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Keywords:

  • Aspergillus;
  • chronic pulmonary aspergillosis;
  • CCPA ;
  • CNPA ;
  • aspergilloma

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Author contributions
  9. Conflicts of interest
  10. Funding
  11. References

Patients with aspergilloma can be safely managed with supportive therapy in absence of massive haemoptysis. We hypothesised that chronic cavitary pulmonary aspergillosis (CCPA) could also be managed on similar grounds. The aim of this prospective, randomised controlled trial was to evaluate the efficacy and safety of itraconazole in CCPA. Consecutive patients of CCPA with presence of chronic pulmonary/systemic symptoms; and pulmonary cavities; and presence of Aspergillus (immunological or microbiological) were randomised to receive either supportive treatment alone or itraconazole 400 mg daily for 6 months plus supportive therapy. Response was assessed clinically, radiologically and overall after 6 months therapy. A total of 31 patients (mean age, 37 years) were randomised to itraconazole (n = 17) or the control (n = 14) group. The number of patients showing overall response was significantly higher in the itraconazole group (76.5%) vs. the control (35.7%) group (P = 0.02). The numbers of patients demonstrating clinical or radiological response were also significantly higher in the itraconazole group (P = 0.016 and 0.01 respectively). Adverse events were noted in eight patients in the itraconazole group, however, none was serious or led to discontinuation of the study drug. Itraconazole was found to be superior to standard supportive treatment alone in stabilising cases of CCPA. (clinicaltrials.gov; NCT01259336).


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Author contributions
  9. Conflicts of interest
  10. Funding
  11. References

The fungus Aspergillus commonly colonises the human respiratory tract and can lead to variety of diseases such as acute invasive pulmonary aspergillosis (IPA), subacute IPA [also called chronic necrotising pulmonary aspergillosis (CNPA)], allergic bronchopulmonary aspergillosis (ABPA) and chronic pulmonary aspergillosis (CPA). CPA is further classified as aspergilloma, chronic cavitary pulmonary aspergillosis (CCPA) and chronic fibrosing pulmonary aspergillosis (CFPA).[1, 2] Pulmonary aspergilloma is the term given to colonisation of preexisting lung cavities with Aspergillus species, and formation of a conglomerate of fungal mass. It may be further divided into simple and complex aspergilloma (or CCPA).[3] Simple aspergilloma is associated with a single fungal ball in a single cavity, and no invasion of surrounding lung tissue by the organism. CCPA is characterised by the presence of multiple aspergillomas in multiple thick walled cavities with or without presence of underlying parenchymal and pleural fibrosis or both with no or little tissue invasion by Aspergillus.[4] In contrast, CNPA (better termed subacute IPA) occurs in patients with mild degree of immune compromise, and is characterised by formation of lung cavities, cavitary consolidation and nodules with or without a fungal ball.[1, 2] In CNPA, there is evidence of invasion of lung tissue by Aspergillus.

Many cavitary lung diseases are complicated by aspergilloma or CCPA including tuberculosis, sarcoidosis, bronchiectasis, bronchial cysts, chronic obstructive lung disease, ankylosing spondylitis and pulmonary infection.[5] Of these, tuberculosis is probably the most common association especially in developing countries.[6] The symptoms and signs of CPA can range from incidentally detected chest radiographic findings to a situation with life-threatening haemoptysis.[4] Patients with CCPA/CFPA commonly present with chronic cough, expectoration, haemoptysis, malaise, weight loss, fatigue and progressive loss of lung function. CNPA presents in a subacute fashion with pulmonary or systemic symptoms in an ill patient in contrast to simple aspergilloma and CCPA where patients may be asymptomatic.[7]

In patients with simple aspergilloma, treatment is not associated with significant improvement in symptoms and/or radiology, with rates of spontaneous complete radiological resolution being approximately 5% over 3 years.[8] Thus, patients with simple aspergilloma may not require any treatment and can be placed under observation. Azoles are reserved for those with constitutional symptoms and/or progressive enlargement of the cavity; surgical resection is generally reserved for patients with massive haemoptysis and good pulmonary reserve.[9] However, there is no information on the natural history of CCPA. Oral therapy with the newer azoles like itraconazole or voriconazole is the preferred treatment approach in symptomatic patients of CCPA (and aspergilloma) who are not candidates for surgery, although no randomised controlled trial support this preference.[10-15] On the other hand, all patients with CNPA require systemic antifungal therapy, initially intravenous followed by oral.[1, 9] We have observed patients with CCPA doing well on supportive measures alone without any antifungal therapy. We hypothesised that therapy with itraconazole is not superior to supportive therapy in patients with CCPA. Herein, we report the results of a randomised controlled trial on the efficacy (clinical, radiological and overall responses) and safety of itraconazole in CCPA. We also systematically review the literature on the efficacy of antifungal agents in CPA.

