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CHAPTER 14 Invasive Fungal Infections in Critically Ill Patients Stijn I Blot, Koenraad Vandewoude ABSTRACT In the past decades, a demographic shift in hospital and intensive care unit (ICU) populations have been taking place with a greater proportion of strongly debilitated patients who are at risk for secondary opportunistic infections such as invasive fungal disease The utmost important fungal pathogens encountered in ICUs are invasive candidiasis and invasive (pulmonary) aspergillosis With the exception of candidemia, the diagnosis of invasive fungal infections is problematic This may lead to a postponed diagnosis and therefore, delayed initiation of antifungal therapy Despite the availability of potent antifungal agents, mortality associated with invasive fungal infections in critically ill patients remains unacceptably high INTRODUCTION Over the past decades, major advances in healthcare have led to an unwelcome increase in the number of life-threatening infections due to true pathogenic and opportunistic fungi Invasive candidiasis and invasive aspergillosis are the major manifestations of opportunistic invasive mycoses.1,2 These infections are being seen in ever increasing numbers, largely because of the increasing size of the population at risk This population includes recipients of hematopoietic stem cell transplants and solid organ transplants, patients with hematological malignancies, patients infected with human immunodeficiency virus (HIV) developing acquired immunodeficiency syndrome (AIDS), and other persons receiving immunosuppressive treatment Furthermore, the use of high-grade supportive care in severe and lifethreatening diseases, specifically in intensive care units (ICUs), burn patients, and premature neonates, has improved survival but has created a demographic shift in hospital and ICU populations with more debilitated patients at risk for secondary invasive opportunistic Chapter_14.indd 214 infections These evolutions in medical practice have led to changes in the epidemiology of fungal infections The importance of fungi as pathogens in hospitalized patients, in general, and in ICU patients in particular, has increased substantially in the past decades In the National Nosocomial Infections Surveillance System (NNIS), 1980–1990, the rate of nosocomial fungal infections rose from 2.0 to 3.8 infections/1,000 discharges.3 In the US, amongst the deaths caused by any infectious disease, those due to mycoses increased from the 10th most common in 1980 to the 7th most common in 1997.4 The increased incidence of fungal infections has coincided with a decreased mortality from bacterial infections This is probably the result of better antibiotic therapy, leading to an increased survival of patients who are predisposed to fungal infections, as well as, inappropriate antibiotic therapy disrupting the normal microbial flora on the skin and the mucosal surfaces The increase in incidence of candidiasis have been most marked during the 1980s,5,6 but rates appeared to have stabilized in the 1990s.7 This increasing trend of Candida infections over the past decades has been noted in all 8/19/2014 3:37:19 PM infections were found in a series of 8,214 autopsies (3.38%) Over 12 years, the prevalence of invasive fungal infection rose from 2.2% (1978–1982) and 3.2% (1983–1987) to 5.1% (1998–1992) (p < 0.001) This was mainly due to a significant increase in Aspergillus infections (p < 0.001), whereas the prevalence of Candida infections was stable and even showed a declining trend.14 The same temporal trend was found in a nationwide Japanese unselected autopsy study, encompassing patients from 1969 to 1994.15 The frequency of visceral mycoses among the annual total number of autopsy cases increased noticeably from 1.60% in 1969 to a peak of 4.66% in 1990 and 3.17% in 1994 Among them, the incidences of candidiasis and aspergillosis increased the most After 1990, however, the frequency of visceral mycoses gradually decreased Until 1989, the predominant causative agent was Candida species, followed in order by Aspergillus species and Cryptococcus species The incidence of invasive candidiasis rose from 0.41% in 1969 to a peak of 1.89% in 1989 and then decreased to 1.12% after 1991. In contrast, the aspergillosis rate rose from 0.39% in 1969 to a peak of 1.55% in 1990 and maintained a constant level of about 1.3% after 1991, surpassing the rate of invasive candidiasis Two German studies confirm these findings In a single center study in a general hospital, the incidence of systemic mycoses was found to be 0.98% in 4,813 necropsies.16 Whereas candidiasis predominated from 1973 till 1991, a shift towards aspergillosis was noticed in the period of 1992–2001 The invasive candidiasis rate was 0.56%, and the aspergillosis rate was 0.37% An incidence of 6.6% for invasive candidiasis and of 1.3% for invasive aspergillosis was found in an autopsy study analyzing records between 1994 and 2003.17 In the setting of tertiary care hospitals, invasive aspergillosis is actually surpassing invasive candidiasis, as the most frequent fungal infection found at autopsy However, one should consider that most cases clinically classified as ‘invasive candidiasis’ effectively are candidemia without tissue invasion This entity of definite fungal infection by Candida species may be underestimated in necropsy studies.18 POSTMORTEM EPIDEMIOLOGICAL EVIDENCE AND TEMPORAL TRENDS DIAGNOSIS OF INVASIVE FUNGAL INFECTION Autopsy data on the incidence of invasive fungal infection provide incontrovertible evidence for the importance of invasive fungal disease in the general population as well as in hospitalized patients In a single tertiary care center study, analyzing trends in the postmortem epidemiology of invasive fungal infection between 1978 and 1992, 278 invasive fungal With the exception of cryptococcal meningitis and candidemia, the diagnosis of invasive fungal infection at an early stage remains difficult Definite or proven diagnosis still remains on positive histopathological examination The sampling of body fluids or tissue from protected anatomical sites is often not feasible in critically ill patients Therefore, diagnosis is often constructed