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* From the Department of Pediatrics and CF Center (Drs. Shoseyov and Kerem), Hadassah University Hospital, Mount Scopus, Jerusalem, Israel; and Paediatric and Adult Regional Cystic Fibrosis Centres (Drs. Brownlee and Conway), St James’ and Seacroft University Hospitals, Leeds, UK.
Correspondence to: Eitan Kerem, MD, Head, Department of Pediatrics and CF Center, Hadassah University Hospital, Mount Scopus, Jerusalem, Israel; e-mail: kerem{at}hadassah.org.il
Abstract
Aspergillus fumigatus, a widely distributed spore-bearing fungus, is commonly grown in sputum cultures of patients with cystic fibrosis (CF). A fumigatus may cause allergic bronchopulmonary aspergillosis (ABPA), a complex condition that leads to worsening of airway inflammation and progressive damage and is diagnosed by specific criteria. In this report, we present six CF patients with respiratory deterioration that did not respond to appropriate antibiotic treatment. All had had A fumigatus in sputum cultures but did not fulfill the criteria of ABPA. Treatment with antifungal agents was followed by improvement in clinical condition. We suggest that in patients with CF, A fumigatus should be considered as a pathogen that may directly cause respiratory exacerbations. Antifungal therapy should be considered when deteriorating respiratory function is not responding to antibacterial therapy and A fumigatus is growing in sputum cultures.
Key Words: allergic bronchopulmonary aspergillosis • antifungal therapy • Aspergillus fumigatus • cystic fibrosis
The airways of patients with cystic fibrosis (CF) are frequently colonized with Aspergillus fumigatus. Reported incidence ranges from < 5% to almost 100%,123 with a cumulative incidence of approximately 50%.1 Intensive antibiotic treatment of Pseudomonas aeruginosa infection may increase susceptibility to A fumigatus. The most common complication of Aspergillus infection in patients with CF is allergic bronchopulmonary aspergillosis (ABPA), with a prevalence of approximately 1 to 15%.123 ABPA may result in a worsening of pulmonary disease, with wheeze, breathlessness, cough, and chest pain.1 ABPA is treated with oral corticosteroids and antifungal antibiotics such as itraconazole, and is defined by a number of clinical, serologic, and radiologic criteria.1 It is characterized by clinical pulmonary deterioration that does not respond to antibacterial treatment, new and flitting pulmonary infiltrates, mucoid impaction or central bronchiectasis on chest radiography, an elevated IgE (> 1,000 IU/mL), presence of specific IgE anti-A fumigatus, and elevated eosinophil count. The patient may have a positive skin-prick test result to A fumigatus allergen. There are also less demanding minor criteria for the diagnosis of ABPA in patients with CF.1
We report six patients with CF and growth of A fumigatus in sputum cultures who presented with worsening respiratory disease that did not respond to standard antibiotic therapy chosen according to bacterial sensitivity patterns. The patients met few of the recognized criteria for diagnosis of ABPA but responded to antifungal treatment.
Materials and Methods
The patients received diagnosis and treatment from 2002 to 2003 at the CF Center, Hadassah University Hospital, Mount Scopus, Jerusalem, Israel (4 of 80 patients in this clinic) and Pediatric Regional Cystic Fibrosis Centre, St James’ and Seacroft University Hospitals, Leeds, UK (2 of 151 pediatric patients in this clinic). Specific IgE anti-A fumigatus were measured by enzyme-linked immunosorbent assay (Dr. Fooke Laboratories; Neuss, Germany) and were scored from 0 to 4: score 0, 0 to 0.34 kU/L; score 1, 0.35 to 0.69 kU/L; score 2, 0.7 to 3.4 kU/L; score 3, 3.5 to 17.4 kU/L; score 4, > 17.5 kU/L.
