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Clinical Investigations: HYPERSENSITIVITY |

Allergic Bronchopulmonary Aspergillosis in Cystic Fibrosis*: Role of Atopy and Response to Itraconazole FREE TO VIEW

Ilynn B. Nepomuceno, MS; Silvia Esrig, MS; Richard B. Moss, MD, FCCP
Author and Funding Information

*From the Department of Pediatrics, Stanford University School of Medicine, Palo Alto, CA. Supported by the Ross Mosier Fund.



Chest. 1999;115(2):364-370. doi:10.1378/chest.115.2.364
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Study objectives: (1) To determine the relationship between IgE levels and the prevalence of allergic bronchopulmonary aspergillosis (ABPA) in cystic fibrosis (CF) patients, (2) to establish the usefulness of assessing atopy as an identifying risk factor for ABPA, (3) to evaluate the clinical course of patients receiving and not receiving itraconazole as reflected in oral steroid dose requirements and number of acute episodes of ABPA, and (4) to determine the role of acute episodes of ABPA in pulmonary exacerbations of CF.

Design: Retrospective review of online clinical database and medical records.

Setting: CF clinic and inpatient services of Lucile Salter Packard Children’s Hospital at Stanford.

Patients: One hundred seventy-two patients with CF for whom serial serum total IgE levels were measured over a 5-year study period, 1992 to 1996.

Interventions: We reviewed records of patients followed up at the CF Center at Stanford who had serum total IgE measured between January 1, 1992, and December 31, 1996. Total IgE and Aspergillus fumigatus (Af) specific IgE antibodies were measured by commercial fluorometric solid-phase immunoassay. Precipitating antibodies to Af were measured by double immunodiffusion. Patients who were diagnosed as having ABPA were treated with itraconazole unless significant liver dysfunction was present. Oral steroid dosing requirements and acute episodes of ABPA for days with vs days without itraconazole were compared.

Measurements and results: Serum total IgE was elevated (> 1 SD > geometric mean for age) in 51% of patients tested. IgE > 500 IU/mL, chosen as a screening cutoff for evaluating possible ABPA, was present in 19% of patients at some time during the study period. Atopy (defined as ≥ 1 IU/mL IgE antibody to ≥ 1 allergen) was present in 61% of 104 patients tested for specific allergen sensitization. ABPA was diagnosed in 16 patients (9%). ABPA occurred in 22% of atopic CF patients but only in 2% of nonatopic patients (p = 0.001). Six percent of pulmonary exacerbations requiring hospitalization were associated with acute episodes of ABPA. Over the study period, itraconazole use was associated with a reduced average daily oral steroid dose of 47% (p = 0.05) and a reduction in the number of acute ABPA episodes by 55% (p < 0.001).

Conclusions: Screening for atopy may be a cost-effective way to select CF patients for periodic monitoring with total serum IgE levels, since there is an increased risk of ABPA developing in atopic CF patients. Itraconazole treatment of ABPA is safe and associated with fewer acute episodes of ABPA despite reduction in average daily oral steroid dose.

Abbreviations: ABPA = allergic bronchopulmonary aspergillosis; Af = Aspergillus fumigatus; ALT = alanine transaminase; AST = aspartate transaminase; CF = cystic fibrosis; CFTR = cystic fibrosis transmembrane conductance regulator; LPCH = Lucile Packard Children’s Hospital; sIgE = specific IgE; tIgE = total IgE

Allergic bronchopulmonary aspergillosis (ABPA), a hypersensitivity disorder to chronic endobronchial infection with Aspergillus fumigatus (Af) was first described in patients with asthma in 1952.1ABPA has long been known to be an important complication of pulmonary disease associated with cystic fibrosis (CF). ABPA has been variously reported in 1 to 15% of CF patients.2,,3,,4,,5,,6,,7,,8,,9 The diagnosis of ABPA in CF patients is difficult for several reasons. Full evaluation requires a constellation of symptoms, signs, serologic tests, and radiographic findings, and several of the diagnostic criteria for ABPA overlap with common manifestations of CF without ABPA.10,,11 Unlike asthma, CF patients with or without ABPA have episodic airway obstruction, pulmonary infiltrates, and bronchiectasis. In addition, patients with CF may have onset of a striking variety of immune responses to Af antigens early in life. These include immediate hypersensitivity skin test responses to Af, presence of specific IgE (sIgE) as well IgG and IgA antibodies to Af and elevated total IgE (tIgE), all of which may vary over time.8,,12,,13,,14,,15,,16 Moreover, reports of geographic variation and clustering of cases suggest environmental influences on the incidence or intensity of Af exposure and consequent ABPA in patients with CF.17,,18 Host factors that might contribute to risk for ABPA, such as CF mutations or immune response genes, are not well defined.

