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The importance of epidemiology in the diagnosis of invasive fungal infections J Peter Donnelly BSc PhD Department of Haematology University Medical Centre.

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Presentation on theme: "The importance of epidemiology in the diagnosis of invasive fungal infections J Peter Donnelly BSc PhD Department of Haematology University Medical Centre."— Presentation transcript:

1 The importance of epidemiology in the diagnosis of invasive fungal infections J Peter Donnelly BSc PhD Department of Haematology University Medical Centre St Radboud Nijmegen, The Netherlands

2 Some issues Microscopy and culture are essentially unavailable to microbiologists with respect to invasive fungal infections (IFI) Because IFI commonly affects the lungs initially but cases can easily go unnoticed IFI commonly affects the lungs initially but cases can easily go unnoticed Even when recognized early, suitable specimens can be difficult to obtain Even when recognized early, suitable specimens can be difficult to obtain Tests for detecting fungal pathogens in clinical material (particularly blood) are available, but there is no consensus about their clinical utility Tests for detecting fungal pathogens in clinical material (particularly blood) are available, but there is no consensus about their clinical utilityHence many expect nothing from diagnosis and do not even attempt to make one. The resulting lack of adequate diagnoses makes estimating the prevalence and incidence of IFI unreliable.

3 Epidemiology This dismal state of affairs serves only to emphasize the importance of epidemiology since, in order to determine the value of any diagnostic test or battery of tests, one has to know the underlying prevalence of the disease, particularly when this is low. The first questions are:- Who gets IFI? Who gets IFI? What do they get and how? What do they get and how? When do they get? When do they get?

4 Who gets IFI?

5 Candidaemia in French hospitals origin central line26% central line26% digestive tract11% digestive tract11% unknown43% unknown43% Incidence/ 1000 admissions Total 0.29 General hospital0.17 Teaching hospital0.38 Cancer center0.71 Andremont et al, ICAAC 1998, San Diego parapsilosis glabrata tropicalis albicans krusei

6 Risk factorCancerICU Neutropenia, HSCT, chemotherapy, GvHD, mucosal barrier injury Candida colonisation Broad-spectrum antibiotics Haemodialysis, azotemia Central venous catheter Severity of illness Hyperalimentation Recurrent/persistent GI tract perforation Prior surgery Neonatal ICU (age, low APGAR, LOS, shock, H2 blockers, intubation) Rex & Sobel Clin Infect Dis ;1191 Risk factors for invasive candidosis

7 Incidence of invasive fungal infections among solid organ transplant recipients TransplantIFI Renal Heart Liver Lung & heart/lung Small bowel Pancreas AspergillusCandida Singh Clin Infect Dis : 545

8 Timing of fungal infections after solid organ transplant CMV Candida Aspergillus Cryptococcus Endemic fungi Pneumocystis Snydman Clin Infect Dis : S5 0

9 Incidence of fatal fungal infections amongst patients other than those with HIV in the USA Mc Neil et al 2001 Clin Infect Dis 33;641 Candidiasis Aspergillosis

10 0%53% Acute Invasive Candidiasis 81 patients 46 NOYES Bacteraemia ++Colonisation Guiot et al, Clin Infect Dis 1994; 18: Invasive candidiasis, colonisation and bacteraemia

11 Risk groupColonisationMucosal barrier injuryTreatment Lownonono Intermediate noyesno yesnoyes or no* High riskyesyesyes MBI and invasive Candida infections * depending on other predisposing factors

12 Invasive aspergillosis and underlying disease Conditionrange (%) Chronic granulomatous disease25-40 Lung ± heart transplant19-26 Liver transplant Heart & renal transplant AIDS0-12 SCID3.5 Burns1-7 SLE1 Acute leukaemia5-24 Allogeneic HSCT4-9 Autologous HSCT (no growth factors)0.5-6 Autologous HSCT (with growth factors)<1 Denning Clin Infect Dis pp

13 % haematopoietic stem cell transplant Denning. Clin Inf Dis 1998 autologous Incidence of invasive aspergillosis under various conditions heart/heart-lung transplant chronic granulomatous disease acute leukemia allogeneic solid organ transplant solid organ transplant AIDS + growth factor

14 Transplant typeincidence (%) Lung 8.4 Haematopoietic stem cell 6.4 Autologous 2.6 Allogeneic Related donor 6.7 Unrelated donor 10.3 Heart 6.2 Liver 1.7 Pancreas 1.3 Kidney 0.7 Transplant typeincidence (%) Lung 8.4 Haematopoietic stem cell 6.4 Autologous 2.6 Allogeneic Related donor 6.7 Unrelated donor 10.3 Heart 6.2 Liver 1.7 Pancreas 1.3 Kidney 0.7 Paterson et al. Medicine 1999;78: Incidence of invasive aspergillosis in transplant recipients

15 Aspergillosis at autopsy - sites of infection aspergillosis Lungs only CNS only Disseminated (not lungs) Disseminated Vogeser et al Eur J Clin Microbiol Infect Dis 1999;18; autopsies (4%) aspergillosis

