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Alessandro C. Pasqualotto Porto Alegre, Brazil What are we looking at? Challenges in the diagnosis of Invasive Mould Diseases.

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Presentation on theme: "Alessandro C. Pasqualotto Porto Alegre, Brazil What are we looking at? Challenges in the diagnosis of Invasive Mould Diseases."— Presentation transcript:

1 Alessandro C. Pasqualotto Porto Alegre, Brazil What are we looking at? Challenges in the diagnosis of Invasive Mould Diseases

2 Potential conflicts of interest Research GrantsResearch Grants Myconostica, Pfizer, Merck, Sigma-Tau, CAPES, CNPq,Fungal Research Trust Myconostica, Pfizer, Merck, Sigma-Tau, CAPES, CNPq, Fungal Research Trust Travel GrantsTravel Grants Pfizer, United Medical, Schering (now Merck), Bagó, Merck Pfizer, United Medical, Schering (now Merck), Bagó, Merck Speaker honorariaSpeaker honoraria Pfizer, United Medical, Merck, Schering (now Merck), Biometrix Pfizer, United Medical, Merck, Schering (now Merck), Biometrix

3 First assumption: IFD are highly lethal diseases

4 p<0.001 Incidence 13.3% in lung transplant recipients Xavier MO, Pasqualotto AC, et al. ECCMID 2009

5 4 days later Rapidly evolving diseases

6 Disseminated infection

7 Second assumption: We need to intervene asap

8 Von Eiff, et al. Respiration 1995; 62: Early versus late intervention Mortality rate (%)

9 Von Eiff, et al. Respiration 1995; 62: Mortality rate (%) Early versus late intervention

10 But how can we achieve such an early diagnosis?

11 A small black scar 2 days earlier + serum GM Patient died 1 day after this picture was taken

12 A small black scar 2 days earlier + serum GM Patient died 1 day after this picture was taken Zygo + A. flavus

13 MD Anderson Cancer Centre Necropsy study over a 15-years period IFD detected in 31% over 1,017 necropsiesIFD detected in 31% over 1,017 necropsies Antemortem diagnosis in only 25%Antemortem diagnosis in only 25% Chamilos G, et al. Haematologica 2006; 91: 986-9

14 MD Anderson Cancer Centre Necropsy rate has reduced over time Chamilos G, et al. Haematologica 2006; 91: %

15 By the way, what is the necropsy rate in your institution? 1.>40% % % 4.<1% 5.Are you kidding?

16 MD Anderson Cancer Centre Trends in the prevalence of IFD Chamilos G, et al. Haematologica 2006; 91: %

17 No need to worry! CT scan and galactomannan are there to help us out!

18 Day 0: halo Day 4: size, halo Day 7: air crescent Caillot, et al. J Clin Oncol 1997; 15: Halo sign surrounding a nodule

19 The sign is not specific for IA VasculitisVasculitis MetastasisMetastasis Pseudomonas infectionsPseudomonas infections Zygomycosis and other angio-invasive infectionsZygomycosis and other angio-invasive infections Greene RE, et al. Clin Infect Dis 2007; 44: 373-9

20 Absence of typical findings at chest CT scan COPDCOPD SteroidsSteroids Other non-neutropenic patients / ICUOther non-neutropenic patients / ICU Lung transplant recipientsLung transplant recipients ? Monoclonal antibodies? Monoclonal antibodies

21 Reversed halo sign Organising cryptogenic pneumonia Wahba H, et al. Clin Infect Dis 2008; 46:

22 Reversed halo sign Wahba H, et al. Clin Infect Dis 2008; 46: Review of 189 cases of invasive mould diseaseReview of 189 cases of invasive mould disease Overall frequency 4% Overall frequency 4%