Once diagnosed, the conventional treatment for ABPA is systemic glucocorticosteroids.10 Such treatment, however, is particularly problematic in patients with CF since side effects of systemic corticosteroids such as osteoporosis and steroid-induced diabetes may be exaggerated in CF patients.19,,20 In 1991, Denning et al21described successful use of the antifungal agent itraconazole, which is effective in vitro against most strains of Af, in 3 patients with CF. However, due to lack of published data on safety and efficacy, the use of itraconazole in ABPA remains controversial.22

We reviewed our experience with ABPA in CF patients at the Stanford CF Center, with particular attention to identification of host risk factors and response to treatment with itraconazole. We also investigated the frequency of acute episodes of ABPA in CF patients experiencing pulmonary exacerbations requiring hospitalization.

There were 222 registered CF patients at the CF Center at Stanford during the study period. Patient data were obtained by retrospective review of the on-line database of Lucile Packard Children’s Hospital (LPCH) at Stanford and medical records. Records of patients followed up at the CF Center at Stanford who had tIgE measured at least once between January 1, 1992, and December 31, 1996, were reviewed. tIgE and Af-sIgE antibodies were measured in the LPCH Allergy Reference Laboratory by fluorometric solid-phase immunoassay (Kabi Pharmacia CAP System IgE fluoroenzymatic immunoassay and Kabi Pharmacia CAP System RAST fluoroenzymatic immunoassay; Kabi Pharmacia Diagnostics AB; Uppsala, Sweden).

Precipitating antibodies to Af were measured by the micro-Ouchterlony method of gel double immunodiffusion using 0.85% agar in borate-saline solution buffer. Five antigen preparations of Af were utilized (Greer Dia-Kit antigens K3B, K14, K16B, and K17B, Greer Laboratories Inc; Lenoir, NC; and Af extract, Hollister-Stier; Spokane, WA). A positive control serum, run in each assay, was rabbit hyperimmune sera to K3B, K16B, and K17B (RAK12) and K14 (RAK14, Greer). Precipitin lines were checked for 1 week, serum wells refilled if none seen, and rechecked for another week.

Patients’ IgE values were grouped into three categories: group 1,≥ 500 IU/mL as a screening cutoff for possible ABPA; group 2, ≤ 500 IU/mL but greater than or equal to the age cutoff value (+ 1 SD above the geometric mean for age as determined by the manufacturer’s protocol values) as an indicator of likely atopy; and group 3, less than or equal to age cutoff value, as an indicator of likely nonatopy.

Patient sensitivities to common aero allergens and food allergens were determined by in vitro measurement of serum IgE antibodies by the CAP method and categorized according to level of sIgE according to the manufacturer’s instructions. Atopy was defined for the purpose of the study as the presence of ≥ 1 IU/mL sIgE (corresponding to CAP class II) to at least one of the allergens in the panel. The following allergens were tested in the basic panel: rye and bermuda grass, oak, olive, sage-mugwort, cat epithelium, dog dander, dust mites (Dermatophagoides pteronyssinus and farinae), Af, Alternaria alternata, cockroach, milk, and egg white. Additional allergens (eg, further molds or foods) were tested at the ordering physician’s discretion.

Medication records were evaluated in those patients with IgE values classified in group 1 who were diagnosed as having acute ABPA by five required immunologic criteria and at least three of five supportive clinical, radiographic, physiologic, or microbiological criteria shown in Table 1. 10,,23 Additional information gathered from the clinical database on the patients diagnosed as having ABPA included liver function tests (aspartate transaminase [AST] and alanine transaminase[ ALT]), pulmonary function tests (FEV1), sputum microbiology, CF genotype, and chest radiographs graded using the Brasfield scoring system.,24

The sum of each of the patient’s cumulative and average per day steroid doses, as well as the number of acute episodes of ABPA, for days before or without itraconazole vs the sum of each of the patient’s values for days receiving itraconazole were compared nonparametrically via the Mann-Whitney two-tailed test.

