TOP PAPERS in MEDICAL MYCOLOGY Laboratory Diagnosis Manuel Cuenca-Estrella Abril 2018

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1 TOP PAPERS in MEDICAL MYCOLOGY Laboratory Diagnosis Manuel Cuenca-Estrella Abril 2018 MCE01

2 Conflict of interest disclosure In the past 5 years, M.C.E. has received grant support from Astellas Pharma, biomerieux, Gilead Sciences, Merck Sharp and Dohme, Pfizer, Schering Plough, Soria Melguizo SA, Ferrer International He has been an advisor/consultant to the Panamerican Health Organization, Astellas Pharma, Gilead Sciences, Merck Sharp and Dohme, Pfizer, and Schering Plough He has been paid for talks on behalf of Gilead Sciences, Merck Sharp and Dohme, Pfizer, Astellas Pharma and Schering Plough MCE02

3 Top Papers in Medical Mycology Diagnostic Topics (April 2017 to April 2018) 800 (approx.) references on PubMed website My review criteria: Diagnostic Relevance Technical Novelty Strength of evidences Recommendations by colleagues

4 Top Papers in Medical Mycology Diagnostic Topics (April 2017 to April 2018) Diagnosis of invasive candidiasis (IC) and candidemia Diagnosis of invasive pulmonary aspergillosis (IPA) Antifungal resistance detection Therapeutic drug monitoring (TDM) Other topics

5 Diagnosis of invasive candidiasis (IC) and candidemia

6 Candida infections in the Intensive Care setting As many as 65% of Intensive Care patients are treated empirically (no positive cultures) with antifungal agents Azoulay et al. Crit Care Med 2012;40: MCE03

7 Candida infections in the Intensive Care setting Scores or rules to treat correctly: Ostrosky-Zeichner score 1 Candida score 2 Colonization index 3 Candida score: 3 points: treatment after 7 d at intensive care units Sepsis Colonization Abdominal surgery Parenteral nutrition Positive Predictive Value: 14% 2 1. Ostrosky-Zeichner et al. Mycoses 2011;54: León et al. Crit Care Med 2009;37: Pittet et al. Ann Surg 1994;220:751 8 MCE04

8 Colombo AL et al. Lancet Infect Dis 2017;17:e344 56

9 A total of 152 patients with Candida positive blood cultures T2 clinical sensitivity was 89% Clancy et al. Clin Infect Dis 2018

10 Mylonakis et al. J Clin Microbiol2018;56:e

11 Muñoz et al. J Antimicrob Chemother 2018;73 Suppl 4:iv13-19

12 Ramos JT et al. J Clin Microbiol. 2017;55:

13 110 ICU patients with high risk of invasive candidiasis. Symptoms and empirical therapy Two groups: 1. Beta-D-Glucan and mannan and antimannan quantification and therapy was discontinued if negative biomarkers 2. Standard of care, 14 days of antifungal therapy Antifungal therapy was discontinued in 29/54 patients in the biomarker group and 1/55 in the standard of care group No significant difference was found in patients with subsequent proven invasive Candida infection, mechanical ventilation-free days, length of ICU stay, cost, and ICU mortality between the two study groups Rouzhe A et al. Inten Care Med. 2017;43:

14 Chowdhary A et al. Plos Pathogenns. 2017;13:e

15 Kohlenberg A et al. Eurosurveillance. 2018;23:9/03/2018

16 Chowdhary A et al. J Antimicrob Chemother. 2018;73:891-9

17 Diagnosis of invasive pulmonary aspergillosis (IPA)

18 Aspergillus infections: What we know Galactomannan (GM) detection shows a good performance to rule out the infection in neutropenic patients PCR-based techniques, beta-d-glucan detection (BDG) and lateral flow devices seem to have a lower performance Combination of techniques could be the best strategy to detect the infection, much better in respiratory samples ESCMID Aspergillus Guidelines. Clin Microbiol Infect 2018;In press MCE03

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20 ESCMID-ECMM-ERS Aspergillus Guidelines. Clin Microbiol Infect 2018;In press