23 Reversed halo sign Wahba H, et al. Clin Infect Dis 2008; 46: Review of 189 cases of invasive mould diseaseReview of 189 cases of invasive mould disease Overall frequency 4% Overall frequency 4% Zygomycosis 19% Zygomycosis 19% Aspergillosis <1% Aspergillosis <1% Fusariosis 0% (p<0.01) Fusariosis 0% (p<0.01)

24 >10 nodules>10 nodules Pleural effusionPleural effusion Concomitant sinusitisConcomitant sinusitis Treatment with voriconazoleTreatment with voriconazole Other predictors of zygomycosis Chamilos G, et al. Clin Infect Dis 2005; 41: 60-6

25 Pfeiffer CD, et al. Clin Infect Dis 2006; 42: Low PPV High NPV Meta-analysis of GM testing

26 Caution with low +ve indexes! Upton A, et al. J Clin Microbiol 2005; 43: Reproducibility

27 Aquino VR, Goldani LZ, Pasqualotto AC. Mycopathologia 2007; 163: Penicillium marneffei Geotricum capitatum Acremonium species Alternaria alternata Rhodotorula rubra Trichophyton species Paecilomyces variotii Botrytis tulipae Cladosporium species Exophiala dermatitidis GM release by non-Aspergillus fungi

28 Cross-reaction with GM testing Xavier MO, Pasqualotto AC, Severo LC. Clin Vaccin Immunol 2009; 16: %

29 Clinical case Maertens J, et al. Clin Infect Dis 2004; 39: year-old man, refractory leukaemia Febrile neutropenia Amox-clav for E. Coli bacteremia

30 Clinical case Maertens J, et al. Clin Infect Dis 2004; 39: year-old man, refractory leukaemia Febrile neutropenia Amox-clav for E. Coli bacteremia Daily GM determination –D1 after antibiotic: GM index of >1.5 –5 +ve tests afterwards

31 Clinical case Maertens J, et al. Clin Infect Dis 2004; 39: year-old man, refractory leukaemia Febrile neutropenia Amox-clav for E. Coli bacteremia Daily GM determination –D1 after antibiotic: GM index of >1.5 –5 +ve tests afterwards Fluoroquinolone: gradual reduction in GM index

32 Clinical case Maertens J, et al. Clin Infect Dis 2004; 39: wk later –Pipe-tazo for appendicitis –GM >2.5; bilateral nodular infiltrate

33 Clinical case Maertens J, et al. Clin Infect Dis 2004; 39: wk later –Pipe-tazo for appendicitis –GM >2.5; bilateral nodular infiltrate Probable IA (EORTC / MSG) –Antifungal therapy + meropenem –Gradual in GM index

34 Clinical case Maertens J, et al. Clin Infect Dis 2004; 39: wk later –Pipe-tazo for appendicitis –GM >2.5; bilateral nodular infiltrate Probable IA (EORTC / MSG) –Antifungal therapy + meropenem –Gradual in GM index Necropsy: leukaemia infiltrate –Absence of IA

35 Pfeiffer CD, et al. Clin Infect Dis 2006; 42: Proven or probable IA SensitivitySpecificity Haematological malignancies 0.58 (52-64)0.95 (94-96) Solid organ transplantation 0.41 (21-64)0.85 (80-89) Meta-analysis of GM testing

36 Tuon FF. Rev Iberoam Micol 2007; 24: Specificity 94% Sensitivity 79% Marked heterogeneity (particularly for sensitivity) BAL PCR testing

37 PCR Critical points Variable sensitivity / specificity Lack of standardised targets / reagents Extraction method Platform (conventional PCR vs Real time) Poor understanding of DNA kinetics Not yet part of the EORTC/MSG criteria De Pauw B, et al. Clin Infect Dis 2008; 46:

38 Detected in IFDs caused by –Candida and Aspergillus Yoshida M, et al. J Med Veter Mycol 1997; 35: Beta-Glucan Phospholipid bilayer of the fungal cell membrane Fungal cell wall -(1,3)-glucan -(1,3)-glucan synthase Ergosterol

