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
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.
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
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
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).
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
Tools for diagnosis of invasive aspergillosis and their applicability in the ICU
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
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
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
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
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
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
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
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
Waiting for GM-BAL studies in the ICU Bouza E et al. J Clin Microbiol 2005; 43:2075-9
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
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
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
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)
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.
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].
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.
# Bassetti M et al. BMC Infect Dis 2006; 6: 21
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
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
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
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
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