The efficacy and tolerability of voriconazole in the treatment of chronic cavitary pulmonary aspergillosis

doi:10.1016/j.jinf.2005.08.022

Journal of Infection

Volume 52, Issue 5, May 2006, Pages e133-e137

https://doi.org/10.1016/j.jinf.2005.08.022 Get rights and content

Summary

Voriconazole is the second oral drug licensed for the treatment of aspergillosis. A retrospective non-comparative study was conducted in 16 patients with chronic cavitary pulmonary aspergillosis (CCPA) treated with voriconazole. All patients had failed or were intolerant of itraconazole. The duration of therapy varied from 3 days to 16.5 months. Eleven patients received at least 3 months of therapy with no significant adverse events. Overall seven (64%) patients had a response at 3 months as assessed by at least some fall in inflammatory markers, weight gain and reduction in pulmonary symptoms and two (18%) remained stable. Inflammatory markers improved in 5/11 (46%) with a mean fall in CRP of 0.08 mg/l and ESR of 12.8 mm/h. Aspergillus precipitins were quantitated by numbers of arcs and serum dilution and 11 (100%) showed improvement of at least one band or fall of titre. Total serum IgE was elevated (>200 IU/mL) in 5/11, and fell by a median of 118 kIU/l. Two patients failed therapy. Of the 17 patients, five (27%) had to discontinue therapy as a result of adverse events (three in under 1 week). Adverse events included erythematous rash (5), headaches (4), hepatotoxicity (3), photosensitive rash (3), retinal flashes (3) and neurological symptoms (3). Voriconazole is a useful alternative therapy for CCPA, with a response rate of 64%, over 3 months, and continuing partial remission of disease for much longer periods.

Section snippets

Materials and methods

Patients included all those referred to the senior author (DWD) up until January 2004 with the following criteria:¹ Chronic pulmonary or systemic symptoms (>3 months) including at least one of weight loss, productive cough or haemoptysis, and cavitary pulmonary lesion with evidence of paracavitary infiltrates or expansion of cavity size over time, and positive serum Aspergillus precipitins test, and elevated inflammatory markers, and exclusion of other pulmonary pathogens by appropriate

Results

We identified 16 patients with CCPA who had received voriconazole. All were intolerant or failing itraconazole. Most had received multiple prior therapies, some for many years. They were commenced on 150–200 mg twice daily of voriconazole, with dose adjustment dependent on plasma monitoring and tolerance. The duration of therapy varied from a few days to >18 months. Eleven patients received at least 3 months voriconazole therapy.

Assessment of symptoms showed a variable response. At 3 months 3/11

Discussion

Voriconazole is active against all common Aspergillus species in vitro,⁹ and is superior to amphotericin B in invasive aspergillosis.¹⁰ Although an azole, it differs in structure from itraconazole and has different pharmacokinetics, an extended spectrum of activity against rarer fungal pathogens, a slightly different drug interaction profile and a different adverse event profile.¹¹ Like itraconazole, but for different reasons, it exhibits wide inter-patient variation in exposure after both

Acknowledgements

This review was conducted as part of a final year student project, and was unfunded.

Conflict of interest statement: Dr Denning has received funding from Pfizer for grants and honoraria for talks, as well as multiple other pharmaceutical companies. Pfizer co-sponsor the Aspergillus website (www.aspergillus.man.ac.uk) which Dr Denning edits. Ms Jain has no conflicts to declare.

References (19)

J.L. Saraceno et al.
Chronic necrotizing pulmonary aspergillosis: approach to management
Chest
(1997)
D.W. Denning
Chronic forms of pulmonary aspergillosis
Clin Microbiol Infect
(2001)
W.E. Caras et al.
Chronic necrotizing pulmonary aspergillosis: pathologic outcome after itraconazole therapy
Mayo Clin Proc
(1996)
D.W. Denning et al.
Chronic cavitary and fibrosing pulmonary and pleural aspergillosis: case series, proposed nomenclature and review
Clin Infect Dis
(2003)
J.H. Campbell et al.
Treatment of pulmonary aspergillosis with itraconazole
Thorax
(1991)
E. Tsubura
Multicenter clinical trial of itraconazole in the treatment of pulmonary aspergilloma. Pulmonary Aspergilloma Study Group
Kekkaku
(1997)
R. el Oakley et al.
Indications and outcome of surgery for pulmonary aspergilloma
Thorax
(1997)
S.H. Lee et al.
Clinical manifestations and treatment outcomes of pulmonary aspergilloma
Korean J Intern Med
(2004)
B. Keevil et al.
Validation of an assay for voriconazole in serum samples using liquid chromatography—tandem mass spectrometry
Ther Drug Monit
(2004)

There are more references available in the full text version of this article.