39 Beta-Glucan Detected in IFDs caused by –Candida and Aspergillus –Trichosporon –Fusarium –Acremonium –Saccharomyces –Pneumocystis Yoshida M, et al. J Med Veter Mycol 1997; 35: 371-4

40 There he is again, speaking about a test that nobody uses in Brazil …

41 The reality in Brazil A survey performed in collaboration with ANVISAA survey performed in collaboration with ANVISA 140 hospitals 140 hospitals >42,000 beds >42,000 beds 65% teaching hospitals 65% teaching hospitals 90% belonging to the Sentinel Network 90% belonging to the Sentinel Network

42 Complexity in hospital care %

43 Is IFD a problem in your centre? 38.7% n=140

44 Do you know your local epidemiology? 40.1% n=140

45 Specialised media for fungi 19.7% n=140

46 58.5% Aspergillus identification at the species level n=140

47 Fungal staining - biopsies 51.1% n=140

48 Biopsy specimens are sent in formalin only? 26.0% n=140

49 Access to high resolution CT 34.3% n=140

50 Galactomannan 83.6% n=140

51 The appropriateness or inappropriateness of feelings is relative to the ground and to the circumstances of those feelings Aristotle The Doctrine of the Mean, BC

52 Fight fire with fire Metallica Ride the Lightning, 1984 AD

53 Invasive diagnostic interventions CT-guided percutaneous lung biopsy: yield of % Nosari A, et al. Haematologica 2003; 88: Crawford SW, et al. Transplantation 1989; 48: Hoffer FA, et al. Pediatr Radiol 2001; 31: Lass-Florl C, et al. Clin Infect Dis 2007; 45: e1001-4

54 Invasive diagnostic interventions CT-guided percutaneous lung biopsy: yield of % Platelets >60,000/ml are required Pneumothorax 18% Haemoptysis 3% Nosari A, et al. Haematologica 2003; 88: Crawford SW, et al. Transplantation 1989; 48: Hoffer FA, et al. Pediatr Radiol 2001; 31: Lass-Florl C, et al. Clin Infect Dis 2007; 45: e1001-4

55 Invasive diagnostic interventions Transbronchial biopsies: False-negative results are frequently seen Lass-Florl C, Freund MC. In: Aspergillosis: from diagnosis to prevention. Pasqulaotto AC, ed. Springer, 2009

56 Invasive diagnostic interventions Open lung biopsies: Provide larger samples of tissue with improved accuracy and specificity Lass-Florl C, Freund MC. In: Aspergillosis: from diagnosis to prevention. Pasqulaotto AC, ed. Springer, 2009

57 Invasive diagnostic interventions Open lung biopsies: Provide larger samples of tissue with improved accuracy and specificity Contradictory results Complication rate of 10-15% Lass-Florl C, Freund MC. In: Aspergillosis: from diagnosis to prevention. Pasqulaotto AC, ed. Springer, 2009

58 Invasive diagnostic interventions Lass-Florl C, Freund MC. In: Aspergillosis: from diagnosis to prevention. Pasqulaotto AC, ed. Springer, 2009 Peripheral lesions Needle biopsy / Surgical resection Focal lesions near the hilum / great vessels Urgent thoracotomy and resection Bilateral / multifocal disease BAL

59 Conclusion It is mostly but not all about IA Invasive mould diseases have to be differentiated from each other

60 Conclusion It is mostly but not all about IA Invasive mould diseases have to be differentiated from each other Diagnosis is the most challenging step in infectious diseases

61 Conclusion It is mostly but not all about IA Invasive mould diseases have to be differentiated from each other Diagnosis is the most challenging step in infectious diseases We need a better understanding on the performance of the available tests

62 Acknowledgments Mycology team Luiz Carlos Severo Valerio R Aquino Cecilia B Severo Luciana Guazelli Melissa Xavier Infection Control Dept Teresa Sukiennik


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