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Fungal lung infections in critically ill patients Prof. Dr. Stijn Blot Dept. of Internal Medicine Faculty of Medicine & Health Sciences Ghent University De Pintelaan 185 9000 Ghent BELGIUM Burns, Trauma & Critical Care Research Centre The University of Queensland, Brisbane, Queensland AUSTRALIA [email protected] AIMS At the conclusion of this activity, learner will have insights in Criteria and categories for diagnosing invasive fungal disease in severely immunocompromized hosts Risk profile for invasive pulmonary aspergillosis (IPA) in immunocompetent ICU patients Approach to diagnose IPA in ICU patients, including discrimination of Aspergillus colonization from IPA Therapeutic options for IPA SUMMARY Introduction Most frequently isolated fungal pathogens in ICU patients are Candida spp. and Aspergillus spp., with Candida being much more involved in critical illness. While Aspergillus is mostly isolated from respiratory tract samples, Candida is frequently cultured from urinary tract samples, intra-abdominal drains, wounds, as well as the respiratory tract, especially in mechanically ventilated patients with exposure to antibiotics. In contrast with Aspergillus of which >90% of isolates are cultured from the lung, Candida spp isolated from the respiratory tract are only rarely pathogenic and therefore of minor clinical relevance. Suggested reading includes the following references: [1-5]. For that reason the accent of this course will be on invasive pulmonary aspergillosis (IPA). Aspergillus spp. Aspergillus is a filamentous fungus and widespread in the environment. Over 90% of the nosocomial aspergillosis cases are caused A. fumigatus [6]. The mechanism of pathogenesis is through the inhalation of conidia that may be followed by haematogenous spread. As such, Aspergillus may affect any organ system, albeit that the lung is responsible for >90% of all cases of invasive aspergillosis. Also in case of disseminated aspergillosis, the lung is often among the affected organs [7, 8]. Incidence of invasive pulmonary aspergillosis Studies reporting on the incidence of IPA and invasive aspergillosis are scarce but in general rates range from 1% to 6.5%. These numbers should be interpreted cautiously as estimates are biased due to the problematic diagnosis and very case-mix depending [9-11]. Outcomes IPA in ICU patients is associated with very mortality ranging 70-95%, and an attributable mortality of about 20% [9, 12-14]. The disease is absolutely lethal if left untreated. In non-ICU patients, diagnosis at an early stage of the disease and prompt initiation of appropriate antifungal therapy is associated with improved outcomes [15]. Risk profile for IPA Classic risk factors for IPA include those reflecting profound immunodeficiency as defined by the EORTC/MSG and generally called ‘host factors’ (i.e. allogeneic BMT, neutropenia, prolonged corticosteroid therapy, therapy with T cell immunosuppressants, and inherited immunodeficiency). In the past 15 years the spectrum of recognized risk factors has been enlarged beyond these classic host factors. In ICUs, the patient at risk for IPA can be characterized by (i) being mechanically ventilated, (ii) a high severity of acute illness with substantial organ derangements, (iii) sepsis and or respiratory distress, and (iv) underlying conditions including but limited to liver cirrhosis, COPD, and renal failure [16, 17]. Aspergillus-positive endotracheal aspirates… What does it mean? The finding of an Aspergillus-positive ETA initiates a clinical dilemma. Very often the diagnostic criteria as defined by the EORTC/MSG cannot help to discriminate IPA from Aspergillus colonization as the diagnosis of proven IPA requires positive histopathological findings. Besides the Aspergilluspositive culture, the diagnosis of probable IPA additionally requires host factors and medical imaging findings on CT scan that are very suggestive for invasive fungal disease (i.e. (i) dense, wellcircumscribed lesions +/- halo sign, (ii) air-crescent sign, or (iii) cavitation). Unfortunately such findings are rarely observed in mechanically ventilated patients. Furthermore the diagnosis of possible IPA according to the EORTC/MSG criteria is based on a combination of host factors and medical imaging, and as such of no use to discriminate colonization from IPA. A clinical algorithm can be used to distinguish colonization from IPA. A diagnosis of putative IPA is achieved when the Aspergillus-positive ETA sample (=entry criterion) is additionally accompanied by (i) compatible signs and symptoms, (ii) any radiologic abnormality either on chest x-ray or CT-scan, and (iii) either (iiia) the presence of a host factor or (iiib) a BAL fluid positive on culture and cytological examination (branching hyphae)[11]. If one of the additional criteria is not fulfilled, the case is considered Aspergillus colonization. This algorithm demonstrated favorable operating characteristics and allows detecting a broader proportion