Case 1
A 22-year-old man with CF (G524X/
F508) and pancreatic insufficiency (Table 1
) presented after 6 months of clinical deterioration despite intensive physiotherapy, inhaled antibiotics, and several courses of treatment with IV antibiotics according to bacterial sensitivity. He had lost 5 kg of weight, from 54 to 49 kg, and showed decreased expiratory flow rates (FEV1, 32% of predicted). Breath sounds were wet with crackles over the lower lobes of both lung, but there were no wheezes. Sputum cultures grew P aeruginosa, Stenotrophomonas maltophilia, and A fumigatus. There was no change after oral and IV antibiotic treatment. His IgE was 41 IU/mL. Aspergillus-specific IgE and skin-prick test results to A fumigatus were negative. Erythrocyte sedimentation rate (ESR) was 50 mm/h. Chest radiography demonstrated bronchiectasis in the middle and lower lobes, moderate linear marking over both lungs, and moderate hyperinflation. The Brasfield score4 was 16. Chest high-resolution CT showed severe cylindrical bronchiectasis and some saccular bronchiectasis in the left lower lung field. Peribronchial infiltrates were observed mainly in the lower lungs areas with some plugging and no air trapping (Bahalla score5 of 17). Oral liquid itraconazole, 200 mg bid, was started with an immediate clinical improvement. After 1 month of therapy, the patient’s weight increased to 60 kg and FEV1 rose to 60% of predicted (Table 2
). Two months after initiation of itraconazole therapy, IgE was 8.5 IU/mL and ESR was 18 mm/h. No significant change in chest radiograph score was observed. Itraconazole was continued for 12 months.
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F508) and pancreatic sufficiency (Table 1) presented with a respiratory exacerbation with increased sputum production, weight loss, and decreased expiratory flow rates. Breath sounds were normal, with no crackles or wheezes. Sputum cultures grew P aeruginosa, M simiae, and A fumigatus. He was treated with oral ciprofloxacin and gentamicin inhalations and subsequently with IV antibiotics according to the sensitivity of the P aeruginosa culture. His clinical condition continued to deteriorate with weight loss and further decrease of expiratory flow rate (Table 2). ESR was 10 mm/h, IgE titer was 192 IU/mL, Aspergillus-specific IgE scored 3 of 4, and skin-prick test result to A fumigatus was positive. Chest radiography demonstrated bronchiectasis in the lower lobes but no infiltrates or hyperinflation. The Brasfield score was 20. Treatment with liquid itraconazole, 200 mg bid, was followed by clinical improvement, increase of FEV1 back to baseline (from 71% to 94% of predicted), and weight gain (from 32.7 to 38 kg) after 2 months (Table 2). There was no significant change in chest radiograph score. Itraconazole has been continued for > 2 years, and clinical condition has remained stable.
Case 3
A 15-year-old boy with CF (W1282X/F508) and pancreatic insufficiency (Table 1) presented with increased sputum production, decreased expiratory flow rate, and weight loss. Breath sounds were reduced with a few dry crackles mainly in the left and right lower lobes. Sputum cultures grew P aeruginosa, M abscessus, and A fumigatus. There was no improvement in respiratory function tests or weight after treatment with IV antibiotics chosen according to the sensitivity profile of the P aeruginosa isolates. IgE level was 56 IU/mL, Aspergillus-specific IgE was negative, ESR was 22 mm/h, and skin-prick test result to A fumigatus was positive (+ 3 of 4). Chest radiography demonstrated moderate hyperinflation, large areas of bronchiectasis in the middle and lower lobes and the hilar regions, with moderate linear marking over both lungs. The Brasfield score was 9. Chest high-resolution CT revealed severe bronchiectasis with thickened walls mainly in the middle and basal lung areas, with some plugging and mild air trapping (Bahalla score of 14). After 1 month of oral liquid itraconazole, 200 mg bid, FEV1 had returned to baseline (from 31 to 42% of predicted), and after 2 months of treatment his weight increased from 45.7 to 52 kg (Table 2). Air entry had improved, but diffuse crackles were heard over both lungs. There was no significant change in chest radiograph score. The ESR decreased to 15 mm/h. Itraconazole was discontinued after 12 months, as sputum culture findings were negative for A fumigatus. Following the discontinuation of itraconazole, slow respiratory deterioration was observed. A one-month trial of itraconazole had no beneficial effect. Sputum culture results remained negative for A fumigatus. Treatment was started against the mycobacterium.
Case 4
A 30-year-old woman with CF (W1282X/unknown), pancreatic sufficiency, and chronic sinusitis (Table 1) presented with increased cough and sputum production. No significant changes in expiratory flow rates or weight were observed. Lung examination revealed a few wet crackles in the left lung. IgE was 542 IU/mL; FEV1, 57% of predicted; ESR, 25 mm/h. Serum Aspergillus-specific IgE and skin-prick test results to A fumigatus were negative. Sputum culture grew A fumigatus, P aeruginosa, and B cepacia complex. Chest radiography demonstrated bronchiectasis in the middle and lower lobes, with moderate linear marking over both lungs and moderate hyperinflation. The Brasfield score was 16. There was no improvement in clinical and laboratory parameters with appropriate antibiotic treatment according to bacterial sensitivity and nasal steroids. Oral liquid itraconazole, 200 mg bid, was started, and within 4 weeks the cough had decreased and the patient reported subjective improvement. There was no change in weight, expiratory flow rate, or ESR, but the total IgE decreased by more than half to 222 IU/mL (Table 2). After 1 month, no significant change in chest radiograph score was observed. The patient received itraconazole for 4 months with eradication of A fumigatus from sputum culture.
