Gestione pratica delle infezioni fungine in terapia intensiva

1. SIMIT 2010 Gestione pratica delle infezioni fungine in terapia intensiva Epidemiologia, fattori di rischio e diagnosi delle infezioni fungine in terapia intensiva Nicola Petrosillo UOC Infezioni Sistemiche e dell’Immunodepresso Istituto Nazionale per le Malattie Infettive “Lazzaro Spallanzani

2. Invasive Aspergillosis (IA) in the ICU • The bulk of literature about IA involves patients with classic risk factors for IA, such as prolonged neutropenia and hematopoietic stem cell transplantation. • However, a broad group of patients who are admitted to ICUs may also be susceptible to these infections.

3. IS IA A PROBLEM IN THE ICU?

4. Estimates about the incidence of IA among critically ill patients are sparse and variable. • For various reasons, figures about the true incidence of IA are difficult to generate: • 1. discrimination between colonization and • infections remains challening; • 2. few istitutions perform autopsies routinely; • 3. characteristic radiological signs of IA are usually absent in the nonneutropenic ICU patient. • 4. diagnostic utility of non-culture based microbiological tools has not been properly validated in the nonhematology ICU population; • 5. EORTC/MSG guidelines were not designed for patient categories other than patients with cancer and patients who have undergone bone marrow transplantation

5. Retrospective autopsy-controlled studies • A study sought unsuspected causes of death in a ICU revealed that, among 100 autopsies, there were 15 cases of IA, of which 5 were missed before death. Roosen J et al. Mayo Clin Proc 2000; 75:562–7. • 127 (6.9%) of 1850 hospitalized patients had microbiologic or histopathologic evidence of aspergillosis during their ICU stay, including 89 cases(70%) in which there was not an underlying hematological malignancy. • The observed mortality rate of 80% was much higher than the mortality rate predicted on the basis of the Simplified Acute Physiology Score II (48%). Meersseman W et al. Am J Respir Crit Care Med 2004;170:621–5

6. Other epidemiological data on IA in the ICU • IA prevalence in pts with septic shock  0.3% • (Vandewoude KH et al. Crit Care 2006; 10:R31). • High prevalence of IA (pathologic and/or microbiologic • evidence of aspergillosis) in a cohort of patients with • severe hospital-acquired pneumonia who had been admitted to the ICU 13 (19%) of 67 episodes of IA in the ICU • (Valles et al. Intensive Care Med 2003; 29:1981–8). • During a 6-year period, Cornillet et al. found that a mean number of 15 patients per year received a diagnosis • of IA; approximately one-half of these patients were in the ICU. • (Cornillet A et al. Clin Infect Dis 2006; 43:577–84).

7. WHO IS AT RISK OF DEVELOPING IAIN THE ICU?

8. Meersseman W et al. Clin Infect Dis 2007; 45: 205-16

9. Which diseases are associated to IA in the ICU?

10. COPD AND ASPERGILLOSIS • In a review of 50 studies, COPD was the underlying condition in 26 out of 1,941 (1.3%) patients with aspergillosis • In one large study, 9% of 595 patients with IA suffered • from pulmonary disease Patterson TF et al. Medicine 2000; 79: 250-60 • Steroids are believed to play a role in the emergence of IA, and some authors have investigated the correlation between the daily dose of corticosteroids and the probability of developing IA Leav BA et al. N Engl J Med 2000; 343: 586 Lin SJ et al. Clin Infect Dis 2001; 32: 358-66

11. Samarakoon P et al. Chronic Resp Dis 2008; 5: 19-27

12. Tools for diagnosis of invasive aspergillosis and their applicability in the ICU

13. CT Halo sign  sign arrives too early (5 days before the onset of disease). Not specific for Aspergillus spp (also other molds) Crescent sign obscured by atelectasis, ARDS, and/or pleural effusion. CT often is not feasible in a patient with a high fraction of inspired oxygen Scarcely applicable for the ICU Balloy V et al. Infect Immun 2005; 73: 494-503

