Itraconazole Serum Trough Concentrations Using Oral Capsules for the Treatment of Chronic Pulmonary Aspergillosis: What is the Target?

BACKGROUND: In regions where there is only itraconazole capsule as a therapeutic option for treatment of chronic pulmonary aspergillosis (CPA), measuring the serum concentrations becomes even more important for therapeutic success. OBJECTIVE: Evaluate the initial itraconazole serum trough concentrations after the administration of oral capsule of itraconazole for the treatment of CPA. METHODS: The measurement was performed at least 7-days after initiation of therapy. The standard treatment at our institution was a 200 mg capsule every 12 h. We defined that an adequate serum trough concentration of itraconazole during treatment was 1-4 mg/L. RESULTS: This study recruited 28 patients. The median value was 0.30 mg/L (IQR 0.01-0.70). Only 11% (n = 3) had adequate serum concentrations based on guideline recommendation. All patients with clinical deterioration had itraconazole serum levels ≤ 0.8 mg/L. CONCLUSION: The initial serum concentrations of itraconazole after capsule formulation administration were low. Increasing the dose should be considered when the itraconazole concentration is low, especially if it is ≤ 0.8 mg/L, and the patient presents with clinical deterioration. Larger studies are needed to evaluate the adequate concentrations recommended for CPA.

Systematic review and meta-analysis of galactomannan antigen testing in serum and bronchoalveolar lavage for the diagnosis of chronic pulmonary aspergillosis: defining a cutoff.

BACKGROUND: A clear cutoff value of galactomannan (GM) has not been established for chronic pulmonary aspergillosis (CPA) and is frequently extrapolated from invasive pulmonary aspergillosis. We performed a systematic review and meta-analysis to evaluate the diagnostic performance of serum and bronchoalveolar lavage (BAL) GM, and to propose a cutoff. METHODS: We extracted from the studies the cutoff of serum or/and BAL GM associated with true positives, false positives, true negatives, and false negatives. We performed a multi-cutoff model and a non-parametric random effect model. We estimated the optimal cutoff and the area under the curve (AUC) for GM in serum and BAL samples. RESULTS: Nine studies from 1999 to 2021 were included. Overall, the optimal cutoff of serum GM was 0.96 with a sensitivity of 0.29 (95%CI: 0.14-0.51); specificity of 0.88 (95%CI: 0.73-0.95); and AUC of 0.529 (with a CI: [0.415-0.682] [0.307-0.713]). The AUC for the non-parametric ROC model was 0.631. For BAL GM the cutoff was 0.67 with a sensitivity of 0.68 (95%CI: 0.51-0.82), specificity of 0.84 (95%CI: 0.70-0.92), and AUC of 0.814 (with a CI: [0.696-0.895] [0.733-0.881]). The AUC for the non-parametric model was 0.789. CONCLUSION: The diagnosis of CPA requires the assessment of a combination of mycological and serological factors, as no single serum and/or BAL GM antigen test is adequate. BAL GM performed better than serum, with better sensitivity and excellent accuracy.

A contemporary investigation of burden and natural history of aspergillosis in people living with HIV/AIDS.

BACKGROUND: Untreated HIV infection can lead to profound immunosuppression and increase susceptibility of people living with HIV/AIDS (PLHA) to aspergillosis. OBJECTIVES: Reporting the burden and natural history of aspergillosis documented in PLHA admitted in five medical centres in Brazil. PATIENTS AND METHODS: Clinical, epidemiological and laboratory data were collected in all sequential cases of proven or probable aspergillosis documented in PLHA hospitalised in five medical centres between 2012 and 2020. RESULTS: We enrolled 25 patients ageing between 23 and 58 years (mean = 39) including 11 patients with invasive aspergillosis (IA) and 14 with chronic pulmonary aspergillosis (CPA). The prevalence rate of aspergillosis was 0.1% of 19.616 PLHA. Overall, 72.7% of patients with IA exhibited CD4 < 100 cells/mL and 42.8% of patients with CPA exhibited CD4 count >200 cells/mL. Most patients had a history of tuberculosis, especially those with CPA (85.7%). IA was documented after a mean of 16.5 days of hospitalisation, mainly in critically ill patients exposed to corticosteroids and broad-spectrum antibiotics. In the CPA group, a positive culture (71.4%) and radiological alterations were the most frequent findings supporting their diagnosis. Episodes of IA were mostly documented by tissue biopsies. Crude mortality rates were 72.7% and 42.8% in patients with IA and CPA, respectively. CONCLUSIONS: Despite being considered an unusual complication in PLHA (0.1%), IA should be considered in patients with profound immunosuppression and pneumonia refractory to conventional therapy. CPA should be investigated in PLHA with chronic deterioration of pulmonary function and previous diagnosis of tuberculosis.