on Chapter_14.indd 215 Invasive Fungal Infections in Critically Ill Patients types of hospitals and wards The NNIS data showed that between 1980 and 1989, the incidence of primary candidemia increased by 487% in large hospitals and by 219% in smaller hospitals.5 The overall rate of nosocomial fungal infections increased almost 5-fold over the same period Candida species may account for approximately 8–15% of all nosocomial bloodstream infections albeit that some studies report a much lower incidence of candidemia.8,9 In the past decades, it has been suggested that in ICUs the incidence of invasive aspergillosis, mainly pulmonary involvement, is on the rise.10,11 However, diagnosis of invasive aspergillosis is problematic as well, and reliable incidence estimates are scarce as such As with all opportunistic infections, the case-mix of patients is most probably a major factor influencing the occurrence rate of invasive fungal infections A sobering observation in infectious disease medicine and critical care is that invasive fungal infections are often not diagnosed or are diagnosed late in the course of the disease, because diagnostic techniques are less than ideal.12,13 In a large autopsy study, only 22% of invasive fungal infections were suspected or documented antemortem.14 Clinicians are often frustrated since the weakness of current clinical, radiological, and mycological diagnostic modalities are nonspecific and insensitive Thus, it hampers the implementation of the concept of timely appropriate treatment, from which is known that it has a positive impact on outcome in bacterial infections In spite of the availability of effective azole and polyene antifungals for more than decades and more recently, the development of the new generation triazoles and the echinocandins, fungal infection continues to carry a grim prognosis and is associated with significant morbidity and mortality, thus, representing a growing healtheconomic burden for modern healthcare systems A robust management strategy for prophylaxis, diagnosis, and therapy of invasive fungal infections, continues to evade clinicians and mycological experts from developing new noninvasive tools for screening patients at risk and to corroborate diagnosis when clinical argumentation is insufficient in a particular patient 215 8/19/2014 3:37:19 PM Textbook of Respiratory and Critical Care Infections 216 clinical and radiological data, and an estimation of the probability of acquiring invasive fungal infection based on estimation of host risk factors and epidemiological data This has led to the concepts of probable and possible fungal disease, which are far more frequent diagnostic categories than proven fungal disease; the latter often being a post-mortem diagnostic finding Historically, invasive fungal infection was first recognized problematic in patients with hematological cancer undergoing chemotherapy and in patients receiving allogeneic stem cell transplants; hence, most efforts in optimizing diagnosis and treatment have been directed to this population However, evidence is accumulating that the groups of patient at risk for developing invasive fungal infection continue to expand Moreover, the spectrum of Candida and Aspergillus species infection is wide Some entities are difficult to characterize, and not always a consensus can be formed definitions in published work For immunocompromized patients, an international consensus has been reached by investigators from the Invasive Fungal Infections Co-operative Group (IFICG) of both the European Organization for Research and Treatment of Cancer (EORTC) and the Mycoses Study Group (MSG) of the US National Institute of Allergy and Infectious Diseases (NIAID).19 The EORTC/MSG developed standard definitions of invasive fungal infections in immunocompromized patients with cancer and in recipients of hematopoietic stem cell transplants These diagnostic criteria were updated in 2008.20 According to the revised definitions, invasive fungal disease is categorized in major categories reflecting the diagnostic degree of certainty: proven, probable, and possible invasive fungal disease.20 A proven diagnosis requires histopathologic evidence of fungal invasion A diagnosis of probable invasive fungal disease is based on the presence of host factors, clinical features, and positive mycology Host factors reflect profound immunodeficiency, such as neutropenia or treatment with immunosuppressive agents Clinical features for invasive fungal disease include medical imaging on computed tomography (CT) scan demonstrating suggestive signs of fungal invasion: dense, well circumscribed lesions, with or without a halo sign, air crescent sign, or cavity Mycological criteria include either a direct test (cytology, direct microscopy, or culture) on any respiratory tract aspirate, or galactomannan antigen detection on bronchoalveolar lavage (BAL) fluid or serum A diagnosis of possible invasive fungal disease is reached in the presence of host factors and clinical features, but in the absence of mycological criteria These diagnostic criteria proved to be useful in research and practice in severely immunocompromized Chapter_14.indd 216 patients.21,22 In mechanically ventilated ICU patients, however, diagnosing invasive fungal disease according to this strict classification is problematic due to a number of reasons First, open lung biopsy might be contraindicated because of coagulation disorders; as such, a diagnosis of proven invasive fungal disease is rare Second, current definitions of probable or possible invasive fungal disease have been validated only in immunocompromized patients However, this is a serious drawback as invasive fungal disease may develop in ICU patients without host factors.23,24 Third, radiological findings in mechanically ventilated patients are nonspecific in the majority of cases24 in contrast to the very strict definitions of radiological lesions according to the EORTC/MSG criteria.20 Moreover, these lesions should be documented by computed tomography (CT) scan, which is not always feasible in ICU patients with hemodynamic or respiratory instability Finally, galactomannan antigen detection on serum is of little value in non-neutropenic patients, as circulating