16 Explaining the current trends in opportunistic fungal infections Singh Clin Infect Dis ;1692 Increase in number of susceptible hosts New medical methods HSCT - CD 34 + selection HSCT - CD 34 + selection Advances in surgical techniques for solid transplant Advances in surgical techniques for solid transplant immunesuppressive regimens for solid transplant immunesuppressive regimens for solid transplant More conservative approachMore conservative approach Less use of corticosteroidsLess use of corticosteroids Use of novel agentsUse of novel agents Antimicrobial prophylaxis Fluoroquinolones for Gram negative bacilli Fluoroquinolones for Gram negative bacilli Fluconazole for Candida Fluconazole for Candida Ganciclovir for CMV Ganciclovir for CMV Improved laboratory expertise detection detection identification identification

17 Invasive fungal infections Haematological malignancy Allogeneic HSCT ICU CGD Burns Liver Heart Transplant Renal Lung Who gets IFI? HIV

18 What do they get and how?

19 The main players Hi Bud! Hi pal! Huh. You guys get all the attention

20 How do they get it?

21 Candida - colonisation Candida parapsilosis Candida albicans Candida parapsilosis Candida albicans Candida tropicalis Candida albicans Candida tropicalis Candida albicans Candida glabrata Candida krusei Candida albicans Candida glabrata Candida krusei

22 GI tract antibiotics insult injuryselection translocation infection Candida species Normal commensal flora Disease Model for invasive candidiasis

23 Aspergillosis

24 Aspergillus from the breeze or the bucket Graybill Clin Infect Dis pp

25 What do they get and how ? Mainly Candida albicans or Aspergillus fumigatus Mainly Candida albicans or Aspergillus fumigatus prior colonisation with Candida species is a prerequisite for infection prior colonisation with Candida species is a prerequisite for infection Spores of Aspergillus and other moulds are inhaled directly through the air or indirectly from aerosols of contaminated water Spores of Aspergillus and other moulds are inhaled directly through the air or indirectly from aerosols of contaminated water

26 When do they get it?

27 days after transplant >180 Cases Wald et al J Infect Dis 1997:175;1459 Time to diagnosis of aspergillosis after BMT

28 Aspergillosis following HSC transplant Granulocytes (log 10 1x 10 6 /L) Temperature °C DaysMonths WeeksTransplant ENGRAFTMENT PRE-TRANSPLANT EARLY POST-ENGRAFTMENT LATE POST-ENGRAFTMENT Stem cells acute GvHD low IgG chronic GvHD neutropeniacorticosteroids

29 Source of stem cells and GVHD Cutler et al 2002 J Clin Oncol 19:

30 Source of stem cells and GVHD Cutler et al 2002 J Clin Oncol 19:

31 FEVER ALKALINE PHOSPHATASE NEUTROPHILS DISSEMINATION MICROCOLONIES "BULLS EYE" HEPATOSPLENIC CANDIDIASIS

32 when do they get? Both candidiasis and aspergillosis occur during neutropenia but also manifest themselves later after bone marrow recovery. Both candidiasis and aspergillosis occur during neutropenia but also manifest themselves later after bone marrow recovery. Patients are at risk of aspergillosis for as long as they have active GvHD or are receiving high dose corticosteroids Patients are at risk of aspergillosis for as long as they have active GvHD or are receiving high dose corticosteroids

33 Diagnosis

34 Sites of infection Candida albicans Candida glabrata Candida krusei Candida albicans Candida glabrata Candida krusei Candida parapsilosis Candida albicans Candida parapsilosis Candida albicans Candida tropicalis Candida albicans Candida tropicalis MouldsMouldsYeastYeast Aspergillus fumigatus MucorMucor Fusarium species

35 Defining invasive fungal infection Host factor Clinical feature Mycology Invasive Fungal Infections Cooperative GroupMycosesStudyGroupMycosesStudyGroup Ascioglu et al 2002 Clin Infect Dis 34:7-14

36 Defining infection - Host factors Host factor neutropenianeutropenia > 4 days unexplained fever despite broad spectrum antibiotics Graft versus Host Disease > 3 weeks corticosteroids 38°C and 38°C and prior mycosisprior mycosis AIDSAIDS ImmunosuppressivesImmunosuppressives > 10 days neutropenia> 10 days neutropenia 38°C and 38°C and prior mycosisprior mycosis AIDSAIDS ImmunosuppressivesImmunosuppressives > 10 days neutropenia> 10 days neutropenia Invasive Fungal Infections Cooperative GroupMycosesStudyGroupMycosesStudyGroup Ascioglu et al 2002 Clin Infect Dis 34:7-14

37 Defining infection - Clinical features Clinical feature Invasive Fungal Infections Cooperative GroupMycosesStudyGroupMycosesStudyGroup Halo sign Air-crescent sign cavity Lower respiratory tract infection Sinonasal infection CNS infection Disseminated fungal infection Chronic disseminated candidiasis Radiological evidence Unexplained papular or nodular skin lesions Chorioretinitisendophthalmitis Bulls eye lesions in liver or spleen MAJOR Ascioglu et al 2002 Clin Infect Dis 34:7-14