Materials and methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Author contributions
  9. Conflicts of interest
  10. Funding
  11. References

This was a prospective, randomised single-centre study conducted between January 2010 and June 2011. An informed consent was taken from all patients and the study was approved by the Ethics Committee.

Patients

A diagnosis of CCPA was made by a multidisciplinary team (pulmonary physicians, radiologists, microbiologists) in patients ≥18 years based on all the following criteria (composite of clinical, radiological and microbiological criteria)[16]: (a) presence of chronic pulmonary/systemic symptoms (usually cough with expectoration, haemoptysis, weight loss and fatigue) lasting ≥6 weeks; (b) elevated erythrocyte sedimentation rate; (c) evidence of slowly progressive pulmonary lesions over weeks to months including cavities with surrounding fibrosis and/or consolidation; or presence of intracavitary mass with a surrounding crescent of air with or without mobility on prone positioning with or without presence of pleural thickening in peripheral lesions on chest radiograph or computed tomography (CT) of the chest; (d) demonstration of Aspergillus precipitins on counter immunoelectrophoresis (Platelia Aspergillus enzyme immunoassay was not included among the diagnostic criteria) or demonstration of Aspergillus in sputum or bronchoalveolar fluid (BALF) and (e) exclusion of other pulmonary pathogens with a similar disease presentation by sputum smear for acid-fast bacilli and sputum/BALF cultures for mycobacteria and other bacterial infections. The following were the exclusion criteria: overt immunosuppressive state (patients on immunosuppressive drugs, intake of prednisolone (or equivalent) >10 mg for at least 3 weeks, uncontrolled diabetes mellitus and others), invasive aspergillosis, ABPA, CNPA, active pulmonary tuberculosis or malignancy, pregnancy and failure to provide informed consent.

Methods

The subjects were randomly assigned to either the control arm (supportive therapy alone) or the itraconazole arm (itraconazole 400 mg day−1 with supportive therapy). The randomisation sequence was computer generated using the statistical package StatsDirect for MS-Windows (Version 2.7.2, England, StatsDirect Ltd, 2005. http://www.statsdirect.com). The assignments were placed in sealed opaque envelopes and each patient's assignment to a particular group was made sequentially. Blinding of treatment allocation was not possible. Itraconazole (Fungitrace, Lifecare Pharma, Gurgaon, India) was administered at a dose of 200 mg twice a day along with meals (or orange juice) for 6 months. Drug levels of itraconazole were not performed. During the study period, no proton pump inhibitors or other acid reducing medicines were allowed. Adherence to itraconazole was assessed by instructing patient to bring the empty pill covers of the drug. Supportive therapy included antitussives (combination of dextromethorphan 10 mg, triprolidine 1.25 mg and phenylephrine 5 mg twice daily), iron and vitamin supplements (100 mg of elemental iron as ferrous ascorbate; folic acid 1 mg day−1), and bronchial artery embolisation and/or surgery as and when indicated.

Study procedure

All patients underwent the following investigations at baseline: chest radiograph, CT of the chest, serum precipitins against Aspergillus species, flexible bronchoscopy, sputum/BALF culture for Aspergillus and mycobacteria, spirometry, complete blood count, liver function tests and electrocardiogram. Aspergillus skin test and total serum IgE levels were performed to exclude ABPA. At 6 months CT chest, spirometry and complete blood count were repeated. Liver function tests were performed every 1–2 months or immediately if patients complained of jaundice, easy fatiguability, loss of appetite or right upper quadrant abdominal pain. All data were recorded on a standard questionnaire.