neutrophils are capable of clearing the antigen The lack of specific criteria for diagnosing invasive fungal disease in critically ill patients hampers timely initiation of appropriate antifungal therapy and may, as such, compromise the odds of survival.22,25,26 One of the black boxes in the diagnostic process is the presence of Aspergillus species in endotracheal aspirate cultures This is observed in up to 2% of mechanically ventilated ICU patients.24,27,28 The relevance of Aspergillus-positive endotracheal aspirates was assessed by Vandewoude et al who proposed a clinical diagnostic algorithm to discriminate Aspergillus colonization from invasive pulmonary aspergillosis.24 The algorithm was derived from the EORTC/MSG definitions and considers an endotracheal aspirate culture to represent invasive pulmonary aspergillosis in the presence of compatible signs, abnormal thoracic medical imaging, and either host factors or BAL fluid positive for Aspergillus on direct microscopy and culture (Table 1) In a cohort of 172 ICU patients with Aspergilluspositive endotracheal aspirate cultures, 83 were judged to have invasive pulmonary aspergillosis (48.3%) Histopathology data were available in 26 patients, 19 in the invasive pulmonary aspergillosis group and in the colonization group In all 26 cases, the diagnosis as based upon the clinical algorithm was confirmed These data were externally validated in a large multicenter epidemiologic study that included 524 critically ill patients with Aspergillus-positive endotracheal aspirates.29 For semantic clarity, the classification of probable invasive pulmonary aspergillosis in the clinical algorithm was renamed to “putative invasive pulmonary aspergillosis”, in order to distinguish from probable invasive pulmonary 8/19/2014 3:37:20 PM TABLE Diagnostic Criteria for Putative Invasive Pulmonary Aspergillosis24,29 When ≥1 criterion necessary for a diagnosis of putative invasive pulmonary aspergillosis is not met, the case is classified as Aspergillus respiratory tract colonization BAL, bronchoalveolar lavage; CT, computed tomography; ANC, absolute neutrophil count; ICU, intensive care unit aspergillosis in the EORTC/MSG criteria for invasive fungal disease In a subset of 115 pathology-controlled cases (‘gold standard’) the clinical algorithm reached an area under the receiver operating characteristic curve of 76% [95% confidence interval (CI) 67–85%] while the criteria for probable aspergillosis as defined by the EORTC/MSG only reached an area under curve of 57% (95% CI 46–68%) The positive and negative predictive values were 61% and 92%, respectively These data stress that in the absence of histopathologic data, the criteria proposed by the EORTC/MSG are of minor value in ICU settings In the total cohort (n = 524), 79 patients had proven invasive pulmonary aspergillosis (15.1%) Chapter_14.indd 217 CLINICAL EPIDEMIOLOGY OF INVASIVE FUNGAL INFECTIONS Because of the uncertainties in diagnosis, it is difficult to assess the true clinical significance of fungal isolates As a result, it is troublesome to appreciate the true incidence of invasive candidiasis and invasive aspergillosis Literature data addressing frequency, diseased pattern, and prognostic data rely on autopsy series, retrospective series, and more recently, prospective series in certain risk groups By far, the greatest wealth of information exists for nosocomial invasive candidiasis For invasive aspergillosis, studies have mostly focused on severely immunocompromized and cancer patients Particularly in non-neutropenic patients, the incidence of invasive aspergillosis is difficult to assess Data about the incidence of invasive pulmonary aspergillosis in the critically ill are scarce INVASIVE CANDIDIASIS AND CANDIDEMIA Clinical Spectrum and Definitions The clinical spectrum of diseases related to Candida species is wide, and a summary is given in table They can be divided in hematogenous, nonhematogenous, and deep seated infections Some entities are difficult to characterize, so in surgical and critically ill patients, there is no uniform consensus in definitions in published work.30 For practical reasons, it can be considered that invasive candidiasis describes close but distinct entities: candidemia and systemic or disseminated candidiasis.31 Candidemia refers to the isolation of Candida species from the blood If the patient temporarily presents signs of infection, candidemia is considered proven invasive fungal infection Candidemia without clinical signs in a neutropenic patient, in the presence of graft vs host disease or in a patient Invasive Fungal Infections in Critically Ill Patients Putative invasive pulmonary aspergillosis (all criteria must be met) Aspergillus-positive lower respiratory tract specimen culture (entry criterion) Compatible signs and symptoms (one of the following) • Fever refractory to at least days of appropriate antibiotic therapy • Recrudescent fever after a period of defervescence of at least 48 hours while still on antibiotics and without other apparent cause • Pleuritic chest pain • Pleuritic rub • Dyspnea • Hemoptysis • Worsening respiratory insufficiency in spite of appropriate antibiotic therapy and ventilator support Abnormal medical imaging by portable chest X-ray or CT scan of the lungs Either 4a or 4b 4a Host risk factors (1 of the following conditions) • Neutropenia (ANC 20 mg/day) • Congenital or acquired immunodeficiency 4b Semiquantitative Aspergillus-positive culture of BAL fluid (+ or ++), without bacterial growth together with a positive cytological smear showing branching hyphae According to the EORTC/MSG criteria, 32 patients had probable aspergillosis (6.1%) and 413 patients were not classifiable (78.8%) The algorithm judged 199 patients to have putative aspergillosis (38.0%) and 246 to have Aspergillus colonization (46.9%) The algorithm demonstrated favorable operating characteristics to discriminate Aspergillus respiratory tract colonization from invasive pulmonary aspergillosis in critically ill patients In comparison to the EORTC/MSG criteria, this algorithm probably encompasses a greater proportion of the true burden of invasive pulmonary aspergillosis in the ICU 217 8/19/2014 3:37:20 PM TABLE Clinical Spectrum of Candida