crit Care Med1994;149,239-241. [PubMed]
 
Pacheco, A, Martin, JA, Cuevas, M Serologic response to itraconazole in allergic bronchopulmonary aspergillosis.Chest1993;103,980-981
 
Linthoudt, H, Van Raemdonck, D, Lerut, T, et al The association of itraconazole and methylprednisolone may give rise to important steroid-related side effects [abstract]. J Heart Lung Transplant. 1996;;15 ,.:1165. [PubMed]
 

Figures

Figure Jump LinkFigure 1. The number of clinical exacerbations in 14 patients and the comparison of the 2-year reference period to the 1-year itraconazole treatment period.Grahic Jump Location
Figure Jump LinkFigure 2. The evolution of daily glucocorticoid treatment.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. Clinical Characteristics of the 14 Patients at the Beginning of the Study*
* 

Data are presented as mean ± SEM or No., unless otherwise noted.

Table Graphic Jump Location
Table 2. Evolution of Laboratory Data and Pulmonary Function Tests*
* 

Data are expressed as mean ± SEM.

 

p < 0.05 significantly different from eosinophilia at the end of the 2-year reference period.

 

p < 0.05 significantly different from the other values.

§ 

p < 0.005 significantly different from the other values.

References

Basich, JE, Graves, TS, Baz, MN, et al (1981) Allergic bronchopulmonary aspergillosis in cortico-dependent asthmatics.J Allergy Clin Immunol68,98-102. [PubMed] [CrossRef]
 
Clayton, DE, Busse, WW Development of allergic bronchopulmonary aspergillosis during treatment of severe asthma with systemic corticosteroids.J Allergy Clin Immunol1981;67,243-246. [PubMed]
 
Nichols, D, Dopico, GA, Braun, S, et al Acute and chronic pulmonary function changes in allergic bronchopulmonary aspergillosis.Am J Med1979;67,631-637. [PubMed]
 
Backman, KS, Greenberger, PA, Patterson, R Airways obstruction in patients with long-term asthma consistent with “irreversible asthma.”Chest1997;112,1234-1240. [PubMed]
 
Greenberger, PA Diagnosis and management of allergic bronchopulmonary aspergillosis.Allergy Proc1994;15,335-339. [PubMed]
 
Rosenberg, M, Patterson, R, Roberts, M, et al The assessment of immunologic and clinical changes occurring during corticosteroid therapy for allergic bronchopulmonary aspergillosis.Am J Med1978;64,599-606. [PubMed]
 
Fournier, EC Trial of ketoconazole in allergic bronchopulmonary aspergillosis [letter]. Thorax. 1987;;42 ,.:831
 
Ellis, ME, Halim, MA, Spence, D, et al Systemic amphoterin B versus fluconazole in the management of antibiotic resistant neutropenic fever: preliminary observations from a pilot, exploratory study.J Infect1995;30,141-146. [PubMed]
 
Jennings, TS, Hardin, TC Treatment of aspergillosis with itraconazole.Ann Pharmacother1993;27,1206-1211. [PubMed]
 
Greenberger, PA, Miller, TP, Roberts, M, et al Allergic bronchopulmonary aspergillosis in patients with and without evidence of bronchiectasis.Ann Allergy1993;70,333-338. [PubMed]
 
National Heart, Lung, and Blood Institute. Asthma management and prevention: guidelines for the diagnosis and management of asthma. Bethesda, MD: National Institutes of Health, April 1997; Publication No. 98–4051.
 
Thompson, BH, Stanford, W, Galvin, JR, et al Varied radiologic appearances of pulmonary aspergillosis.Radiographics1995;15,1273-1284. [PubMed]
 
Cleveland, KO, Campbell, JW Hallucinations associated with itraconazole [letter]. Clin Infect Dis. 1995;;21 ,.:456. [PubMed]
 
Stark, JE Allergic pulmonary aspergillosis successfully treated with inhalations of nystatin: report of a case.Dis Chest1967;51,96-99. [PubMed]
 
Shale, DJ, Faux, JA, Lane, DJ Trial of ketoconazole in non-invasive pulmonary aspergillosis.Thorax1987;42,26-31. [PubMed]
 
Pannelier, C, Vienet, A, Chwetzoff, E Itraconazole in systemic aspergillosis: experience in 22 cases [abstract]. Chemotherapy. 1992;;38(suppl 1) ,.:54
 
Kane, GC, Salazar, A, Israel, HL Aspergillosis: expanding spectrum of pulmonary disease.Clin Pulm Med1998;5,151-157
 
Denning, DW, Van Wye, JF, Lewiston, NJ, et al Adjunctive therapy of allergic bronchopulmonary aspergillosis with itraconazole.Chest1991;100,813-819. [PubMed]
 
Nepomuceno, BIB, Esrig, S, Moos, RB Allergic bronchopulmonary aspergillosis in cystic fibrosis: role of atopy and response to itraconazole.Chest1999;115,364-370. [PubMed]
 
Germaud, P, Tuchais, E, Canfrere, I, et al Therapy of allergic bronchopulmonary aspergillosis with itraconazole [abstract]. Am Rev Respir Dis. 1992;;145 ,.:A736
 
Spencer, DA, John, P, Ferryman, SR, et al Successful treatment of invasive pulmonary aspergillosis in chronic granulomatous disease with orally administered itraconazole suspension.Am J Respir Crit Care Med1994;149,239-241. [PubMed]
 
Pacheco, A, Martin, JA, Cuevas, M Serologic response to itraconazole in allergic bronchopulmonary aspergillosis.Chest1993;103,980-981
 
Linthoudt, H, Van Raemdonck, D, Lerut, T, et al The association of itraconazole and methylprednisolone may give rise to important steroid-related side effects [abstract]. J Heart Lung Transplant. 1996;;15 ,.:1165. [PubMed]
 
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Find Similar Articles
CHEST Journal Articles
Allergic Bronchopulmonary Aspergillosis in Cystic Fibrosis*: Role of Atopy and Response to Itraconazole
PubMed Articles
Guidelines
  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543