Outcome

Clinical response was classified as improved, stable or worsened based on assessment of patient's sense of well-being, gain in weight, improvement in cough and exercise capacity, decrease in the number, and frequency and quantity of haemoptysis. Radiological response was considered present if there was decrease in the size/number of the fungal balls, attenuation of the paracavitary infiltrates or pleural fibrosis. The response was assessed objectively by measuring the longest diameter of various lesions and a 50% reduction was taken as criteria for improvement. Overall response was classified as[2]: (a) improved: improved or stable clinical response and radiologically improved or stable disease; and (b) failed: worsening of symptoms or radiological progression. All outcomes were assessed at the end of 6 months of therapy. Patients were followed up for at least 6 months following completion of treatment.

Safety

The incidence of hepatitis [defined as elevation of liver enzymes (AST, ALT) greater than three times the upper limit of normal], gastritis and other adverse events was noted. We also recorded the number of patients who quit itraconazole therapy secondary to adverse reactions.

Sample size

The sample size for the study was calculated (StatsDirect 2.7.2, www.statsdirect.com) assuming a 60% improvement (and 40% worsening) in the itraconazole group and 10% improvement (and 90% worsening) in the control group. With this calculation, 14 subjects were required in each group to detect these differences [confidence level (1 − α) of 95%, power level (1 − β) of 80%].

Statistical analysis

Data are presented as median (interquartile range) or number (percentage) as appropriate. Differences between categorical variables at baseline were analysed using Chi-square or Fisher exact test as applicable. The difference between categorical variables with ordering was analysed using Cochran–Armitage test for trend. The difference between quantitative variables was assessed using the Mann–Whitney U test.

Systematic review

We first searched the literature for existing systematic reviews on the role of antifungal agents in CPA. No reviews were found. Two authors (RA, GV) then searched the PubMed and EmBase databases, without any limits, to identify the relevant studies published from 1952 onwards describing the role of antifungal agents in CPA. The following search terms were used: (‘aspergilloma’ OR ‘CNPA’ OR ‘CCPA’ OR ‘CNPA’ OR ‘chronic necrotizing pulmonary aspergillosis’ OR ‘CPA’ OR ‘CCPA’ OR ‘CFPA’ OR ‘CPA’) AND (‘itraconazole’ OR ‘azole’ OR ‘voriconazole’ OR ‘posaconazole’ OR ‘micafungin’ OR ‘antifungal’ OR ‘amphotericin’ OR ‘caspofungin’). In addition, we reviewed our personal files. We included studies reporting on the efficacy of antifungal agents in CPA. We excluded single patient case reports or studies involving <10 patients. Data were recorded on a standard data extraction form. The following items were extracted: publication details (title, authors and other citation details); type of study (prospective or retrospective); antifungal agent, dose and duration of treatment; duration of follow-up; definitions for overall response used in the individual studies and the overall response rates.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Author contributions
  9. Conflicts of interest
  10. Funding
  11. References

During the study period, 34 patients qualified for inclusion in the study of which three patients were excluded (two patients refused consent and one patient was diagnosed as CNPA). Finally, 31 patients (18 men) with a median (IQR) age of 35 (26–44) years were included in the study. Seventeen patients were randomised to the itraconazole group and 14 to the control group (Fig. 1). Majority of the patients (90%) had past history of pulmonary tuberculosis. Aspergillus precipitins were positive in 21 patients. Sputum or BAL fluid culture grew Aspergillus fumigatus in 13 patients. Immediate cutaneous hyperreactivity to Aspergillus antigen was demonstrated in 13 patients but in none, the IgE level exceeded 500 IU ml−1 and A. fumigatus-specific IgE was <0.35 kUA l−1. The most common site of the disease was right upper lobe followed by left upper lobe. The baseline characteristics of the patients were similar in the two groups (Table 1). The number of episodes of moderate-massive haemoptysis during the study period did not differ significantly between the groups (four in each group). The total number of radiological interventions (two bronchial artery embolisation procedures in each group) and the number of surgical procedures (three in itraconazole group and four in the control group) were also similar in the two groups during the trial.

Table 1. Baseline characteristics of the study population
 Itraconazole (n = 17)Control (n = 14)P value
  1. All values are in number (percentage) unless otherwise stated.

  2. BAL, bronchoalveolar lavage; HRCT, high-resolution computed tomography; IQR, interquartile range; IU, international units.