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Endobronchial amphotericin B to treat hemoptysis in an inoperable patient with aspergillosis
2024, Medical Mycology Case Reports
A 37-year-old man presented with chronic cavitary pulmonary aspergillosis and hemoptysis refractory to systemic antifungal therapy with voriconazole and bronchial artery embolization. Surgical excision was unfeasible due to the patient's refusal of blood transfusions. Ten sessions of intracavitary instillation of amphotericin B via flexible bronchoscopy were then performed. Hemoptysis cessation and aspergilloma resolution were achieved, with no toxicity or side effects, and the clinical benefits were sustained at six months of follow-up.
Instillation of Amphotericin B by bronchoscopy combined with systemic voriconazole in advanced non-small cell lung cancer patients with chronic cavitary pulmonary aspergillosis: A case series and literature review
2023, Journal of Medical Mycology
Although the treatment of aspergillosis has been studied for years, the optimal nonsurgical treatment of chronic cavitary pulmonary aspergillosis (CCPA) remains unsatisfactory, especially in lung cancer. We report two advanced non-small cell lung cancer (NSCLC) patients who recovered from CCPA following instillation of Amphotericin B (AmB) by bronchoscopy combined with systemic voriconazole. The first patient was diagnosed with lung adenocarcinoma after right upper lobe resection and was treated with anaplastic lymphoma kinase-targeted therapy. Chest computed tomography (CT) revealed a right pulmonary cavity containing solid materials. The second patient was diagnosed with squamous cell carcinoma and received immunotherapy following surgery, chemotherapy, and radiotherapy. Chest CT tomography revealed a mass in the right lung cavity. Both patients' cultures and next-generation sequencing of their bronchoalveolar lavage (BAL) samples revealed presence of Aspergillus fumigatus. In addition, the galactomannan test of both patients BAL samples was positive. Systemic voriconazole was prescribed based on in vitro susceptibility testing. The chest images and clinical symptoms of both patients did not improve after one month of voriconazole therapy within the therapeutic blood concentration. Considering the low local concentrations of antifungals against CCPA, AmB instillation by bronchoscopy combined with systemic voriconazole was utilized. The chest CT images and clinical symptoms of both patients markedly improved in the following third month. Instillation of AmB combined with systemic voriconazole may be a promising treatment option for NSCLC patients with CCPA who fail voriconazole monotherapy.
Risk factors for relapse of chronic pulmonary aspergillosis after discontinuation of antifungal therapy
2020, Clinical Infection in Practice
Citation Excerpt :
Long-term oral triazole therapy is the mainstay of treatment for most patients, with the exception of some with localised disease who may be offered surgery [1,2]. However, acquired resistance during therapy, drug-related side effects and disease recurrence after cessation of treatment are the major management challenges [3–6]. Recurrence is thought to be common in CPA following discontinuation of triazole maintenance therapy.
We aimed to identify the frequency and risk factors for disease relapse following cessation of antifungal therapy in CPA.
This retrospective audit at the National Aspergillosis Centre, Manchester, UK assessed outcomes for patients with CPA who had received antifungal treatment and for whom therapy was discontinued for at least one month between August 2009 and May 2017. We defined relapse as a deterioration in two of the following parameters: clinical, radiological, serological or sputum microbiological markers of CPA activity.
Therapy was discontinued in 102 patients. Age distribution was 63.7 ± 11.5 years. Therapy was recommenced in 43 (42%) patients of whom 21 met our definition of relapse — 31% of those with bilateral and 11% of those with unilateral disease. Patients with bilateral disease and those with ≥ 1 aspergillomas were more likely to relapse on univariate analysis. In a multivariable logistic regression analysis, bilateral disease was the only independent risk factor for relapse (OR: 3.0; 95% CI: 1.0–8.8; p = .044).
Bilateral CPA is a risk factor for relapse after treatment discontinuation. A longer duration of treatment may be associated with a lower rate of relapse in extensive CPA, whereas more limited disease may respond to shorter courses.
Monitoring treatment response in chronic pulmonary aspergillosis: role of clinical, spirometric and immunological markers
2019, Clinical Microbiology and Infection
Citation Excerpt :
In a study of subjects with ABPA, A. fumigatus-specific IgG increased in 37% of those who responded to treatment, similar to the current study [12]. Two studies have also evaluated the trends of Aspergillus precipitins in response to treatment [16,17]. The Aspergillus precipitation test is, however, a qualitative measure and has poor sensitivity in CPA [4].
The treatment response in chronic pulmonary aspergillosis (CPA) is usually assessed based on the improvement in clinical and imaging findings. Herein, we evaluate serum Aspergillus fumigatus-specific IgG, serum galactomannan, weight change, and lung function for assessing treatment response in subjects with CPA.
We categorized treatment response as favourable (improved or stable clinical response with radiologically improved or stable disease) or unfavourable (worsening of symptoms or radiological progression) after 6 months of treatment with antifungal azoles. We measured A. fumigatus-specific IgG, serum galactomannan, weight, and lung function at baseline, 3 months, and 6 months in those with favourable and unfavourable treatment response.
