Figures
- FIGURE 1
Schematic representation of the diagnostic classification of invasive pulmonary aspergillosis (IPA) according to the European Organization for Research and Treatment of Cancer and Mycoses Study Group Education and Research Consortium. Possible IPA must include at least one host criterion and one clinical criterion. Probable IPA must include at least one host criterion, one clinical criterion and one mycological criterion. Proven IPA is defined independently from the presence or absence of host/clinical/mycological criteria. For details, see reference [9]. BAL: bronchoalveolar lavage; CT: computed tomography; PCR: specific polymerase chain reaction for Aspergillus species.
- FIGURE 2
Diagnostic approach of invasive pulmonary aspergillosis (IPA) in high-risk haematologic cancer patients. AF: antifungal; BAL: bronchoalveolar lavage; CT: computed tomography; EORTC/MSGERC: European Organization for Research and Treatment of Cancer and Mycoses Study Group Education and Research Consortium; GM: galactomannan; GVHD: graft versus host disease; HSCT: haematopoietic stem cell transplantation; IA: invasive aspergillosis; MRI: magnetic resonance imaging; ODI: optical density index; PCR: specific polymerase chain reaction for Aspergillus species.
Tables
- TABLE 1
Characteristics of nonculture commercialised diagnostic tests for invasive pulmonary aspergillosis
Target Type of test (manufacturer) Technique Spectrum of detection Type of sample Cut-off Galactomannan PlateliaTM Aspergillus EIA (Bio-Rad) Immunoenzymatic sandwich assay All Aspergillus species (specific)# Serum, BAL 0.5–1.0 ODI¶ Soña Aspergillus galactomannan LFA (IMMY) Immunochromatographic assay (LFA) Visual reading or cube reader: 0.5–1.0¶ (index values) Aspergillus galactomannan VirCliaTM (Vircell) Chemoluminescent assay 1.0 (index value) (1→3)-β-d-Glucan FungitellTM (Associates of Cape Cod) Colorimetric assay (microplate) All Aspergillus species (not specific)+ Serum 60–80 pg·mL−1§ Fungitell STATTM (Associates of Cape Cod) Colorimetric assay (single tube) 0.75–1.2 (index values)§ Wako β-glucan test (Fujifilm Wako Chemicals) Turbidimetric assay (single tube) 7.0 pg·mL−1 Dynamiker Fungus (1–3)- β-d-glucan (Dynamiker Biotechnology) Colorimetric assay (microplate) 70–95 pg·mL−1§ Aspergillus DNA MycAssay AspergillusTM (Myconostica Ltd., now Microgen Bioproducts Ltd.) Real-time PCR (18S rDNA) Most relevant Aspergillus species BAL, other respiratory samples, serum NA AsperGeniusTM (PathoNostics) Multiplex real-time PCR (28S rDNA and Cyp51A) Most relevant Aspergillus species, Cyp51A mutations (L98H, TR34, T289A, Y121F) NA MycoGenieTM (AdemTech) Real-time PCR (28S rDNA and Cyp51A) Aspergillus fumigatus, Cyp51A mutations (L98H, TR34) NA Fungiplex Aspergillus azole-RTM (Bruker Daltonics GmbH) Multiplex real-time PCR Aspergillus species, Cyp51A (TR34, TR46) NA Note: the table is limited to the most relevant currently available test methods. BAL: bronchoalveolar lavage; EIA: enzyme immunoassay; LFA: lateral flow assay; NA: not applicable; ODI: optical density index. #Cross-reaction with some other fungal pathogens, e.g. Fusarium, Histoplasma. ¶ODI 0.5 is recommended by the manufacturer. Higher cut-offs (e.g. 1.0) are recommended for better specificity, notably in non-serum samples (BAL, cerebrospinal fluid). +Detection of most other fungal pathogens with some exception (e.g. Mucorales). §Values below, within and above this range are considered as negative, indeterminate and positive, respectively.