Age (in years), median (IQR)36 (26–42)35 (28–44)0.95
Male gender10 (58.8)8 (57.1)0.93
History of prior lung disease
Pulmonary tuberculosis14 (82.4)14 (100.0)0.49
No history of prior lung disease2 (11.8) 
Wegener's granulomatosis1 (5.9) 
Symptoms
Cough14 (82.4)14 (100)0.30
Haemoptysis15 (88.3)12 (85.7)0.99
Constitutional symptoms13 (76.5)10 (71.4)0.99
Duration of symptoms (in months), median (IQR)6 (3–48)4 (1–10)0.20
Investigations
Aspergillus precipitins12 (70.6)9 (64.3)1.0
Sputum/BAL Aspergillus cultures9 (52.9)4 (28.6)0.28
IgE levels (IU ml−1), median (IQR)320 (90–500)240 (80–500)0.49
HRCT chest findings
Unilateral/bilateral disease9/88/60.81
Fungal ball14 (82.4)13 (92.9)0.39
Pulmonary fibrosis11 (64.7)10 (71.4)0.99
Pleural fibrosis5 (29.4)4 (28.6)0.99
image

Figure 1. CONSORT diagram depicting the flow of participants in the study.

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Response

The number of patients showing overall response was higher in the itraconazole group (76.5%) compared with the control group (35.7%), and was statistically significant (P = 0.02). The numbers of patients demonstrating a clinical response and radiological response (Fig. 2) were also significantly higher in the itraconazole group (Table 2). The mean longest diameter of pulmonary lesions in the itraconazole and control groups, respectively, was 32.4 (13.9) and 28.2 (11.7) mm, and 26.3 (9.1) and 32.4 (9.7) mm at baseline and 6 months respectively.

Table 2. Clinical outcomes of patients in both the groups after 6 months
 Itraconazole (n = 17)Control (n = 14)P value
  1. All values are in number (percentage) unless otherwise stated.

Overall response
Improved13 (76.5)5 (35.7)0.02
Failed4 (33.5)9 (64.3)
Clinical response
Improved6 (35.2)1 (7.1)0.016
Stable7 (41.2)4 (28.6)
Worsened4 (23.6)9 (64.3)
Radiological response
Present4 (23.6)00.01
Stable9 (52.8)5 (35.7)
Progressive4 (23.6)9 (64.3)
image

Figure 2. Lung window (a) and mediastinal window (b) in two different patients showing response to itraconazole therapy.

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Safety of itraconazole therapy

Adverse events were noted in 8 (47.1%) patients in the itraconazole group, however, none was serious and none led to any discontinuation of the study drug. Transient abnormality of liver function was noted in two patients in the itraconazole group. In both the cases, the liver enzymes were elevated between 1.5 and 2 times the upper limit of normal. The liver function was found to be deranged at the second and third month of therapy, respectively, in the two patients. The liver functions normalised on follow-up in these two patients despite continuation of itraconazole therapy. Gastrointestinal disturbances were documented in six patients in the itraconazole group.

Follow-up

All the patients were followed up for a median (IQR) of 11 (7–16) months after completion of the trial. On follow-up, 9/17 (5 of 13 with overall response) and 10/14 (1 of 5 with overall response) patients worsened in the itraconazole and control group respectively. There was radiological and clinical worsening in six and clinical worsening alone in four patients in the control group, whereas there was radiological and clinical worsening in seven and clinical worsening alone in two patients in the itraconazole group. During the follow-up four patients died, two in each group. Two patients died from uncontrolled massive haemoptysis, one patient died from postoperative sepsis whereas one patient died due to acute coronary syndrome.

Systematic review of antifungal agents in CPA

Our initial search retrieved 372 citations, of which 19 studies have evaluated the role of antifungal agents in CPA (Table 3).[2, 10-13, 17-30] The studies have utilised oral (itraconazole, voriconazole, posaconazole) and intravenous (amphotericin B, itraconazole, voriconazole, micafungin) antifungal agents in patients with CPA. The overall response ranges from 14% to 93% with the response lower in patients with CCPA and highest in those with CNPA (Table 4). The efficacy of itraconazole and voriconazole ranges from 38–93%[2, 12, 13, 17, 24, 26, 30] and 50–67%,[10, 11, 19, 20, 23, 27, 29] respectively, whereas that of micafungin varies between 53% and 68%.[18, 21, 23, 25, 28] One study reported on the efficacy of amphotericin B in CPA with response rate of 82% whereas another study looked at a combination of itraconazole and micafungin and observed a response rate of 59%.[2, 28] A RCT has also compared micafungin with voriconazole, and found no difference in the efficacy between the two agents.[23] There is no randomised controlled study comparing antifungal agents with standard supportive therapy as done in our study.