Total IgE

During the study period, 172 patients had tIgE screened at least once, representing 77% of all patients followed up by the Center. Although a care goal, universal IgE screening was not achieved for a number of reasons, including patient/family refusal of venipuncture, patients unavailable for follow-up, ordering omission errors, and variance in physician ordering practices. In most patients, IgE values were obtained annually and whenever a patient was admitted for hospital treatment of pulmonary exacerbation. Serum tIgE was elevated (> 1 SD > geometric mean for age) in 51% of patients tested.

Specific IgE

A total of 104 patients were screened for atopy by CAP panel for common environmental allergens, representing 60% of the patients screened for tIgE. sIgE panels were ordered at the discretion of the physicians providing care to assess clinical suspicion of atopic disease (usually symptoms of rhinitis or wheezing). Atopy, defined herein serologically as ≥ 1 IU/mL sIgE to ≥ 1 allergen, was present in 61% of patients tested. Atopy was present in 96% of patients with tIgE > 500 and 79% of patients with elevated tIgE < 500 IU/mL. Only 27% of patients with normal tIgE were atopic, and 25% of these had sIgE to food allergens only. Atopic CF patients were sensitized to the following groups of inhalant allergens: pollens (rye, bermuda, olive, oak, mugwort) in 36%, Af in 34%, Alternaria and/or other molds in 30%, animal danders (cat, dog) in 22%, and house dust (mites, cockroach) in 20%. Nine patients were sensitized to common foods, usually milk or egg.

ABPA

Acute ABPA was diagnosed in 16 patients (9%) of those screened according to the criteria for diagnosis in patients with CF given in Table 1. There were 19 further patients who had tIgE > 500 IU/mL who did not have all of the other four serologic criteria for diagnosis of acute ABPA given in Table 1 and who were therefore not treated. There were nine female patients and seven male patients with diagnosed ABPA. Mean age at diagnosis of ABPA was 22.5 years; four patients had their conditions diagnosed in the preteen years. Six patients died during the study period. Fifteen of the 16 patients were atopic, ie, had sIgE to at least one other common aeroallergen in addition to Af. ABPA occurred in 22.2% of atopic CF patients vs 2.4% of nonatopic patients (relative risk 9.25, p = 0.001).

Acute ABPA and Pulmonary Exacerbations of CF

To investigate the role of acute episodes of ABPA in patients with pulmonary exacerbations, we defined a pulmonary exacerbation as a hospital admission for treatment of pulmonary symptoms of CF with IV antibiotics. Acute episodes of ABPA were defined as shown in Table 1.

For calendar year 1995, CF pulmonary exacerbation admissions to LPCH were analyzed. There were 162 admissions in 92 patients. Total IgE was > 500 IU/mL on 22 admissions in 12 patients (13% of patients admitted). Ten admissions in nine patients (10% of the patients admitted) were associated with acute episodes of ABPA by criteria in Table 1, representing a concomitant or causal acute episode of ABPA during a pulmonary exacerbation of CF.

Treatment of ABPA

Of 16 patients diagnosed as having ABPA, prednisone was the initial treatment drug in 14 (Table 2). Prednisone was initially given in single daily doses of 2 mg/kg/d for 1 week, followed by reduction of dose to 1 mg/kg/d for a second week. Patients were then switched to alternate-day dosing that was gradually tapered over several months to the lowest dose producing no rebound in tIgE or recurrence of suggestive symptoms and signs such as wheezing, eosinophilia, or new infiltrates. The rapidity and extent of steroid tapering was therefore quite variable and necessarily individualized. tIgE values were followed initially every week for the first month, then at gradually greater intervals according to patient course. To sustain the diagnosis of acute ABPA, a serologic response (≥ 50% decrease in tIgE) to systemic corticosteroids after 2 weeks was required (Table 1).