Infections Hematogenous infections • • • • • • Candidemia Endophthalmitis Vascular access-related candidemia Septic thrombophlebitis Infectious endocarditis Arthritis • Osteomyelitis Spondylodiscitis Meningitis Pyelonephritis Pulmonary candidiasis Hepatosplenic candidiasis • Vaginitis • • • • • Nonhematogenous infections • • Cutaneous candidiasis Oropharyngeal candidiasis Deep-seated Candida species infections Textbook of Respiratory and Critical Care Infections • 218 • Esophageal candidiasis Cystitis • • Peritonitis Tracheitis, bronchitis receiving steroids, is considered probable ‘Disseminated candidiasis’ refers to conditions where Candida invasion is shown from culture or histology results at nonadjacent, normally sterile sites Such findings confirm hematogenous dissemination, and accordingly, these infections can be categorized as proven The term invasive candidiasis is sometimes used instead of hematogenous candidiasis, referring to the fact that the development of infection follows host colonization.32-34 Candida albicans is responsible for most infections, but compared to older reports, the share of non-albicans species is increasing.35-38 Incidence and Temporal Trends Over the past decades, Candida species has become increasingly important as nosocomial pathogens Since Candida species infections are not reportable diseases, published data have been derived from institution-based registries and more recently in multicenter studies, often in predefined patient type groups, such as the critically ill Invasive candidiasis was estimated to account for 17% of hospital-acquired infections reported during the European Study on the Prevalence of Nosocomial Infections in Critically Ill Patients (EPIC study).39 This large multicenter study included 10,038 patients from 1,417 ICUs in 17 European countries in 1992 A criticism to the study concept was that due to imperfection in case definitions, patients categorized as having invasive candidiasis were merely colonized; hence, the point-prevalence estimate of 17% is likely to be an overestimation In the EPIC II study, comparable data were reported regarding presumed Candida infections, Chapter_14.indd 218 hereby, illustrating the ongoing diagnostic fog in these opportunistic infections.40 Candidemia represents 10–20% of all invasive candidiasis This may be considered as the ‘tip of the iceberg’ of infections by Candida species.3,41,42 In the 80s, a candidemia rate of 0.5% of all medical and surgical discharges was described in a tertiary care center, representing a 20-fold increase as compared to the 70s Overall mortality in candidemic patients was 57%.43 In the US, the NNIS program between 1980 and 1989 showed an increase in the proportion of nosocomial infections caused by Candida species from 2% in 1980 to approximately, 5% in the period 1986–1989.44 In an active populationbased surveillance for candidemia in North-American metropolitan areas in 1992–1993, the average annual incidence was 8/100,000 population;6 19% of patients developed candidemia prior to or on the day of admission Subsequently, between 1990 and 1999, the NNIS based registry showed that Candida species were responsible for 5–10% of all bloodstream infections45,46 Candida species represented the fourth leading organism, after coagulase-negative staphylococci, Staphylococcus aureus, and enterococci In a retrospective study on candidemia in a tertiary care hospital in Switzerland between 1989 and 2000, the annual incidence ranged from 0.2 to 0.46/10,000 patientdays During the study period, a decrease in incidence of candidemia has been noted The species distribution in patients with candidemia showed that the most commonly identified species were C albicans (66%), followed by C glabrata (17%), and C parapsilosis (6%) In spite of an increase in fluconazole use, the proportion of non-C albicans species remained stable The overall mortality among patients with candidemia was 44%, with the highest rate in patients over 65 years (52%) Factors independently associated with higher mortality were patient age greater than 65 years, ICU admission, and underlying cancer The European Confederation of Medical Mycology (ECMM) prospective, sequential, hospital populationbased study through 1997–1999 revealed rates of candidemia ranging from 0.20 to 0.38/1,000 admissions with a 30-day mortality rate of 37.9%.47 C albicans was identified in 56% of cases Non-albicans Candida species were most frequently isolated from patients with hematological malignancies (65%) With increasing age, an increasing incidence of C glabrata was seen The 30-day mortality rate was 37.9% In a series of 294 consecutive candidemia patients between 1989 and 2000 at a large referral center, candidemia incidence ranged from 0.21 to 0.56/10,000 patient days with the highest incidence in 1993 and the lowest in 2000.48 8/19/2014 3:37:20 PM Chapter_14.indd 219 The second important type of invasive candidiasis is Candida peritonitis In contrast to candidemia, Candida peritonitis is more challenging, because of a problematic clinical and microbiological diagnosis In some reports Candida species were the leading or second most frequently isolated pathogens in secondary or tertiary peritonitis.56-58 On the other hand, in a study of 120 patients with secondary peritonitis, Candida species was present in only 12% of the cases, thereby, ranking seventh.59 Sandven et al demonstrated Candida involvement in 32 of 81 patients with secondary (nonappendicitis) peritonitis (39.5%).60 After exclusion of cases with communityacquired peritonitis, this percentage increased to 45% In critically ill patients with secondary or tertiary peritonitis, the significance of Candida isolation is controversial.61 Some studies have found Candida species to have only a limited significance,61,62 while others found it quite relevant.63 Only in cases with perioperatively documented Candida plaques on the peritoneum, or on histology, can a definite diagnosis of Candida peritonitis be made Yet, as soon as Candida is cultured from the peritoneum, antifungal therapy is recommended, irrespective of whether this represent colonization or established infection.64 Emergence of Non-Albicans Candida Species An increase in the proportion of