Table 3. Studies reporting the use of antifungal agents in the treatment of CPA
AuthorType of studyNo. of patientsAntifungal agent and doseDuration of treatmentDuration of follow-upDrug levels
  1. BD, twice a day; CCPA, chronic cavitary pulmonary aspergillosis; CNPA, chronic necrotising pulmonary aspergillosis; d, days; ITCZ, itraconazole; m, months; MCFG, micafungin; NA, not available; PA, pulmonary aspergilloma; PCZ, posaconazole; PO, per oral; VCZ, voriconazole; w, weeks; y, years.

De Beule et al. [13]Retrospective, multicentre44 CNPA; 42 PAOral ITCZ: 50–400 mg d−111–780 dNANA
Dupont et al. [12]Retrospective, multicentre14 CNPA; 14 PAOral ITCZ: 200–400 mg d−1CNPA: mean – 5.7 m, PA: mean – 7 m3–36 mNA
Tsubura et al. [17]Prospective49 PAOral ITCZ: 100–200 mg d−1Not specifiedNADone
Denning et al. [2]Prospective11 CPAIV ampho 0.5–1 mg kg−1NA12 d to >10 yNA
Denning et al. [2]Prospective17 CPAOral ITCZ: 400 mg d−1NA12 d to >10 yDone
Kohno et al. [18]Prospective9 CNPA; 22 PAIV MCFG: 12.5–150 mg d−17–56 d11–57 dNA
Jain et al. [10]Retrospective11 CCPAOral VCZ: 300–400 mg d−1 for at least 3 months3–16.5 mAt least 3 mDone
Sambatakou et al. [19]Prospective, multicentre10 CNPA; 15 CCPAOral VCZ: 400 mg d−14–24 w4–24 wNA
Camuset et al. [11]Retrospective15 CNPA; 9 CCPAOral VCZ: as per body weight6.5 m medianNANA
Hagiwara et al. [20]Retrospective45 CNPAOral VCZ: 100–400 mg d−11–26 mNANA
Yasuda et al. [21]Non-randomised19 CNPA; 7 PAIV MCFG: 100–250 mg d−115–56 dNANA
Felton et al. [22]Retrospective79 CPAOral PCZ: 400 mg d−128–31 w2 yDone
Kohno et al. [23]Prospective, randomised97 CPA (50 MCFG, 47 VCZ)MCFG: 150–300 mg d−1; VCZ: 6 mg kg−1 BD on day 1, then 4 mg kg−1 BDMaximum 4 w4 wNA
Nam et al. [24]Retrospective26 CNPAOral ITCZ: 200–400 mg d−1Median 6 mMedian 15 mNA
Kohno et al. [25]Prospective38 CPAIV MCFG: 50–300 mg4–84 dNANA
Tomioka et al. [26]Prospective14 CNPA; 6 PAITCZ: IV for 12 days then PO 400 mg d−13 m3 mDone
Cadranel et al. [27]Prospective19 CNPA 22 CCPAOral VCZ: 200 mg BD6–12 m12–18 mNA
Fujita et al. [28]Prospective17 PACombination of IV MCFG 150 mg d−1 and ITCZ 200 mg d−11 m1 mNA
Saito et al. [29]Prospective71 CPAIV or PO VCZ 100–600 mg d−112 wNADone
Yoshida et al. [30]Prospective29 CNPAITCZ: IV for 2 weeks followed by oral capsules 400 mg d−13 m12 wDone
Table 4. Overall response and criteria used for defining treatment response in various studies
 Criteria for improvement in individual domainsOverall response criteriaOverall response rate (% of patients)
  1. CCPA, chronic cavitary pulmonary aspergillosis; CNPA, chronic necrotising pulmonary aspergillosis; ITCZ, itraconazole; MCFG, micafungin; PA, pulmonary aspergilloma; PCZ, posaconazole; VCZ, voriconazole.