Itraconazole was added to prednisone in 12 cases. In five cases (cases 2, 6, 11, 12, and 16), ABPA had been diagnosed long before the availability of itraconazole; these patients therefore represent a subset who received several years of prednisone monotherapy and a retrospective historical control group for a substantial fraction of their clinical history of ABPA. In the other seven cases diagnosed in 1991 or later, itraconazole was added within 2 to 3 weeks of diagnosis in the absence of liver dysfunction.

Starting in 1992, patients receiving both prednisone and itraconazole were also started on a regimen of inhaled steroids administered by metered-dose inhaler via spacer at a dose of ≥ 1,000 μg/d in divided doses. In two patients with recently diagnosed disease with mild clinical symptoms and serologic evidence of ABPA (cases 13 and 14), inhaled steroid therapy alone was initiated in one patient and a combination of inhaled steroids and itraconazole in the second. In these two patients, favorable clinical and serologic courses allowed follow-up without addition of prednisone during the remainder of the study period.

Itraconazole was not given to three patients with preexisting liver disease, defined as ALT or AST > 3 times upper limit of normal persisting > 1 month and/or clinically apparent cirrhosis (Table 2, cases 8, 9, and 15). In the remaining 13 patients diagnosed as having ABPA and treated with itraconazole, liver function test results were monitored. Three patients treated with itraconazole (18%) had increased ALT/AST values at least once during the study while taking itraconazole. These elevations were mild, transient, and self-limiting. No patient had to discontinue itraconazole therapy because of biochemical or clinical liver toxic reactions. Concomitant use of drugs affecting itraconazole bioavailability (eg, antacids, omeprazole) was monitored. Patients were instructed to take itraconazole with meals and avoid agents reducing gastric acidity when possible, or if required, to take itraconazole 1 h before such drugs.

Results of analysis of prednisone doses and acute episodes of ABPA for days receiving itraconazole vs days not receiving itraconazole are shown in Table 3. Days receiving itraconazole were associated with a 47% lower average daily steroid dose (p = 0.05), although there was no significant difference in the number of days treated or total cumulative dose of prednisone. Days receiving itraconazole were also associated with a 55% reduction in the number of acute episodes of ABPA over the entire study period (p < 0.001).

Lung Function

The last measured FEV1 in the study period averaged 50.7% predicted, with a wide range (17 to 98%) (Table 2). To better gauge the possible effect of ABPA on pulmonary status over time, we analyzed the slope of decline of FEV1 over the study period. Thirteen of the patients with ABPA (81%) had serial spirometry tests available (FEV1). The mean annual rate of FEV1 decline in these patients was 3.3% per year.

Sputum Microbiology

Five of the patients with ABPA (31%) had cultures with Af in their sputum at least once during the study period. All 16 patients were chronically infected with Pseudomonas aeruginosa throughout the study period. In addition, 11 (69%) cultured positive for Staphylococcus aureus, 5 (31%) were positive for Stenotropomonas maltophilia, and 2 (12.5%) were positive for Burkholderia cepacia.

Genotype

Six of the 16 patients with ABPA (37.5%) were homozygous forΔ F508 for the CF transmembrane conductance regulator (CFTR) mutation, and another 6 were heterozygous for ΔF508 (2 unknowns, R334W, W1282X, 3659delC, and G542X). Four patients were homozygous for non-ΔF508 mutations, including one with two novel mutations (G9704/449delGCTTCCTA; article in preparation).

In this study, we reviewed our recent experience with atopy and ABPA in a CF sample population at a single center. We found that atopic sensitization to common aeroallergens is a major risk factor for ABPA. Atopy is common in CF patients described in the literature,2,,4,,9,,25,,26 and was present by our serologic definition in 61% of those tested in our series. However, this does not represent a true cross-section of CF patients, but rather patients believed to have likely or possible allergic disease on clinical grounds. Common aeroallergens such as pollen, molds, animal danders, and dust mites were frequently involved in atopic sensitization in CF. These findings may not be generalizable to other geographic regions. Nevertheless, we believe the data suggest that atopic CF patients—who had a nearly one-in-four risk for developing ABPA over a 5-year period in our study—should be periodically tested by tIgE levels to screen for ABPA, and Af serologic tests along with other diagnostic studies for ABPA (Table 1) should be performed if tIgE exceeds 500 IU/mL. In addition, we found that tIgE levels > 500 IU/mL were present in 13% of patients admitted to the hospital for a pulmonary exacerbation. Finally, 10% of CF patients admitted to the hospital for treatment of pulmonary exacerbation were found to have a concomitant acute episode of ABPA, suggesting the possibility that acute episodes of ABPA may be difficult to differentiate from bacterial or viral respiratory tract infection in CF patients without appropriate serologic studies.