Case 5
A 10-year-old boy, homozygous F508 (Table 1), presented with a productive cough, severe exercise restriction, lethargy, and weight loss. Wheeze was not a feature. FEV1 fell from 79 to 47% of predicted over a 9-month period. Sputum samples were consistently positive for A fumigatus, and no other respiratory pathogens were identified. There was no improvement in clinical parameters or respiratory function with broad-spectrum IV antibiotics. Aspergillus-specific IgE was negative, while total IgE and eosinophil counts remained normal throughout. A chest CT scan showed a heterogeneous appearance of the lung parenchyma, nodulation in the lower lobes, and an area of dense atelectasis in the right middle lobe. He was given a 3-month regimen of liquid itraconazole and prednisolone without improvement in symptoms or respiratory function, and A fumigatus continued to be present in all sputum specimens. The trough itraconazole blood level was satisfactory (0.5 mg/L), but the 4-h peak level was low (0.78 mg/L). The dose of itraconazole was increased from 5 to 10 mg/kg/d. Two repeat levels were satisfactory (4-h peak: 1.24 mg/L and 1.61 mg/L, respectively). Following this, there was a gradual improvement in all clinical parameters and respiratory function. A fumigatus was not detected in sputum culture.
Case 6
A 12-year-old boy (F508
Y1898 + 1) [Table 1] presented with chest pain, breathlessness, a productive cough, and weight loss. FEV1 and FVC had fallen from 80 to 47% of predicted and 88 to 54% of predicted, respectively; and oxygen saturation decreased from 98 to 92% over a 3-month period. Sputum culture results were repeatedly positive for A fumigatus. Total IgE was 123 IU/mL, Aspergillus-specific IgE was negative, and eosinophil count remained normal. Aspergillus-precipitating antibodies became weakly positive. Chest radiography showed no confluent collapse or consolidation, but there was an area of ground glass-like opacity in the right lower lobe and generally increased nodularity in all lobes, suggestive of mucous plugging. Although P aeruginosa was present on one occasion, there was no improvement with broad-spectrum IV antibiotics administered for 2 weeks on two occasions. There was no improvement with oral prednisolone, 1 mg/kg, and liquid itraconazole, 5 mg/kg, administered for 4 weeks. Sputum culture results remained positive for A fumigatus. Treatment with IV ambisone, 4 mg/kg, for 2 weeks was followed by a slow improvement in respiratory function and symptoms. Oral voriconazole was continued for 4 months. Symptoms completely resolved. Respiratory function and capillary oxygen saturation returned to baseline (Table 2), and sputum culture results became negative for Aspergillus.
Discussion
In this report, six patients with CF and positive sputum culture findings for A fumigatus but not meeting criteria for ABPA had acute or subacute clinical deterioration. The patients did not respond to appropriate antibiotic treatment directed to microorganisms identified in sputum cultures, but responded over varying periods of time and degree to antifungal medications. All patients grew A fumigatus in sputum culture, but none met the criteria required for diagnosis of ABPA1 (Table 3 ).
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In contradistinction to asthma, pulmonary infiltrates, bronchiectasis, and obstructive lung disease are common in patients with CF, with or without ABPA, resulting from recurrent and chronic bacterial infections. It may be difficult to recognize ABPA in patients with CF because of overlapping clinical, radiographic, microbiologic, and immunologic features. Many patients do not have all the classical criteria. Therefore, in a consensus document,1 minimal criteria for ABPA were defined: (1) acute or subacute clinical deterioration (cough, wheeze, exercise intolerance, exercise-induced asthma, change in pulmonary function, or increased sputum production) not attributable to another etiology; (2) total serum IgE concentration > 500 IU/mL (1,200 ng/mL); (3) immediate cutaneous reactivity to Aspergillus (skin-prick test wheal > 3 mm in diameter with surrounding erythema, with the patient not receiving systemic antihistamines) or in vitro demonstration of IgE antibody to A fumigatus; and (4) one of the following: precipitins to A fumigatus or in vitro demonstration of IgG antibody to A fumigatus, or new or recent abnormalities on chest radiography (infiltrates or mucus plugging) or chest CT (bronchiectasis) that were not cleared with antibiotics and standard physiotherapy.