non-albicans Candida strains has been reported in several series, since the late 1980s In some studies, predominantly in cancer centers, more than half of Candida fungemia was due to nonalbicans isolates This evolution is in parallel with the widespread introduction of antifungal prophylaxis with triazoles in the 1980s in hemato-oncological patients receiving intensive cytostatic treatment and bone marrow or stem cell transplantation Antifungal prophylaxis in this patient population is associated with a higher risk of infection with non-albicans strains, such as C krusei (with intrinsic resistance to triazoles) or C glabrata (with dose-dependent sensitivity to triazoles).65,66 During the 1990s, surveillance programs were established to provide more general epidemiological information on species distribution These registries show that C albicans remains the most predominant strain in most countries, more in particular in studies in critically ill patients, as well as, in series in which severely immunocompromized patients did not represent a major proportion.38,67 The long-term effect of fluconazole consumption on distribution of species causing candidemia was investigated in a university hospital during a period of 11 years (1994–2004).68 Despite long- Invasive Fungal Infections in Critically Ill Patients Candidemia rates vary according to the characteristics of the population considered and the type of the institution Rates calculated as incidence-densities (i.e., per 10,000 patient days) better express the risk associated with the case-mix of the population and hence allow some comparisons between studies.31 The incidence of candidemia reported in observational series range from 2.8 to 22.0 candidemia/10,000 patient-days.48-50 As already mentioned, case-mix should be considered in the interpretation of such data Trends over time are also important to consider as indicated in some of the abovementioned studies Although ICUs generally account for only 5% or less of the total admission capacity in acute care hospitals, the majority of patients with invasive candidiasis are diagnosed in those facilities In a 2-year large-scaled population-based study of nosocomial candidemia in England and Wales, 45.5% of cases occurred in ICUs.51 In the EPIC study, 9.3% of bloodstream infections in ICUs were caused by Candida species.39 Voss et al reported an average incidence of Candida bloodstream infections of 5.5/10,000 patients days, ranging from 2.4 (1990) to 7.4/10,000 patient days (1994) with an overall mortality of 58%.52 In a large Spanish prospective multicenter survey, the incidence of ICU-acquired candidemia was 1/500 admissions.53 In a 10-year retrospective cohort study (1990–2000) in critically ill medical and surgical patients in France, the mean yearly incidence of candidemia was 2.1/1,000 admissions with C albicans accounting for 55% of all candidemia The overall mortality was 60.8%.54 During 1989–1999, a significant decrease in the incidence of hospitalacquired candidemia among ICU patients was noted in US hospitals participating to the NNIS system.55 More specifically, there was a significant decrease in the incidence of C albicans, whereas the incidence of nonalbicans species of Candida remained stable Analyzing the bloodstream infections due to non-albicans species, there was a significant increase in C. glabrata bloodstream infections This shift was related to the exponentially increased use of fluconazole in ICUs in the past decade A prospective hospital-based surveillance of the surgical ICU patients in particular has demonstrated a high incidence of fungal infection In the National Epidemiology of Mycosis Survey (NEMIS) study concerning patients admitted to surgical ICU in 1993–94, an incidence of even 9.8 Candida bloodstream infections/1,000 admissions was observed In this survey, Candida species caused 9.2% of all bloodstream infections diagnosed in surgical ICUs More than half of these were due to non-albicans Candida species.49 219 8/19/2014 3:37:21 PM Textbook of Respiratory and Critical Care Infections term exposure to fluconazole, no change in Candida ecology was observed More recently, however, French investigators found a relationship between antifungal drug use in an ICU and changes in drug susceptibility of Candida species.69 The epidemiological shift in species distribution has implications for the guidelines for antifungal management of invasive Candida species infections.34,70 On the individual patient level, prior exposure to fluconazole increases the likelihood of nonalbicans Candida involvement in case of candidemia.68,71 Of particular interest, is the large variation in species distribution in large therapeutic trials (1994–2003), including those evaluating the newer antifungals, in mixed patients populations, as well as non-neutropenic patients with invasive Candida infections, showing a progressive decrease of C albicans over time to about half of the isolates In most of these series, the proportion of C krusei with intrinsic resistance to triazole compounds remains below 5% Hence, the effect of the ongoing slow shift in species distribution for management of invasive Candida infections, in particular in the ICU, may not be exaggerated, since the proportion of strains with high potential or intrinsic resistance to triazole antifungals remains relatively low This indicates that international therapeutic guidelines should be implemented after careful consideration of the local fungal ecology, exposure to antifungal prophylaxis, patient mix and proportion of immunosuppressed patients Pathophysiology of Candida Infection Candida species are normal inhabitants amongst the human endogenous flora Mucocutaneous surface colonization is rare under normal conditions.41 Colonization is a prerequisite for the development of invasive infection; it develops as a consequence of Candida overgrowth on mucosal or skin surfaces.72,73 Translocation across a damaged gut barrier is also possible Exposure to risk factors creates additional opportunities to develop invasion and secondary hematogenous dissemination Though endogenous colonization is in most cases responsible for the development of invasive disease, nosocomial cross contamination as a result of