The diagnosis of ABPA in CF patients may be difficult. Many studies have shown that serologic features previously thought rather specific for ABPA, based on experience in patients with asthma,10 are often present in patients with CF without ABPA11,,12,,13,,14,,15; also, radiographic features cannot discriminate changes of ABPA from underlying CF.27,,28

The incidence of Af in sputum cultures in our patients with ABPA was only 31%. In this respect, our findings are in accord with those of Milla et al,29 who reported that the recovery of Af from sputa of CF patients is not an independent risk factor for ABPA or more severe lung disease. Our data from pulmonary exacerbations support the findings of Marchant et al,24 who proposed that the increase and elevation in tIgE is a key diagnostic feature, and that IgE response to therapy is a particularly useful additional criteria for ABPA diagnosis in patients with CF. Our criteria for diagnosis of acute ABPA in CF (Table 1) are based on those originally developed for ABPA in asthma,,10 with modifications reflecting the peculiarities of CF.23 The development of standardized immunoassays for immune responses to well-characterized antigens of Af is likely to improve the limited accuracy of current diagnostic criteria for ABPA.30Recent studies with recombinant Af allergens Asp f 2, Asp f 4, and Asp f 6 show promise in distinguishing serologic responses of ABPA patients from other patients without ABPA who have IgE responses to Af.31,,32

The treatment of ABPA with oral corticosteroids has also been adapted from experience with asthmatics to patients with CF. However, CF patients have a higher risk of adverse events, in particular osteoporosis, pathologic fractures, and diabetes mellitus, due to their underlying disease.19,,20 This led us to adopt aggressive use of itraconazole as a steroid-sparing agent in CF patients diagnosed as having ABPA.33Itraconazole was reported previously to produce positive responses in several patients with asthma or CF. Pacheco et al34reported that itraconazole reduced Af-specific IgG in a patient with asthma. Germaud and Tuchais35 found that itraconazole prevented flares in six asthmatics after tapering off oral corticosteroid therapy. Denning et al21 reported that itraconazole allowed steroid tapering with improved pulmonary function and reduced tIgE in three asthmatics and three CF patients. Mannes et al36 found that itraconazole allowed steroid tapering with reduced tIgE and Af-specific IgG in two CF twins with ABPA. Because of the retrospective nature of the analysis, a causal relation of use of itraconazole to reductions in systemic steroid dosage over time and number of episodes of acute ABPA (Table 3) cannot be proved. Our results suggest, however, that itraconazole may be an effective steroid-sparing agent and additionally reduce the number of acute ABPA episodes in CF.

Use of itraconazole is not without its disadvantages and risks in patients with CF. Itraconazole is extensively metabolized in the liver and may be hepatotoxic.37 Care should be taken to evaluate underlying liver disease in CF patients. We excluded patients with cirrhosis, portal hypertension, or grossly elevated liver enzyme levels (> 3 times upper limit of normal) from itraconazole therapy. Second, itraconazole can interfere with the metabolism of several hepatically transformed drugs important in CF therapy, including cisapride, cyclosporine, digoxin, and several antihistamines. Itraconazole bioavailability is increased with food and decreased by drugs that reduce gastric acidity, which are commonly used for GI symptoms in CF.37 When clinical or immunologic responses to itraconazole are suboptimal, determination of itraconazole levels can be useful. Denning et al21 suggested that efficacy is greatest when steady-state sputum levels exceed 5 μg/mL. In several cases, we found low steady-state serum itraconazole levels (< 0.6μ g/mL) in patients with poor serologic response (failure of IgE reduction) that were improved after reviewing and revising concomitant medication use, dietary habits, or increasing the dose of itraconazole employed (data not shown).