38 Defining infection - Clinical features Clinical feature Invasive Fungal Infections Cooperative GroupMycosesStudyGroupMycosesStudyGroup Cough, chest pain, haemoptysis, dyspnoea Physical finding of pleural rub Any new infiltrate not fulfilling major criterion Lower respiratory tract infection Sinonasal infection CNS infection Nasal discharge, stuffiness Nose ulceration, eschar or epistaxis Periorbital swelling Maxillary tenderness Black necrotic lesions or perforation of the hard-palate CSFNo pathogens no malignant cells abnormal biochemistry abnormal cell count Focal neurological seizureshemiparesis cranial nerve palsy Mental changes Meningeal irritation MINOR Ascioglu et al 2002 Clin Infect Dis 34:7-14

39 Defining infection - Mycology Mycology antigen in BAL, CSF or blood Culture of mould from tissue, aspirate BAL or sputum mould seen in sinus aspirate Fungi seen in tissue or sterile body fluids Invasive Fungal Infections Cooperative GroupMycosesStudyGroupMycosesStudyGroup Ascioglu et al 2002 Clin Infect Dis 34:7-14

40 Proven invasive fungal infective disease Host factor Clinical features+ Tissue+ Mycology+ Invasive Fungal Infections Cooperative GroupMycosesStudyGroupMycosesStudyGroup Ascioglu et al 2002 Clin Infect Dis 34:7-14

41 Host factor Probable invasive fungal infective disease Clinical features+ Mycology+ Invasive Fungal Infections Cooperative GroupMycosesStudyGroupMycosesStudyGroup Ascioglu et al 2002 Clin Infect Dis 34:7-14

42 Possible invasive fungal infective disease Host factor Clinical features+ MycologyOR Invasive Fungal Infections Cooperative GroupMycosesStudyGroupMycosesStudyGroup Ascioglu et al 2002 Clin Infect Dis 34:7-14

43 Mycology EORTC/MSG definitions of fungal infections - aspergillosis Host factor Clinical features Halo sign on chest CT scan cough pleural rub antigenaemiaGVHD OR Probable disease

44 EORTC/MSG definitions of fungal infections - candidosis elevated alkaline phosphatase Small, peripheral, target-like abscesses (Bulls eye) in liver and/or spleen demonstrated by CT, MRI or ultra sonogram. Neutropenia + +/- Host factor Clinical features Mycology Probable disease

45 Strategy

46 include all patients likely to have aspergillosis and treat them pre-emptively with the safest and most effective drug Aim of the strategy AND exclude all patients unlikely to have the disease and adopt a WAIT-and-SEE policy By using techniques that offer a high negative predictive value i.e. a low false-negative rate

47 AML HSC transplant Risk factor selection Risk factorsdiagnosis HSC transplant febrile RadiologyMycology febrile PulmonaryInfiltrate Antigen +

48 Screening test for a potentially fatal disease with a low prevalence + - ControlsTests -- + ± not ruled out start treatment ruled out withhold treatment

49 CT scan At risk 3 x weekly GM-ELISA yes no ELISA GM positive OROR > 5 d unexplained fever OROR abnormal chest X-ray EORTC/MSG criteria A strategy for managing pulmonary aspergillosis

50 therapywait-and-see yes yes probable no unlikely yes no possible Clinical features Prevalence 10% yes no Microbiological evidence A strategy At risk Pre-emptive therapy eg. CT scan halo-sign or air-crescent sign

51 Obtaining a specimen - tools of the trade BronchoscopyBronchoscopy Brush Biopsy Bronchoalveolar lavage Lung biopsy SputumSputum Fine needle aspirate

52 Bronchoscopy specimen - processing BALBALCultureCulture cytologycytology Centrifuge 500 g 5 min Martin et al 1987 Mayo Clin Proc 62: Aerobic bacteriaS. pneumoniae, Ps aeruginosa EnterobacteriaKlesiella spp Legionella spp MycobacteriaM. tuberculosis Nocardia spp Mycoplasma spp YeastsCandida spp MouldsA. fumigatus VirusCMV, HSV, RSV GramGiemsaSilver Acid-fast stain IFA-Legionella mL CytospinCytospin Shell vial culture culture IFA-CMV -HSV -RSV influenza A & B

53 Mycolog y Clinical features Host factors ++ Probable= =Proven Mycolog y Clinical features Host factors ++ tissue Mycolog y + Host factors Negative or Not done Clinical features + Host factors Negative or Not done = = Possible Invasive Fungal Infection

54 Conclusions Patients at risk are better known Patients at risk are better known The timing of the risk is better understood The timing of the risk is better understood Diagnosis is improving Diagnosis is improving Criteria now exist for defining invasive mycosis Criteria now exist for defining invasive mycosis


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