poor hand hygiene procedures has been described in ICU settings Risk Factors for Candida Bloodstream Infection 220 Several retrospective studies have identified multiple risk factors for candidal bloodstream infection.72,74-79 Most of the risk factors have been repeatedly verified, although others are more controversial Major risk factors include Chapter_14.indd 220 the use of central venous catheters, total parenteral nutrition (TPN), receipt of multiple antibiotics, extensive surgery and burns, renal failure and hemodialysis, mechanical ventilation, and prior fungal colonization The NEMIS evaluated in a prospective way, the risk factors for the acquisition of Candida bloodstream infection in surgical ICU patients.49 The dominant risk factors were prior surgery (relative risk (RR) 7.3), acute renal failure (RR 4.2), and total parenteral nutrition (RR 3.6), with a significant trend toward Candida bloodstream infection developing in association with shock, disseminated intravascular coagulation (DIC), and adult respiratory distress syndrome (ARDS) Other important findings included the contributory role of the triple-lumen catheter in surgical patients Remarkably, in this study, colonization with Candida species was not found to be an independent risk factor for Candida bloodstream infection This observation is in contrast to the findings of several previous studies in which colonization was linked to the risk of candidemia.72,74,77 Diagnostic Tools Timely clinical diagnosis of invasive disease caused by Candida species remains a challenge for the clinician Cultures other than blood or obtained from normally sterile sites are nonspecific Moreover, the mycological cultures may only contribute to diagnosis, late in the course of the infection Early clinical manifestations of Candida infection are nonspecific with the exception of a positive fundoscopic examination Candida endophthalmitis is a rare, but specific finding present in up to 25% of patients in prospective series.80-82 Diagnosis remains dependent on a high index of suspicion and critical patient assessment and clinical experience The finding in a large autopsy study that only 22% of invasive fungal infections were suspected or documented antemortem is sobering.14 Diagnostic failure or delayed diagnosis and institution of therapy may be a cause of the persisting high mortality, despite the availability of new potent antifungals with less toxicity In spite of this, serological or molecular techniques to detect Candida infections have not been applied in routine clinical practice until now Multisite Candida Colonization The relationship between multisite colonization and subsequent development of candidemia has been demonstrated by several investigators.83-86 Yet, efforts to define a precise cut-off value based on a ratio of cultures positive for Candida and the total number of cultures 8/19/2014 3:37:21 PM Impact of Invasive Candidiasis The impact of invasive candidiasis on patient outcome has only been established in patients with candidemia In general, the crude mortality is over 50% and has remained at this level in recent years The attributable mortality, defined as the proportion of deaths directly related to candidemia, can be determined by a simple comparison of the mortality rates between candidemic and noncandidemic patients in a cohort of consecutive patients One must be cautious in interpreting these data which are calculated as such, since it is possible to overestimate attributable mortality Matched cohort studies with strict adjustment for confounding factors are more appropriate The attributable mortality derived from matched cohort studies range from dramatic proportion (>30%)50,74 to nonsignificant fractions (5%).90 High rates of early initiated empiric appropriate antifungal therapy may contribute to better survival.88,91,92 Candida peritonitis in critically ill surgical patients carries a very poor prognosis but studies addressing the attributable mortality are lacking Mortality rates between 52 and 75% have been described.63,79,93 In a series of 271 patients with peritonitis, Dupont et al.94 investigated outcome and risk factors for mortality in patients with Candida peritonitis Mortality in patients without Candida involvement was 41%, while in the 83 patients with Candida peritonitis, ICU mortality was 52% In a multicenter matched cohort study, Montravers et al compared 91 patients with Candida isolated from the peritoneal cavity with 168 matched control subjects.63 Chapter_14.indd 221 Patients eligible for study inclusion were those operated for peritonitis with focus on complex problems, such as perforation, bowel necrosis, and anastomotic leakages In nosocomial peritonitis, mortality was significantly higher among patients with Candida peritonitis (48% vs 28%; p < 0.05) Additionally, Candida peritonitis was identified as an independent predictor of mortality, after adjustment for major confounders, such as source of peritonitis and inappropriate empiric antimicrobial therapy, but not for failure of source control, which is well known as a major factor contributing to unfavorable outcomes.95 INVASIVE PULMONARY ASPERGILLUS INFECTIONS Clinical Spectrum and Definitions The term ‘aspergillosis’ refers to several categories of infection: life-threatening acute invasive aspergillosis, chronic necrotizing aspergillosis, aspergilloma or fungus ball, and allergic bronchopulmonary aspergillosis The lung is the most frequent site of disease The clinical manifestation and severity of Aspergillus disease depend upon the immunologic state of the patient.96 The principal entities are allergic bronchopulmonary aspergillosis, pulmonary aspergilloma, and invasive aspergillosis Depending on the immune status of the patient, it can be speculated that a spectrum of invasive pulmonary aspergillosis exists, from the well-known acute invasive form characteristic for severely immune debilitated patients, over subacute invasive aspergillosis—still with fungal tissue invasion—to chronic cavitary and fibrosing pulmonary and pleural aspergillosis and simple aspergilloma; the latter disease entities with histologic evidence of hyphae in cavities but not in tissues and a chronic inflammation with fibrosis in the tissue