- TABLE 2
Performance of galactomannan (GM) and Aspergillus PCR in serum and bronchoalveolar lavage fluid (BAL) for the diagnosis of invasive pulmonary aspergillosis (IPA) in haematologic cancer patients: results of the most relevant meta-analyses
Fungal biomarker Study Sensitivity (%) (95% CI) Specificity (%) (95% CI) Serum GM Pfeiffer et al. [38] 58 (52–64) 95 (94–96) Leeflang et al. [98]¶ 78 (70–85) 85 (78–91) Arvanitis et al. [28] 92 (83–96) 90 (81–95) PCR Mengoli et al. [99] 88 (75–94) 75 (63–84) Arvanitis et al. [28] 84 (71–92) 76 (64–85) GM and PCR# Arvanitis et al. [28] 99 (96–100) 98 (94–100) BAL GM Guo et al. [100]¶ 85 (72–93) 94 (89–97) Avni et al. [29]¶ 85 (62–95) 100 (97–100) Zou et al. [101]¶ 86 (76–92) 95 (91–97) Heng et al. [30] 75 (55–88) 95 (87–98) De Heer et al. [102]¶ 78 (61–95) 93 (87–98) PCR Sun et al. [103]¶ 91 (79–96) 92 (87–96) Avni et al. [29]¶ 93 (70–98) 98 (93–99) Zou et al. [101]¶ 82 (61–93) 98 (85–100) Heng et al. [30] 57 (31–80) 99 (60–100) GM and PCR# Avni et al. [29]¶ 97 (83–99) 97 (93–99) Heng et al. [30] 84 (79–88) 94 (91–97) Results are displayed for the diagnosis of proven and probable IPA. For GM, results are displayed for the cut-off of optical density index 0.5 for serum and 1.0 for BAL. #Where a positive result is considered as either GM or PCR positive and a negative result as both GM and PCR negative. ¶Mixed populations, but with a predominance of haematologic cancer patients.
- TABLE 3
Antifungal agents for the treatment of pulmonary aspergillosis
Antifungal class Drugs Dosage Therapeutic use Comments Polyenes Deoxycholate amphotericin B 1–1.5 mg·kg−1 once daily (intravenous only) Should be avoided (privilege lipid formulations of amphotericin B if available) Monitor kidney function and electrolytes (K+)
Consider co-administration of paracetamol if fever and/or rigors
Consider alternative therapy for Aspergillus terreusLiposomal amphotericin B 3–5 mg·kg−1 once daily (intravenous only) Treatment of IPA (second choice after triazoles; first choice in areas with high prevalence of azole-resistant Aspergillus fumigatus isolates if no culture/fungigram available) Amphotericin B lipid complex 5 mg·kg−1 once daily (intravenous only) Treatment of IPA (privilege liposomal amphotericin B if available) Amphotericin B colloidal dispersion 6 mg·kg−1 once daily (intravenous only) Treatment of IPA (privilege liposomal amphotericin B if available) Triazoles Itraconazole 200 mg once daily or twice daily (intravenous or oral)
TDM recommended (target: Ctrough: 1–4 mg·L−1)Treatment of CPA Monitor hepatic tests (ALT, AST, ALP, GGT, bilirubin)
Monitor ECG (QT interval, in particular voriconazole)
DDIs (in particular voriconazole)
Consider alternative therapy for Aspergillus calidoustus or cryptic species of section Fumigati (e.g. Aspergillus lentulus)Voriconazole Intravenous: 6 mg·kg−1 twice daily (D1), then 4 mg·kg−1 twice daily
Oral: 400 mg twice daily (D1), then 200–300 mg twice daily
TDM recommended (target: Ctrough: 1–5 mg·L−1)Treatment of IPA (first choice)
Treatment of CPAPosaconazole Intravenous or oral tablets: 300 mg twice daily (D1), then 300 mg once daily
Oral suspension: 200 mg three times daily
TDM recommended (target: Ctrough: >1 mg·L−1 for therapy and >0.7 mg·L−1 for prophylaxis)Prophylaxis or treatment of IPA
Treatment of CPA (privilege itraconazole or voriconazole)
Oral suspension should be avoided or limited to prophylaxis (privilege intravenous formulation or oral tablets)Isavuconazole 200 mg three times daily (D1–2), then 200 mg once daily
TDM not routinely recommended (may be considered)Treatment of IPA
Treatment of CPA (privilege itraconazole or voriconazole)Echinocandins Caspofungin 70 mg (D1), then 50 mg once daily (intravenous only) Treatment of IPA as monotherapy (third choice after triazoles and lipid formulations of amphotericin B)
Treatment of IPA in combination with triazoles (severe cases and/or positive GM; azole-resistant Aspergillus fumigatus isolates)Anidulafungin 200 mg (D1), then 100 mg once daily (intravenous only) Micafungin 100 mg once daily (intravenous only) ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; CPA: chronic pulmonary aspergillosis; D1: day 1; DDI: drug–drug interaction; GGT: gamma glutamyltranspeptidase; GM: galactomannan; IPA: invasive pulmonary aspergillosis; TDM: therapeutic drug monitoring, W1: week 1.