De Beule et al. [13]Clinical, radiological, mycologicalImprovement in clinical and radiological with negative mycologyCNPA: 29/44 (66%); PA: 23/42 (57%)
Dupont et al. [12]Clinical, radiological, mycological: cure, improvement, no change, deteriorationImprovement in clinical and radiological with negative mycologyCNPA: 13/14 (93%); PA: 7/14 (50%)
Tsubura et al. [17]Clinical improvement (cough, fever, haemosputum): improvement, no change, deterioration, lost to follow-up; Radiological Improvement: total disappearance, moderate reduction (30–100%), mild reduction (10–30%), no change, exacerbation (increase by 10%); Mycological improvement: improved, no changeClinical, radiological and mycological trend towards improvement26/41 (63%)
Denning et al. [2]Clinical, radiological, mycologicalImproved, stable or failed. Improvement- clinical and/or mycological deterioration were absent. Failure was the outcome if there was no improvement in a patient's clinical, serological or radiological findings9/11 (82%) with amphotericin, 12/17 (71%) with ITCZ
Kohno et al. [18]Clinical response: significant improvement in clinical findings; Mycological response: eradication of the causative fungi or 30% decrease in serological findingsSuccess: defined by radiological and clinical improvement (complete or partial) or radiological improvement without any deterioration in clinical and mycological findings. Other responses were failure or not evaluableCNPA: 6/9 (67%); PA: 12/22 (55%)
Jain et al. [10]Clinical and mycological. Radiology used only for worseningPatient responses were categorised as improved, stable or failed. Improvement- clinical and/or mycological deterioration were absent. Failure- no improvement in clinical, serological or radiological findings7/11 (64%)
Sambatakou et al. [19]

Subacute IPA: complete response – resolution of all signs and symptoms, nearly complete resolution of radiological findings and other supportive evidence (mycology). Partial response – clinically meaningful improvement and >50% improvement in radiological findings. Stable disease – no or minor improvement in signs and symptoms and <50% radiological improvement. Failure – worsening of clinical and/or radiographic abnormalities

CCPA: clinical, radiological and mycological

CNPA: complete and partial responses

CCPA: marked improvement in patient's symptoms and signs, stable or improved radiology, and negative fungal cultures

CNPA: 5/10 (50%); CCPA: 10/15 (67%)
Camuset et al. [11]Clinical improvement: improvement in more than half the symptoms; Radiological improvement: partial or complete resolution of findings related to CPACombination of clinical and radiological improvement, and negative findings from the testing of mycological samples. The other outcomes were classed as stabilisation or worseningCNPA: 10/15 (67%); CCPA: 4/9 (44%)
Hagiwara et al. [20]Radiological findings, clinical symptoms, serological findingsImprovement in 2/330/45 (67%)
Yasuda et al. [21]The following endpoints were rated as ‘improvement’, ‘no change’ or ‘worsening’: clinical symptoms and physical findings; imaging findings; mycological/serological testsRated as either ‘effective’ or ‘ineffective’ based on improvement in two of the three endpointsCNPA: 10/19 (53%); PA: 5/7 (71%)
Felton et al. [22]Clinical improvement: weight gain, increased energy levels, reduced breathlessness, increased exercise tolerance; Radiological improvement: improvement in the extent of pericavitary and/or pleural thickening, or cavity size and/or number, and loss of any fungal ball; Clinical deterioration: if intercurrent infection was absent and respiratory and constitutional signs and symptoms were progressive; Radiological deterioration: increased pericavitary and/or pleural thickening, new or increased size of pulmonary cavities, progressive pulmonary fibrosis, new or increased size of intracavitary fungal ball

Response: clinical and/or radiological deterioration was absent

Overall improvement: clinical improvement in the presence of radiographic stability, radiographic improvement in the presence of clinical stability, or combined clinical and radiographic improvement

Response: 41/67 (61%); Overall improvement: 9/67 (13%)
Kohno et al. [23]Clinical (haemosputum, cough, dyspnoea, fever): reduction or disappearing of these symptoms or signs; Laboratory (CRP level, WBC counts, ESR): reduction in these inflammatory markers; Radiological: improvement in the newly appeared lesions on radiological images; Mycological: disappearing of Aspergillus from clinical samples

Success: improvement in at least two of the four groups of factors without deterioration in other two groups