Challenges, Characteristics, and Outcomes of Chronic Pulmonary Aspergillosis: A 11-Year Experience in A Middle-Income Country.

OBJECTIVES: Chronic pulmonary aspergillosis (CPA) is a research priority in fungal diseases with a need for new studies to reduce misdiagnosis with more common diseases, discuss improvement in diagnostic methods and better characterize gaps in antifungal and surgical treatments to improve clinical outcomes. METHODS: In this retrospective study, we reviewed medical records of patients diagnosed with CPA from January 2010 to June 2021 at University of São Paulo, São Paulo, Brazil. We evaluated clinical characteristics, radiological findings, serology, treatment, and outcomes. RESULTS: The study included 91 participants, with 43 (47.3%) patients who underwent surgery and 69 (75.8%) received antifungal therapy. We found a predominance of middle-aged adults (median 51 years), males (n = 58, 64%) with lower BMI (median 21.3 kg/m2). The most common underlying lung disease was pulmonary tuberculosis (n = 70, 76.9%). The commonest symptoms were cough (n = 67, 74%), haemoptysis, and dyspnea (n = 63, 70%). The most common chest computerized tomography abnormalities were cavity (n = 86, 94.5%), with a predominance of mycetomas (n = 78, 91%). The serology was positive in 81% (61/75). The one-year mortality was low (3.3%). Clinical improvement and stability occurred in 89% of participants for constitucional symptoms and 86% for pulmonary symptoms. While serological improvement and stability occurred in 71%. Radiological improvement and stability occurred in 75%. CONCLUSION: We observed a good outcome after 1-year follow-up, in which the majority had improvement or stability of pulmonary and constitutional symptoms, decrease in CIE titers and low mortality.

Prevalence of chronic pulmonary aspergillosis regarding time of tuberculosis diagnosis in Brazil.

BACKGROUND: Data on the prevalence of chronic pulmonary aspergillosis (CPA) in patients with active or cured tuberculosis (TB) are scarce, mainly due to diagnostic difficulties. The diagnosis of CPA is based on pulmonary symptoms and chest computed tomography (CT) scans and is considered confirmed when there is microbiological or serological evidence of Aspergillus spp. OBJECTIVES: To estimate the prevalence of CPA in patients treated or undergoing treatment for PTB, seen in two referral hospitals in Mato Grosso do Sul, Brazil. PATIENTS AND METHODS: A total of 193 consecutive patients who were treated or previously treated for pulmonary tuberculosis underwent prospective evaluation: (a) clinical evaluation; (b) chest CT scan; (c) sputum examination-culture for fungi and smears for direct mycology; (d) detection of anti-Aspergillus fumigatus antibodies using an enzyme-linked immunosorbent assay Platelia® test; and (e) anti-Aspergillus spp. antibodies were assessed via a DID test. RESULTS: The global prevalence of CPA was 10.9% (95% confidence interval, 7.2%-16.1%), but it increased with the time of TB diagnosis. The variables independently associated with CPA were previous pulmonary tuberculosis over 4 years ago and haemoptysis. Cavities, pleural thickening and the presence of a fungal ball were the most frequent tomographic findings in patients with CPA. CONCLUSIONS: The high prevalence observed and its increase over time suggest the need for continuous surveillance of CPA in patients with active or previous pulmonary tuberculosis and throughout life, with clinical, tomographic and serological evaluations (ELISA) for a timely diagnosis and a better prognosis.