surrounding the cavity.18 Invasive Fungal Infections in Critically Ill Patients sampled (‘colonization index’) have been less successful For example, in a group of 92 medical ICU patients, 36 of whom had a colonization index of 0.5 or more, only 1 patient developed invasive candidiasis.87 AgvaldÖhman et al found that of 29 patients with a colonization index of more than 0.5 developed invasive candidiasis, whereas still of 30 patients with an index of less than 0.5 developed systemic Candida infection as well.83 Yet, in logistic regression analysis, the investigators could demonstrate an increased risk for invasive candidiasis in case of increased colonization density in combination with extensive abdominal surgery The relative weight of distinct body sites being colonized has never been investigated, but it appears that candiduria deserves extra attention as a risk factor for candidemia.88 Other investigators have also linked the relevance of multisite colonization to other significant risk factors.89 Therefore, the decision to start presumptive therapy should be based on a broad clinical evaluation instead of multisite Candida colonization alone Incidence of Invasive Pulmonary Aspergillosis Invasive pulmonary aspergillosis mainly affects severely immunocompromized patients, but evidence is emerging that this disease entity is encountered and possibly emerging in other categories of patients without apparent immunodeficiency.97-102 An important study addressing epidemiology of invasive aspergillosis in an ICU was published by Meersseman et al.23 The EORTC/MSG diagnostic criteria were applied in this retrospective 221 8/19/2014 3:37:22 PM Textbook of Respiratory and Critical Care Infections study One hundred twenty seven patients out of 1,850 admissions (6.9%), hospitalized between 2000 and 2003 had microbiological or histopathological evidence of Aspergillus during their ICU stay There were 89 cases (70%) without hematological malignancy These patients were classified as proven invasive aspergillosis (n = 30), probable invasive aspergillosis (n = 37), possible invasive aspergillosis (n = 2), or colonization (n = 20) In these patients, mean Simplified Acute Physiology Score II (SAPS II) was 52 with a predicted mortality of 48% The observed mortality was 80% (n = 71) Mortality of the proven and the probable invasive aspergillosis was 97% and 87%, respectively Postmortem examination was done in 46 out of 71 patients, and 27 autopsies (59%) showed hyphal invasion with Aspergillus Aspergillus infections occurred in critically ill patients with proven invasive aspergillosis who did not have any predisposing factors according to the currently available definitions In an autopsy study of ICU patients, an incidence of invasive aspergillosis of 2.7% of the patients undergoing postmortem examination was found, and COPD was the underlying disease in most of the cases.103 The epidemiology of invasive aspergillosis is changing Invasive disease is increasingly observed in the non-neutropenic phase of hematopoietic stem cell transplantation, and in nonclassic settings, such as critically ill patients in ICUs.104 These studies imply that invasive disease caused by Aspergillus species should be considered in critically ill patients, even in the absence of classic risk factors such as prolonged neutropenia, hematological malignancy, and bone marrow or stem cell transplantation Aspergillus Species The genus comprises about 180 species, of which 33 have been associated with disease in humans Most infections are caused by Aspergillus fumigatus, A flavus, A terreus, and A niger, and less commonly, A nidulans can be implicated as a causative pathogen, especially in the setting of chronic, granulomatous disease.105 Some species, such as A terreus, may exhibit inherent resistance to available antifungal drugs This species is often resistant to amphotericin B, but still susceptible to the echinocandins and the new-generation triazoles.106,107 Pathophysiology of Pulmonary Aspergillus Infection 222 The development of aspergillosis requires the exposure of a susceptible host to a relevant inoculum The incubation period between exposure and development of the Chapter_14.indd 222 disease is unclear Invasive aspergillosis most commonly involves the sinopulmonary tract, reflecting inhalation as the principal port of entry While it is generally accepted that neutrophils and pulmonary macrophages represent the first lines of (innate) host defense against invasive aspergillosis, the recognition of T-cell-mediated immunity is increasing Specifically pulmonary alveolar macrophages ingest and kill inhaled conidia, while polymorphonuclear neutrophil leucocytes are fungicidal to the hyphal form of Aspergillus species It is likely that neutrophils actively participate in the generation of a subsequent adaptive T-helper cell response, with production of a series of cytokines influencing the inflammatory response and phagocytic activity In the absence of an adequate neutrophil count and if macrophage function is disturbed, ‘escaped’ conidia will germinate and form hyphae with the capacity to invade tissue There is evidence that acquired dysfunction of neutrophils, monocytes, or macrophages is an important cause of infection in patients with diabetes mellitus, renal or hepatic failure, alcoholism, auto-immune diseases, influenza or HIV infection, burns, and trauma Distinguishable mechanisms of acquired phagocyte dysfunction include inhibitory effects of metabolic disturbances (e.g., hyperglycemia, uremia), chemical toxins (e.g., ethanol), viral proteins on phagocyte activation, and pathologic activation of phagocytes in the circulation (e.g., after hemodialysis, burns, or cardiopulmonary bypass) Tissue invasion by Aspergillus hyphae may be promoted by temporary dysfunction of phagocytic cells In animal models, the protective role of lung surfactant proteins (SP)-A and SP-D and mannose-binding lectin (MBL) in the host defense against invasive aspergillosis was identified Therapeutic administration of SP-D and MBL proteins in a murine model of pulmonary invasive aspergillosis rescued mice from death The results suggested that individuals with any structural or functional defects in these innate immune molecules