of the true burden of disease compared with the EORTC/MSG diagnostic criteria [18]. IPA in the absence of Aspergillus-positive respiratory tract cultures. A main limitation of the clinical algorithm is that it requires an Aspergillus-positive culture as entry criterion. IPA might occur in the absence of positive cultures [19]. This is probably the main reason why invasive aspergillosis is frequently found as a missed diagnosis in autopsy series in ICU patients [20, 21]. Galactomannan antigen detection on serum is a standard approach to diagnose invasive aspergillosis in neutropenic patients. However, the antigen is cleared by circulating neutrophils and as such of little value in non-neutropenic critically ill patients. Galactomannan detection on BAL fluid however appeared to have strong operating characteristics to diagnose IPA in ICU patients [19]. A recent study successfully demonstrated that the clinical algorithm works equally well when the entry criterion (Aspergillus-positive culture) is replaced by a positive galactomannan test on BAL fluid [22]. The challenge is to organize the laboratory for frequent galactomannan detection analyses and to identify the patients at risk for IPA (preferably at an early stage) that might benefit from (regular) BAL procedures. Recently a lateral-flow device test has been developed to diagnose IPA [23]. The test is easily executed (no need for BAL fluid pre-treatment) and the result is rapidly ready (10-15 min.). In ICU patients this test demonstrated to have a high negative predictive value while the positive predictive value was moderate. To treat or not treat? A proven diagnosis is difficult to achieve in a critically ill patient and if so, in many cases too late to secure a favorable outcome. In order to keep a realistic chance for survival it seems crucial to start appropriate antifungal therapy at an early stage, i.e. when there exists a “substantial degree of suspicion for IPA”. Therefore, the clinician should balance the following elements that contribute to a reasonable degree of diagnostic certainty: Risk profile o ICU patients at risk IPA are on mechanical ventilation and experience severe acute illness as evidence by organ failure. Severe respiratory distress and sepsis are very common admission diagnoses. In case the patient has presence of host factors (i.e. being severely immunocompromized) the risk profile for invasive fungal disease is obvious. Very often the patients has one or more severe underlying conditions such as severe liver cirrhosis, COPD, or chronic renal insufficiency. Medical imaging o o Any abnormality on medical imaging (either on chest x-ray or CT scan) may hide Aspergillus involvement. In case medical imaging reveals robust sings of invasive fungal disease (cf. the EORTC/MSG ‘clinical features’) appropriate antifungal therapy must be considered. Mycology o o o o Galactomannan antigen detection on BAL fluid is a strong indicator for IPA in nonneutropenic patients (cut-off value OD ≥0.5). Aspergillus-positive respiratory tract cultures are equivocal but should never be discarded. Especially, repeatedly positive cultures should awake suspicion for invasive disease. Also a cytological smear demonstrating fungal elements might be an important sign, particularly with branching hyphae as this is an indication for tissue invasion. Finally a positive lateral-flow test also contributes to the diagnosis of IPA. Antifungal agents Voriconazole is the drug of choice for IPA [24]. The drug is preferably administered intravenously as absorption might be disturbed due to critical illness [25]. Monitoring of the renal function is recommended as the IV vehicle (SBECD) may accumulate. In case of moderate hepatic insufficiency (Child Pugh A & B) the maintenance dose can be halved (use identical loading dose). In case of severe liver cirrhosis the benefits of the drug must outweigh the risks. Substantial pharmacokinetic variability with voriconazole is observed. Therefore, therapeutic drug monitoring (TDM) is recommended in order to ensure adequate drug concentrations. The use of TDM for voriconazole has been associated with improved efficacy and outcomes in non-ICU patients [26]. Alternatives for voriconazole include lipid-associated amphotericin B, caspofungin, micafungin, and posaconazole. Combination therapy can be considered for salvage therapy. REFERENCES 1. el-Ebiary M, Torres A, Fàbregas N, la Bellacasa de JP, González J, Ramirez J, del Baño D, Hernández C, Jiménez de Anta MT. Significance of the isolation of Candida species from respiratory samples in critically ill, non-neutropenic patients. An immediate postmortem histologic study. Am. J. Respir. Crit. Care Med.; 1997; 156: 583–590. 2. Krause R, Halwachs B, Thallinger GG, Klymiuk I, Gorkiewicz G, Hoenigl M, Prattes J, Valentin T, Heidrich K, Buzina W, Salzer HJF, Rabensteiner J, Prüller F, Raggam RB, Meinitzer A, Moissl-Eichinger C, Högenauer C, Quehenberger F, Kashofer K, ZollnerSchwetz I. 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