One hundred and twenty-six consecutive treatment-naïve subjects (53.2% (67/126) males; mean ± SD age, 42.3 ± 14.7 years) with CPA were included. One hundred and six and 20 were classified as having favourable and unfavourable response, respectively. After 6 months of treatment, the decline in serum A. fumigatus-specific IgG (n = 119) was similar in those with favourable or unfavourable response (mean ± SD, -26.3 ± 45.5 mgA/L vs. –3.4 ± 65.6 mgA/L; p 0.20). There was no significant change in the serum galactomannan (favourable vs. unfavourable: mean ± SD, –0.11 ± 2.8 vs. -0.62 ± 2; p 0.92) or FEV1 (favourable vs. unfavourable: mean ± SD, 24 ± 250 mL vs. –62 ± 154 mL; p 0.19) after 6 months of treatment. There was significant loss of weight (mean ± SD, –2.5 ± 4.5 kg) in subjects with unfavourable response.
Serum A. fumigatus-specific IgG and serum galactomannan inconsistently decrease following treatment and may not be useful indicators for monitoring treatment response in CPA. Similarly, there is little change in pulmonary function following treatment. A gain in body weight is seen in those with favourable response.
The spectrum of pulmonary aspergillosis
2018, Respiratory Medicine
Citation Excerpt :
A. fumigatus IgG and precipitins levels may decrease but do not usually return to normal [67]. Declining levels of ESR and hrCRP in patients receiving therapy may also indicate adequate response [98]. Patients who undergo partial surgical resection need to be monitored closely [60].
Notable progress has been made in the past years in the classification, diagnosis and treatment of pulmonary aspergillosis. New criteria were proposed by the Working Group of the International Society for Human and Animal Mycology (ISHAM) for the diagnosis of allergic bronchopulmonary aspergillosis (ABPA). The latest classification of chronic pulmonary aspergillosis (CPA) suggested by the European Society for Clinical Microbiology and Infectious Diseases (ESCMID) has become widely accepted among clinicians. Subacute invasive pulmonary aspergillosis is now considered a type of CPA, yet it is still diagnosed and treated similarly to invasive pulmonary aspergillosis (IPA). Isavuconazole, an extended-spectrum triazole, has recently been approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of IPA. The most recent Infectious Diseases Society of America (IDSA) guidelines strongly recommend reducing mold exposure to patients at high risk for pulmonary aspergillosis. The excessive relapse rate following discontinuation of therapy remains a common reality to all forms of this semi-continuous spectrum of diseases. This highlights the need to continuously reassess patients and individualize therapy accordingly. Thus far, the duration of therapy and the frequency of follow-up have to be well characterized.
CT Imaging Assessment of Response to Treatment in Chronic Pulmonary Aspergillosis
2016, Chest
Long-term antifungal therapy is usually the only treatment option for chronic pulmonary aspergillosis. However, response rates are difficult to compare because the reported clinical, mycologic, or radiologic criteria are not standardized. Objective parameters are therefore needed. To define the most relevant CT imaging variables in assessment of response to treatment, we investigated changes over time in CT imaging variables.
Changes in CT imaging variables were assessed by systematic analysis of the CT scan findings of 36 patients at diagnosis and 6 months after initiation of treatment. The relevant radiologic variables were determined by selecting those showing significant changes over time. Two experienced thoracic radiologists, blinded for clinical and serologic response, independently performed CT scan analyses. Interreader agreement and concordance between radiologic and clinical response were evaluated.
Of the 36 patients, seven experienced clinical deterioration while undergoing therapy. Significantly evolving radiologic variables included cavity and pleural wall thickening (P < .05), which were associated with clinical improvement. There was a strong association between fungus ball disappearance and cavity/pleural wall thickening reduction and clinical improvement (P = .04). There was poor agreement between size changes of cavities or nodules, and clinical evolution (Cohen’s κ, –0.13 to –0.24).
Variations in cavity and pleural wall thickness may be the most relevant CT imaging variables for assessing response to treatment. Loss of fungus ball is strongly associated with clinical and radiologic improvement, but cavity size changes are unrelated to chronic pulmonary aspergillosis evolution. All these CT imaging variables may be applied in future clinical trials to assess treatment outcome.

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Case ReportThe efficacy and tolerability of voriconazole in the treatment of chronic cavitary pulmonary aspergillosis

Summary

Section snippets

Materials and methods

Results

Discussion

Acknowledgements

Chest

Clin Microbiol Infect

Mayo Clin Proc

Chronic cavitary and fibrosing pulmonary and pleural aspergillosis: case series, proposed nomenclature and review

Clin Infect Dis

Treatment of pulmonary aspergillosis with itraconazole

Thorax

Multicenter clinical trial of itraconazole in the treatment of pulmonary aspergilloma. Pulmonary Aspergilloma Study Group

Kekkaku

Indications and outcome of surgery for pulmonary aspergilloma

Thorax

Clinical manifestations and treatment outcomes of pulmonary aspergilloma

Korean J Intern Med

Validation of an assay for voriconazole in serum samples using liquid chromatography—tandem mass spectrometry

Ther Drug Monit

Case Report
The efficacy and tolerability of voriconazole in the treatment of chronic cavitary pulmonary aspergillosis