Failure: absence of success

MCFG: 30/53 (57%); VCZ: 25/54 (53%)
Nam et al. [24]Clinical improvement: disappearance of more than half of the symptoms; Radiological improvement: partial or complete disappearance of findings related to CNPAClinical and radiological improvement10/26 (38%)
Kohno et al. [25]Clinical symptoms: improved, worsened, unchanged; Radiological: improved, worsened, unchangedEffective: clinical symptoms ‘improved’ and radiological findings not ‘worsened’; radiological findings ‘improved’ and clinical symptoms not ‘worsened’; Not effective: both clinical symptoms and radiological findings ‘unchanged’ or either of them ‘worsened’26/38 (68%)
Tomioka et al. [26]Radiological: improved, unchanged, deteriorated; Symptoms (fever, cough, bloody sputum): present or absentDegree of improvement in chest CT findingsCNPA: 7/12 (58%); PA: 2/5 (40%)
Cadranel et al. [27]Radiological response: complete, partial, stabilisation, failure; Mycological response: eradication, presumed eradication in patients without sputum production, persistence (sputum or bronchopulmonary sample culture positive for Aspergillus fumigatus); Clinical response not includedComplete or partial (≥50% improvement) radiological response, and mycological eradication/presumed eradication

CNPA: 10/19 (53%)

CCPA: 3/22 (14%)

Fujita et al. [28]

Clinical symptoms: improved (major symptoms and signs improved); unchanged; worsened

Radiological (chest CT): area (cm2) was defined as maximum diameter multiplied by minimum diameter. Improvement (>50% reduction); Worsening (>25% growth); Unchanged (all other cases)

Mycological and serological tests: clearance (documented clearance of infected sites plus normalisation of serological tests); presumed clearance (clearance of infected sites not documented and improvement in serological findings); persistent (documented Aspergillus spp. at infected sites or worsening in serological findings). All other cases were classified as not evaluable

Not effective: clinical or radiological findings ‘worsened’; radiological findings ‘unchanged’ and clinical symptoms ‘unchanged’; clinical symptoms ‘improved’ and radiological findings ‘unchanged’ and mycological findings ‘persistent’

Effective: radiological findings ‘improved’ and clinical symptoms either ‘unchanged’ or ‘improved’; clinical symptoms ‘improved’ and radiological findings ‘unchanged’ and mycological findings not ‘persistent’

10/17 (59%)
 

Imaging findings: disappeared, improved, unchanged, worsened, not assessable

Clinical symptoms/signs: markedly improved, improved, unchanged, worsened, not assessable

Mycological response: eradicated, decreased, unchanged, worsened, not assessable

Haematological/serological findings (β-d glucan, Aspergillus antigen, Aspergillus antibody, CRF, WBC, etc.): negative conversion, improved, unchanged, worsened, not assessable

Image findingsClinical findingsMycological responseSerological findings43/71 (61%)
 Disappeared/improvedNot worsenedNot worsenedNot worsened
 UnchangedImprovedNot worsenedImproved or negative
 Not assessableImprovedNot worsenedImproved or negative
 No response: patients not meeting the above criteria; Not assessable: clinical symptoms/signs and imaging findings in a patient are ‘not assessable’ and clinical response is also ‘not assessable’
Yoshida et al. [30]

Major items: clinical symptoms (fatigue, sputum, sputum cruentum, cough), fever, diagnostic imaging

Minor items: nutrition status, inflammation findings improvement, no change, aggravation, indetermination

Effective: ‘improvement’ in ≥2 major items or ‘improvement’ in one major and two minor items; No change: ‘no change’ in all three major items; Deterioration: ‘deterioration’ in at least one major item; Death: death: Undeterminable: states other than these conditions10/23 (44%)

The major drawback of these studies is the heterogenous criteria used for defining overall response with some utilising stabilisation and some using improvement in clinical, radiological and mycological (or serological) findings or their combination thereof. For instance, the response rates vary from 13–14% to 44–61% in CCPA if one uses improvement or stabilisation, respectively, to define response.[11, 22, 27] Another drawback is that many studies have not differentiated between the different entities of CPA.