14. Bulpa P et al. Eur Respir J 2007; 30: 782-800

15. Bulpa P et al. Eur Respir J 2007; 30: 782-800

16. Bulpa P et al. Eur Respir J 2007; 30: 782-800

17. Bulpa P et al. Eur Respir J 2007; 30: 782-800

18. Histopathologic evidence [acutely branching (45°), septated hyphae mainly in lung tissue] It is a global standard for ICU Roosen J et al. Mayo Clin Proc 2000; 75: 562-7  100 IA Meersseman W et al. Am J Respir Crit Care 2004; 170:621-5 129 IA However, biopsies often are not feasible in patients with thrombocytopenia or a high fraction of inspired oxygen

19. Culture (Sabouraud agar) • Poor sensitivity and specificity. • Isolation of the species takes several days. • 50% of cases are missed on the basis of culture • and microscopy findings. • Discrimination of colonization versus invasive • disease is difficult • Positive predictive value increases with increased • immunosuppression. Moderated applicability in the ICU

20. Direct microscopy • PAS, Grocott stain, calcofluor visualization • of hyphal elements (not only Aspergillus spp), • rapid test. • Same problems of Culture Moderated applicability in the ICU

21. Galactomannan serum assay (threshold, 0.5-1.5 ng/mL) • Tested mainly for haematologic non-ICU patients • False positive (Pip/Taz) • In the nonneutropenic critically ill patients, BAL • may perform better than serum Moderated applicability in the ICU

22. Meersseman W et al. Am J Respir Crit Care Med 2008; 177:27-34

23. Meersseman W et al. Am J Respir Crit Care Med 2008; 177:27-34

24. Meersseman W et al. Am J Respir Crit Care Med 2008; 177:27-34

25. Paziente con COPD in terapia cronica steroidea. • Ricovero in ICU per esacerbazione di COPD ed insufficienza respiratoria. • BAL colturale positivo per Haemophilus influenzae e negativo per funghi. • Galattomannano serico negativo, ma positivo su BAL. • Trattato con terapia antiaspergillare, ma deceduto. • Autopsia aspergillosi limitata al polmone Meersseman W et al. Clin Infect Dis 2007; 45: 205-16

26. PCR • PCR holds promise for patient with haematologic • malignancy, but has not been systematically studied • for the diagnosis of IA in the ICU • In the nonneutropenic, critically ill patient, BAL may • perform better than blood • PCR of respiratory secretion specimens as a modality of • surveillance is an interesting topic of research Not tested in the ICU

27. Beta-(1,3)D-glucan • hampered by false positive results (albumin, • wound gauze, hemodialysis, bacterial infection). • Not specific for Aspergillus spp; also present in • yeasts and bacteria • May be useful as a negative predictor of fungal • infection Not tested in the ICU

28. What is the meaning of Aspergillus colonization?

29. Khaasawneh F et al. J Crit Care 2006; 21: 322-7

30. Waiting for GM-BAL studies in the ICU Bouza E et al. J Clin Microbiol 2005; 43:2075-9

31. Candida in ICU

32. Suspected invasive candidiasis in the ICU • An invasive Candida infection is typically considered when a febrile nonneutropenic patient in the ICU who has some risk factors for Candida infection • vascular access, • administration of TPN, • the receipt of corticosteroids, • therapy using broad-spectrum antimicrobial agents, • recent surgery, • a prolonged stay in the ICU, • colonization with Candida • fails to respond to broad-spectrum antibacterial therapy De Pauw BE et al. Clin Infect Dis 2008; 45: 1813-21

33. Rapid progression of IC: a reason for suspecting Candida infection in the ICU Day to start of fluconazole Garey KW et al. Clin Infect Dis 2006; 43:25-31

34. Delay in starting antifungal therapy is an independent determinant of hospital mortality in pts with candidemia Morrell M et al. Antimicrob Agents Chemother 2005; 49:3640-5