21 Eigl et al. Med Mycol. 2017; 55:528-34

22 Taghizadeh-Armaki M et al. J Med Microbiol. 2017; 66:

23 Signature of alveolar cytokines could be associated with the development of IPA and used as a diagnostic biomarker Case-control study, 113 patients (57 cases of IPA) IL-1b, IL-6, IL-8, IL-17A, IL-23, and TNFa were significantly increased among patients with IPA IL-8 was the best performing cytokine, with alveolar levels 904 pg/ml predicting IPA with elevated sensitivity (90%), specificity (73%), and negative predictive value (88%) Goncalves SM et al. Front Microbiol. 2017; 8:2362

24 Van de Veerdonk FL et al. Nature Rev. 2017; 15:661-74

25 Evaluation of performance in sputum of GM compared to PCR-based method to detect chronic pulmonary aspergillosis (CPA) and allergic bronchopulmonary aspergillosis (ABPA) 159 patients. 223 sputum sample pairs were retrospectively analysed A GM index of 6.5 was associated with approximately 50% of strongly positive PCR values GM quantification is not reliable for detection of those clinical entities

26 370 cases from 21 countries. 5% of clinical samples positive for moulds. AMB median MIC: 8 mg/l Risslegger B et al. Clin Microbiol Infect. 2017; 23:776e1-e5

27 Antifungal Resistance Detection

28 Perlin DS et al. Lancet Infect Dis 2017; 17:e383-92

29 García-Rubio R et al. Drugs 2017; 77:

30 Haematological patients, 432 high risk cases for IPA 36 cases (8.3%) of probable and proven IPA 2/36 cases (5.5%) triazole resistance Low rate of resistance in patients with IPA but it could be underestimated. Vigilance needed Lestrade et al. J Antimicrob Chemother. 2018;

31 Perlin DS et al. Lancet Infect Dis 2017; 17:e383-92

32 Multicenter study. 2,018 Candida isolates Rezafungin showed species-specific activity in vitro similar to other echinocandins Resistance in vitro is scantly detected Further studies warranted to set breakpoints Arendrup MC et al. Clin Microbiol Infect 2018

33 Therapeutic Drug Monitoring

34 Therapeutic Drug Monitoring (TDM) ESCMID-ECMM-ERS Aspergillus Guidelines. Clin Microbiol Infect 2018;In press

35 Other Topics

36 Temfack E et al. Front Microbiol 2018;9:409 Detection of serum cryptococcal antigen (Ag) predicts development of meningitis in HIV-infected patients with severe immune depression. Pre-emptive oral fluconazole is thus recommended. A semi-quantitative Ag screening approach could offer clinically relevant advantages

37 Lactate dehydrogenase may be elevated Computed tomography scans of the chest are bilateral groundglass opacities with or without cystic lesions Bronchoalveolar lavage shows better diagnostic yield compared to induced sputum. Immunofluorescence has higher performance than conventional staining Combination of different diagnostic tests such as microscopy, PCR-based methods, and beta-d-glucan detection could be the standard of care Salzer HJF et al. Respiration 2018;

38 40 cases evaluated Dantas KC et al. PLOS One 2018;13:e

39 Availability of MLP (Microsatellite Length Polymorphism) and MLST (Multilocus Sequence Analysis) to analyze infection chain, outbreaks and hospital transmission Alanio A et al. Clin Microbiol Rev 2017;30:

40 Alanio A et al. EBioMedicine 2017;22:155-67

41 Chindamporn A. et al. Med Mycol :1-10

42 Laboratory techniques (241 Asian centers, 7 countries) Independent Mycology Laboratory % Diagnostic Service Availability Antifungal susceptibility testing 59% Comments 53% Accredited <50% >90% reference methods Therapeutic Drug Monitoring 38% 50% HPLC Galactomannan quantification 23% 47% 2 days/week Beta-D-Glucan determination 10% 30% have Candida mannans PCR-based tests 38% 70% In-house tests HPLC: High Pressure Liquid Chromatography Chindamporn A. et al. Med Mycol :1-10

43 Conclusions The ESCMID-ECMM-ERS Aspergillus Guidelines is probably the 2018 Top Paper in Laboratory Mycology The biomarkers can be useful into therapeutic algorithms on invasive candidiasis. The T2MR test is an interesting novelty The GM quantification in bronchoalveolar lavage in combination with PCR could become the diagnostic standard of care of invasive pulmonary aspergillosis (same biomarker-based strategy for other IFDs)