due to genetic variations, or acquired by severe lung disease, might be susceptible to invasive aspergillosis Risk Factors for Invasive Pulmonary Aspergillosis For many years, it has been known that several types of immunosuppression predispose to invasive aspergillosis Numerically, the most numerous patients are those with prolonged neutropenia and transplant recipients In addition to neutropenia, corticosteroid treatment is a clear risk factor Advanced HIV infection, even in the 8/19/2014 3:37:22 PM Diagnostic Tools An accurate diagnosis of invasive aspergillosis is important for several clinical reasons Early diagnosis is associated with improved patient survival.22 Deep tissue diagnostic specimens are often difficult to obtain from severely ill patients Tests with a high negative predictive value may allow expensive and potentially toxic antifungal treatments to be withheld Timely diagnosis of invasive aspergillosis, in early stage, remains difficult in immunocompromized patients In patients with critical illness, the diagnostic process is very difficult, because the symptoms and signs are atypical and the initiation of additional diagnostic examinations is often delayed due to a low index of suspicion—the diagnosis of invasive aspergillosis in apparently immunocompetent patients is often discarded or considered as not plausible Although a positive Aspergillus species culture in a respiratory tract specimen is neither sensitive, nor Chapter_14.indd 223 specific, it is often the first clue for the diagnosis in critically ill patients.24,27 Excluding the possibility of contamination during preanalytical phase of a sample, isolation of Aspergillus species in the respiratory tract may represent one of the three scenarios: • Evidence of current disease • True colonization • A marker for the future development of disease Direct Diagnostic Techniques In clinical scenarios of high suspicion of opportunistic fungal infections, direct microscopic examination of respiratory samples is of paramount importance These samples may be obtained either by simple endotracheal aspiration or BAL.109 Microscopy is an important investigation for several reasons First, diagnostic yield may be more than for culture alone in infections The second reason is the rapid turnaround tie of microscopy: results should be available within hours after sampling Combining microscopy and culture may optimize the diagnostic yield by 15% or more over that of culture alone.110,111 The use of special stains may increase the sensitivity of microscopy Within tissue secretions, Aspergillus typically appears as slender septate hyphae that exhibit angular dichotomous branching Demonstration of septate hyphae by direct microscopy is, however, not an unequivocal diagnostic confirmation, because other fungi may have similar appearances Culture A culture yielding Aspergillus species in addition to enabling a diagnosis of invasive aspergillosis, may further define therapeutic options via susceptibility testing or the isolation of a species possessing inherent antifungal resistance The main disadvantage of culture is that it is relatively slow, as the process may take days, is relatively insensitive, and requires specialized expertise for species determination A positive culture of a tissue sample or sample of a normally sterile site obtained by aseptic technique, establishes the diagnosis of proven invasive diagnosis In the absence of such samples, samples obtained from contiguous nonsterile sites, such as the upper or lower respiratory tract, can serve as a surrogate to establish a “putative” diagnosis of invasive pulmonary aspergillosis.29 It can be assumed that viable hyphal elements are shed into the respiratory tract from infected parenchyma However, this shedding may appear late in the natural course of the disease, and hence, this can indicate an advanced stage of the disease, Invasive Fungal Infections in Critically Ill Patients absence of neutropenia or corticosteroid use, may also be predisposing to invasive disease Patients with chronic granulomatous disease are also at risk for invasive aspergillosis As immunosuppressive protocols change and new immunosuppressive agents are made available for patients with autoimmune diseases, it is expected that the traditional risk factors for invasive aspergillosis may also change Examples of new therapeutic advances are the use of T-cell ablative agents, such as alemtuzumab in solid organ transplantation, and the use of immunomodulatory agents, such as etanercept in rheumatoid arthritis In a multicenter hospital-based survey, most Aspergillus species culture isolates from nonsterile body sites did not represent disease.108 However, for high-risk patients, a positive culture result was associated with invasive disease, such as in allogeneic bone marrow transplant recipients (60%), persons with hematologic cancer (50%), and those with signs of neutropenia (60%) or malnutrition (30%) Diagnosis of invasive aspergillosis on the basis of an Aspergillus species positive culture of a specimen obtained from a nonsterile body site remained most difficult in the group of patients with an intermediate risk for invasive aspergillosis (10–30%): HIV infection (20%), solid-organ transplantation (20%), corticosteroid use (20%), or an underlying pulmonary disease (10%) It was concluded that in this intermediate risk group with specimens from nonsterile body sites, the clinician must aggressively determine by means of histopathological tests, radiology, and/or serologic tests, the relevance of an Aspergillus isolate with regard to disease 223 8/19/2014 3:37:22 PM ... retrospective 22 1 8/19 /20 14 3:37 :22 PM Textbook of Respiratory and Critical Care Infections study One hundred twenty seven patients out of 1,850 admissions (6.9%), hospitalized between 20 00 and 20 03 had... insufficient in a particular patient 21 5 8/19 /20 14 3:37:19 PM Textbook of Respiratory and Critical Care Infections 21 6 clinical and radiological data, and an estimation of the probability of acquiring... Nonhematogenous infections • • Cutaneous candidiasis Oropharyngeal candidiasis Deep-seated Candida species infections Textbook of Respiratory and Critical Care Infections • 21 8 • Esophageal candidiasis