More recently we have begun experimenting with the use of itraconazole in combination with inhaled corticosteroids as an alternative to use of oral corticosteroids. Several studies indicate that high doses of inhaled steroids may be effective in treatment of ABPA in asthmatics.38,,39,,40,,41 Benefits in the single multicenter, double-blind, placebo-controlled trial reported did not achieve statistical significance, but the dose was low (400 μg beclomethasone per day) and spacers were not used.42 Further investigation is needed to ascertain the potential benefits of inhaled steroids for ABPA in CF patients.

Most recent pulmonary function tests performed within the study period (Table 2) show a wide variety of airflow obstruction severity. However, longitudinal testing showed that our CF patients with ABPA experienced a more rapid decline of lung function (−3.3% FEV1 per year) than expected when compared with the general US CF population in the CF Foundation Registry database (−1.9% for children and −1.1% for adults) (S. FitzSimmons, personal written communication, February 1998). Although the numbers are small and not amenable to statistical analysis, this finding raises concern that ABPA may cause more rapid decline in pulmonary function in CF patients. Thus, while culturing Af in the sputum is not associated with an increased risk for more severe lung disease,29 our results are consistent with those recently reported by Wojnarowski et al,43 in which the presence of an allergic immune response to Af is associated with more rapid progression of CF lung disease.

Miller et al44 demonstrated that patients with ABPA but without CF had a significantly higher frequency of CFTR mutations at one or both CF alleles than control subjects with chronic bronchitis or the normal population. The national CF Registry notes 18% ΔF508 heterozygosity and 49% ΔF508 homozygosity.9 In our analysis of CF patients diagnosed as having ABPA, we found 37.5%Δ F508 heterozygosity and 37.5% ΔF508 homozygosity. Interestingly, 4 of 16 patients were homozygous for non-ΔF508 mutations, including several novel mutations. The possibility that particular mutations in CFTR may predispose to ABPA warrants further study in larger numbers of CF and non-CF populations with ABPA.

In conclusion, we have found that atopy is an important risk factor for ABPA in patients with CF. Screening for atopy may be a cost-effective way to select CF patients for periodic monitoring with total serum IgE levels. ABPA flares accompany a significant minority of pulmonary exacerbations of CF and should be considered, particularly when response to conventional intervention is poor. Long-term itraconazole treatment of ABPA in CF patients is well tolerated, nontoxic in properly selected patients, and is associated with approximately 50% reductions in average oral steroid dose and acute episodes of ABPA.

Ms. Nepomuceno is a recipient of a Cystic Fibrosis Foundation Student Traineeship Award. Portions of this work were presented at the 1996 North American Cystic Fibrosis Conference (Pediatr Pulmonol 1996; suppl 13: 327) and the 1997 International Lung Conference of the American Thoracic Society (Am J Respir Crit Care Med 1997; 155:AG44).

Correspondence to: Richard B. Moss, MD, FCCP, Division of Pediatric Pulmonology, Stanford University Medical Center, 701 Welch Rd, Suite 3328, Palo Alto, CA 94305-5786; e-mail: ma.rbm@forsythe.stanford.edu

Table Graphic Jump Location
Table 1. Criteria for Diagnosis of Acute ABPA in Patients With CF
Table Graphic Jump Location
Table 2. Clinical Data on CF Patients With ABPA*
* 

Age, yr dx = age at diagnosis of ABPA; Initial rx = drugs used in first month of treatment of ABPA; Wt = weight at last recorded value during study period or prior to death; FEV1, % = predicted at last recorded value during study period or prior to death; CXR = Brasfield chest radiograph score23 at last recorded value during study period or prior to death; Pdn = prednisone; itra = itraconazole; ICS = inhaled corticosteroid; NA = data not available.

Table Graphic Jump Location
Table 3. Association of Itraconazole Treatment With Prednisone Dose and Acute Episodes of ABPA in CF*
* 

Total dose = prednisone dose/day × days on treatment over study period; Avg daily dose = average daily prednisone dose (mg) over study period; Acute ABPA episodes = total number of episodes over study period; Episodes per patient = number of acute ABPA episodes per patient over study period; NS = not significant.

 

Mean ± SEM.