35. Marriot DJE et al. Critical Care 2009; 13: R115

36. Candida in the ICU - epidemiology- • The past two decades have marked a dramatic rise in the frequency of infections caused by Candida species. • 1% to 8% of patients residing in the hospital develop invasive candidiasis versus 10% of patients residing in ICUs • (Eggimann P et al. Lancet Infect Dis 2003; 3:685–702). • Invasive candidiasis accounts for up to 15% or 30% of all nosocomial infections in critically ill patients. • (Eggimann P et al. Lancet Infect Dis 2003; 3:685–702; Magnason S et al. Acta Anaesthesiol Scand 2008;52: 1238–45)

37. Candida in the ICU - epidemiology- • About 80% of cases of candidemia arise from or evolve in the presence of a vascular access, including access related to central venous catheters, hemodialysis catheters, peripherally inserted central catheters, and implanted ports. • An estimated 33% to 55% of all episodes of candidemia occur in patients in the ICU, and the associated mortality rates range from 5% to 71%. Ben-Ami R et al. J Clin Microbiol 2008;46:2222–6 Bouza E et al. Int J Antimicrob Agents 2008;32(Suppl 2):S87–91.

38. Candida in the ICU • Risk factors • Two main factors predispose to infections with Candida spp.: • - colonization of skin and mucous membranes with Candida and • - alteration of natural host barriers (wounds, surgery, and insertion of indwelling intravascular and urinary catheters). • The gastrointestinal tract, the skin and the urogenital tract are the main portals of entry for Candida infections. • Since 1994, colonization by Candida spp. has been established as a major risk factor for invasive candidiasis [Pittet D et al. Ann Surg 1994; 220:751-758].

39. Candida in the ICU - Risk factors- • Risk factors for candidemia in patients in the ICU include: • the use of intravascular catheters, • parenteral nutrition, • prior abdominal surgery, • the use of broad-spectrum antibacterial therapy, • the use of corticosteroids, • acute renal failure, • a prolonged stay in the ICU, • and Candida colonization, particularly if it is multifocal. Bouza E et al. Int J Antimicrob Agents 2008;32(Suppl 2):S87–91.

40. Leroy O et al. Crit Care Med 2009; 37: 1612-18

41. Bassetti M et al. BMC Infect Dis 2006; 6: 21

42. Bassetti M et al. BMC Infect Dis 2006; 6: 21

43. Bassetti M et al. J Antimicrob Chemother 2009; 64: 625-29

44. # Bassetti M et al. BMC Infect Dis 2006; 6: 21

45. Epidemiology of Candidaemia in Europe: Results of 28-Month European Confederation of Medical Mycology (ECMM) Hospital-Based Surveillance Study Tortorano AM et al. Eur J Clin Microb Infect Dis 2004; 23: 317-22

46. 76 pts with Fl-R C glabrata BSI • 68 pts with Fl-S C glabrata BSI • 512 controls Lee I et al. Arch Intern Med 2009; 169: 379-83

47. In vitro susceptibility to fluconazole of Candida species in patients naive for azole agents and in previously exposed to azole agents S= susceptible S-DD= susceptible dose dependant R= resistant Leroy O et al. Crit Care Med 2009; 37: 1612-8

48. Epidemiology of Candidaemia in Europe: Results of 28-Month European Confederation of Medical Mycology (ECMM) Hospital-Based Surveillance Study Mortality rates by etiological agent Tortorano AM et al. Eur J Clin Microb Infect Dis 2004; 23: 317-22

49. Prospective, observational, multicenter, French study conducted from October 2005 to May 2006 • Among the 136 patients analyzed, 78 (57.4%) had candidemia caused by C. albicans. • These patients had • earlier onset of infection (11.1 ± 14.2 days after ICU admission vs. 17.4 ± 17.7, p = 0.02), • higher severity scores on ICU admission (SOFA: 10.4 ± 4.7 vs. 8.6 ± 4.6, p = 0.03; SAPS II: 57.4 ± 22.8 vs. 48.7 ± 15.5, P = 0.015), and • were less often neutropenic (2.6% vs. 12%, p = 0.04) • than patients with candidemia due to non-albicans Candida species. Leroy et al. Critical Care 2010, 14:R98

50. Role of Colonization