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Author contributions
  9. Conflicts of interest
  10. Funding
  11. References

Chronic pulmonary aspergillosis is a progressive pulmonary syndrome characterised by the presence of multiple cavities and evidence of the presence of Aspergillus (either immunological or microbiological detection). In some patients, the disease can follow a progressively relentless course. The results of this study suggest that there was better outcome with itraconazole, but it may not confer long-term clinical or radiological benefit in patients with CCPA. In fact, five patients had clinical and/or radiological worsening in the next 6 months after stopping itraconazole. Most of our patients had been treated for pulmonary tuberculosis in the past, which reflected the occurrence of CCPA in the upper lobes similar to previous reports.[31, 32] Itraconazole can penetrate into the walls of the cavity and even inside the fungal balls.[17] Hence, azoles are considered as an important therapeutic option in patients with aspergilloma (and CCPA). The earliest study on CPA by De Beule et al. showed global improvement in 66% of CNPA and 56% of aspergilloma treated with oral itraconazole.[13] In this study, patients with CNPA demonstrated good radiological response whereas most patients with aspergilloma showed only symptomatic response.[13] Similarly, Dupont et al. showed an overall improvement of 92.8% with itraconazole given at a dose 100–200 mg day−1 in CNPA.[12] Denning et al. have reported the efficacy of oral itraconazole, voriconazole and posaconazole in patients with CPA with majority of the cases being those of CCPA.[2, 10, 19, 22] The efficacy rates of different azoles in various studies ranged from 61% to 71% and the efficacy rates were not different between the azoles.[2, 10, 19, 22] The results of our systematic review suggest a wide variation in efficacy rates with different agents, with the response lower in CCPA and highest in CNPA.

Although both CNPA and CCPA are characterised by lung cavities what differentiates them is the course of the disorder which is far more rapid and destructive in the former.[10] CCPA generally complicates preexisting lung disease with gradual increase in size/number of cavities over months to years rather than weeks which is generally the case with CNPA. This is also reflected by a greater radiological and microbiological response in CNPA compared with CCPA. In fact, in one study 53% of patients with CNPA showed radiological and/or microbiological improvement compared to only 14% in CCPA.[27] The aim of treatment in CCPA is prevention of progressive lung damage. Hence, treatment with oral azoles for 6–12 months would be the preferred mode of therapy. The outcome in CCPA is not radiological or mycological improvement primarily, but prevention of radiological and clinical deterioration. Even in this study, radiological response was seen in only four patients whereas 13 patients showed an overall improvement in the itraconazole arm.

The efficacy of itraconazole in CCPA has been demonstrated only in non-randomised studies. We had hypothesised that CCPA akin to simple aspergilloma will show clinical stabilisation and spontaneous improvement. However, we found that radiological and clinical improvement was significantly more frequent in the itraconazole group. In this study, 36% of patients in the control group showed an overall response suggesting that spontaneous stabilisation does occur in patients with CCPA although the improvement is significantly higher after itraconazole therapy. On the other hand, once antifungal therapy is stopped there can be worsening of symptoms as seen in this study. Hence, if tolerated, many patients could be administered azole therapy for periods even greater than 6 months. Intravenous therapy for prolonged periods is not practical in most patients with CCPA, and should generally be reserved in those with acute and subacute IPA.

Finally, our study is not without limitations. This is a single-centre study and there was no placebo in the control arm. Also, the follow-up was based on subjective symptoms without use of any quality-of-life questionnaire. Importantly, therapeutic drug monitoring for itraconazole was not performed in our study, which is another major limitation given the poor bioavailability of itraconazole, although during the study period, no proton pump inhibitors or other acid reducing medicines were allowed. Moreover, the patients had to take itraconazole with meals or orange juice. Voriconazole has better pharmacokinetics and tolerability than itraconazole, and is currently preferred over itraconazole in management of aspergillosis. However, voriconazole is significantly expensive and is rarely afforded by most of our patients. The strengths include the fact that this is the first randomised study comparing itraconazole vs. supportive therapy alone in patients with CCPA. Not only the treatment duration was adequate (6 months) but we also followed these patients for almost a year after cessation of therapy.

Conclusion

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Author contributions
  9. Conflicts of interest
  10. Funding
  11. References

In conclusion, itraconazole was found to be superior to conservative treatment in stabilising the clinical and radiological manifestations in patients of CCPA.

Author contributions

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Author contributions
  9. Conflicts of interest
  10. Funding
  11. References

RA conceived the idea, involved in patient management, data collection, statistical analysis, drafted and revised the manuscript for intellectual content. GV was involved in patient management and data collection. ANA was involved in patient management, data analysis and revised the manuscript. DG was involved in patient management and revised the manuscript. AC was involved in patient management, data collection and revised the manuscript.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Author contributions
  9. Conflicts of interest
  10. Funding
  11. References
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