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Mannes, GP, van der Heide, S, van Aalderen, WM, et al Itraconazole and allergic bronchopulmonary aspergillosis in twin brothers with cystic fibrosis [letter]. Lancet. 1993;;341 ,.:492. [PubMed]
 
Como, JA, Dismukes, WE Oral azole drugs as systemic antifungal therapy.N Engl J Med1994;330,263-272. [PubMed]
 
Heinig, JH, Weeke, ER, Groth, S, et al High-dose local steroid treatment in bronchopulmonary aspergillosis.Allergy1988;43,24-31. [PubMed]
 
Balter, MS, Rebuck, AS Treatment of allergic bronchopulmonary aspergillosis with inhaled corticosteroids.Respir Med1992;86,441-442. [PubMed]
 
Imbeault, B, Cormier, Y Usefulness of inhaled high-dose corticosteroids in allergic bronchopulmonary aspergillosis.Chest1993;103,1614-1617. [PubMed]
 
Seaton, A, Seaton, RA, Wightman, AJ Management of allergic bronchopulmonary aspergillosis without maintenance oral corticosteroids: a 15-year follow-up.QJM1994;87,529-537. [PubMed]
 
Research Committee of the British Thoracic Association.. Inhaled beclomethasone dipropionate in allergic bronchopulmonary aspergillosis.Br J Dis Chest1979;73,349-356. [PubMed]
 
Wojnarowski, C, Eichler, I, Gartner, C, et al Sensitization toAspergillus fumigatusand lung function in children with cystic fibrosis.Am J Respir Crit Care Med1997;155,1902-1907. [PubMed]
 
Miller, PW, Hamosh, A, Macek, M, Jr, et al Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in allergic bronchopulmonary aspergillosis.Am J Hum Genet1996;59,45-51. [PubMed]
 

Figures

Tables

Table Graphic Jump Location
Table 1. Criteria for Diagnosis of Acute ABPA in Patients With CF
Table Graphic Jump Location
Table 2. Clinical Data on CF Patients With ABPA*
* 

Age, yr dx = age at diagnosis of ABPA; Initial rx = drugs used in first month of treatment of ABPA; Wt = weight at last recorded value during study period or prior to death; FEV1, % = predicted at last recorded value during study period or prior to death; CXR = Brasfield chest radiograph score23 at last recorded value during study period or prior to death; Pdn = prednisone; itra = itraconazole; ICS = inhaled corticosteroid; NA = data not available.

Table Graphic Jump Location
Table 3. Association of Itraconazole Treatment With Prednisone Dose and Acute Episodes of ABPA in CF*
* 

Total dose = prednisone dose/day × days on treatment over study period; Avg daily dose = average daily prednisone dose (mg) over study period; Acute ABPA episodes = total number of episodes over study period; Episodes per patient = number of acute ABPA episodes per patient over study period; NS = not significant.

 

Mean ± SEM.

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Como, JA, Dismukes, WE Oral azole drugs as systemic antifungal therapy.N Engl J Med1994;330,263-272. [PubMed]
 
Heinig, JH, Weeke, ER, Groth, S, et al High-dose local steroid treatment in bronchopulmonary aspergillosis.Allergy1988;43,24-31. [PubMed]
 
Balter, MS, Rebuck, AS Treatment of allergic bronchopulmonary aspergillosis with inhaled corticosteroids.Respir Med1992;86,441-442. [PubMed]
 
Imbeault, B, Cormier, Y Usefulness of inhaled high-dose corticosteroids in allergic bronchopulmonary aspergillosis.Chest1993;103,1614-1617. [PubMed]
 
Seaton, A, Seaton, RA, Wightman, AJ Management of allergic bronchopulmonary aspergillosis without maintenance oral corticosteroids: a 15-year follow-up.QJM1994;87,529-537. [PubMed]
 
Research Committee of the British Thoracic Association.. Inhaled beclomethasone dipropionate in allergic bronchopulmonary aspergillosis.Br J Dis Chest1979;73,349-356. [PubMed]
 
Wojnarowski, C, Eichler, I, Gartner, C, et al Sensitization toAspergillus fumigatusand lung function in children with cystic fibrosis.Am J Respir Crit Care Med1997;155,1902-1907. [PubMed]
 
Miller, PW, Hamosh, A, Macek, M, Jr, et al Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in allergic bronchopulmonary aspergillosis.Am J Hum Genet1996;59,45-51. [PubMed]
 
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