Our patients met only some of these minimal criteria: a slightly elevated serum IgE in one patient, a positive skin-prick test result to A fumigatus in two patients, and weakly positive IgE-specific antibodies to A fumigatus in one patient (Table 3). IgG antibody to A fumigatus or precipitins were not measured, as they are not available in our centers and are rarely done in other centers. Precipitating antibodies have been found to be a sensitive marker, both in CF and in asthma patients.310 Although a key diagnostic feature of ABPA, precipitating antibodies have been found to be present in patients with CF without ABPA. In the study of Laufer et al,10 precipitating antibodies were detected in 50% of their patients with CF. Furthermore, the level of these antibodies fluctuates over time.3 Allowing for the fact that eosinophil counts have been found to be of limited value in diagnosing ABPA in both CF patients10 and asthma patients, and that eosinophilia may be present because of chronic P aeruginosa infection, our patients nonetheless did not demonstrate serum eosinophilia or an IgE-mediated allergic inflammatory response. None of them received steroids, but there was a clinical improvement with appropriate antifungal therapy (itraconazole, voriconzole, or IV ambisone) in all six patients.
Colonization with A fumigatus occurs in 60% of CF patients, but the full picture of ABPA develops in only 7 to 15%,1 particularly after the age of 6 years, and it is generally associated with worse lung disease.11 The optimal management of patients with Aspergillus airway colonization is unclear, since only a small proportion (3%) progress to invasive disease, and the long-term outcome of untreated patients with Aspergillus airway colonization is unknown. In contrast, the available data support an aggressive approach to the diagnosis and treatment of Aspergillus tracheobronchitis in lung transplant recipients, since this condition may progress to invasive pneumonia if management is delayed.12
The current report suggests that A fumigatus should be considered as a potential pathogen in CF and that treatment with antifungal therapy may be indicated in such cases. We therefore suggest calling this condition Aspergillus bronchitis or nonallergic bronchopulmonary aspergillosis. An alternative classification might be obstructing bronchial aspergillosis, as has been seen in AIDS and transplant patients.1213 Although it is possible that this condition is in part an early stage of ABPA since reduction of IgE levels was noted in all our patients, none of our patients received systemic corticosteroids, the standard therapy of ABPA, while showing good recovery. Therefore, it is likely that the Aspergillus caused bronchitis without an allergic response.
The current recommendation in early stages of ABPA is to wait and follow the IgE levels until they increase above the limit. However, the deterioration in our patients required immediate intervention.
The first-line treatment for A fumigatus is itraconazole, a triazole antifungal agent with a broad activity spectrum and favorable pharmacokinetic and safety profiles. Numerous clinical trials have established the efficacy and safety of itraconazole in the treatment of aspergillosis, candidiasis, coccidioidomycosis, blastomycosis, cryptococcosis, and histoplasmosis.14 Itraconazole is metabolized by side-chain hydroxylation to 14-hydroxy itraconazole. In the steady state, 14-hydroxy itraconazole is found in concentrations nearly twice that of the unaltered drug. Many fungi are susceptible to both the parent drug and the hydroxylated metabolite.15 The use of itraconazole oral solution formulation is preferred in patients with CF, as higher itraconazole blood concentrations are achieved than with the capsule formulation. The absorption of the solution is more rapid in the fasting state. Conway et al16 demonstrated that the administration of oral itraconazole solution, 2.5 mg/kg bid, in patients with CF achieves steady-state concentrations in a maximum of 8 days. Herbrecht et al17 suggested that voriconazole should be the first drug for Aspergillosis. However, voriconazole has not been used for the treatment of ABPA, and therefore there is some uncertainty about this.
The association between nontuberculous mycobacterium, ABPA, and steroid therapy has recently been reported.18 Two of our patients had mycobacterium growth in sputum cultures. Neither of these patients received steroids prior to mycobacterium growth. It is possible that the respiratory deterioration was in part associated with mycobacterium infection. However, the response to anti-Aspergillus therapy makes this possibility unlikely.
These data suggest that antifungal therapy should be considered for patients with respiratory exacerbations associated with A fumigatus isolation from respiratory tract cultures when there is no response to appropriate antimicrobial therapy. Since they do not meet the criteria for ABPA, no steroid therapy is indicated. The recommended duration of treatment is not known and should be judged according to the clinical response and until there are negative culture findings for A fumigatus.
Footnotes
Abbreviations: ABPA = allergic bronchopulmonary aspergillosis; CF = cystic fibrosis; ESR = erythrocytes sedimentation rate
The authors have no conflicts of interest on this topic.
Received for publication November 23, 2005. Accepted for publication January 11, 2006.
References
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