Approach to invasive pulmonary aspergillosis in critically ill patients.

REVIEW URRENT C OPINION

Approach to invasive pulmonary aspergillosis in critically ill patients Despoina Koulenti a,b, Jose Garnacho-Montero c, and Stijn Blot d

Purpose of review Apparently immunocompetent critically ill patients represent an increasing population at risk for invasive pulmonary aspergillosis (IPA). The current review gives an update on the epidemiology, diagnosis, and management of IPA in the ICU. Recent findings Patients without apparent severe immunosuppression (e.g. chronic obstructive pulmonary disease, decompensated liver disease, etc.) represent the majority of ICU IPA cases. IPA diagnosis is problematic and the true incidence of IPA is difficult to be estimated because of the nonspecific clinical presentation. A user-friendly clinical diagnostic algorithm for IPA is valuable, particularly through a high negative predictive value. IPA carries a poor prognosis and has an important impact on hospital costs. Timely diagnosis and prompt administration of appropriate treatment may improve the outcomes. Intravenous voriconazole is the recommended primary IPA treatment, but liposomal amphotericin B also has clinical utility. Voriconazole presents bioavailability and toxicity issues, and drug level monitoring is advocated. Caspofungin or antifungal combinations are recommended as salvage therapy. Summary A high level of suspicion in critically ill patients presenting with Aspergillus-positive respiratory tract cultures or nonresolving pulmonary infection may lead to earlier IPA diagnosis. Dosage individualization may decrease treatment discontinuation and improve clinical efficacy. Keywords critical care, diagnosis, invasive pulmonary aspergillosis, outcomes, risk factors

INTRODUCTION

expansion of the spectrum of patients at risk beyond those with the classic risk factors [2 ,5 ]. Critically ill patients without apparent immunosuppression have emerged as an increasing and understudied population at IPA risk [2 ,5 ]. &&

Aspergillus is an ubiquitous filamentous fungus, typically found in soil and decaying material. Inhaled conidia of Aspergillus can cause life-threatening disease in severely immunocompromised patients, such as patients with prolonged neutropenia and bone marrow transplant recipients [1]. Although every organ can be affected by Aspergillus species, sinopulmonary involvement is the most common [2 ]. Aspergillus fumigatus is the most frequent species isolated in invasive aspergillosis (80–90%), while there has been a trend over the last few years for an increasing incidence of nonfumigatus species, especially Aspergillus flavus and Aspergillus terreus [3 ]. Because of advances in medical care during the last 30 years, the ‘traditional’ population at risk has increased with subsequent increase of invasive pulmonary aspergillosis (IPA) incidence [4]. Moreover, the use of high-grade supportive care in life-threatening diseases, especially in ICUs, not only has improved survival, but also has led to an &&

&&

www.co-infectiousdiseases.com

&&

&&

&&

EPIDEMIOLOGY The previously reported incidence of IPA in ICU patients varies widely from 0.3 to 6.9% [6–8]. a 2nd Department of Critical Care Medicine, Attikon University Hospital, Athens, Greece, bBurns, Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Queensland, Australia, c UnidadClıńica de Cuidados Crı´ticos y Urgencias, Hospital Universitario Virgen del Rocıó, Sevilla, Spain and dDepartment of Internal Medicine, Faculty of Medicine & Health Science, Ghent University, Ghent, Belgium

Correspondence to Professor Dr Stijn Blot, Department of Internal Medicine, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium. Tel: +32 9 332 6216; e-mail: [email protected] Curr Opin Infect Dis 2014, 27:174–183 DOI:10.1097/QCO.0000000000000043 Volume 27 Number 2 April 2014

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Invasive pulmonary aspergillosis Koulenti et al.

KEY POINTS IPA is a life-threatening opportunistic fungal infection that, although it usually occurs in severely immunocompromised patients, has been increasingly recognized in apparently immunocompetent ICU patients, with COPD patients comprising the largest group. IPA diagnosis is especially problematic in the ICU because of the nonspecific clinical and radiological signs in critically ill patients; EORTC/MSG criteria fail to diagnose IPA in the ICU setting. A diagnostic algorithm for IPA that probably encompasses a larger proportion of the true burden of IPA in the ICU setting has been recently externally validated; ‘Putative’ aspergillosis, a new diagnostic category of IPA in ICU patients, is included in the algorithm.

critically ill patients. It is noteworthy that in the ICU setting 30–70% of patients who develop invasive aspergillosis do not have the ‘classic’ host factors and that only 10–15% present with neutropenia [3 ,6,13]. The impaired immune response of apparently immunocompetent critically ill patients, including depressed monocyte and macrophage function and neutrophil deactivation, especially in the late phase of multiorgan dysfunction, puts the patients at risk for invasive aspergillosis [14,15]. In ICUs, chronic obstructive pulmonary disease (COPD) is the most common invasive aspergillosisassociated underlying condition (around 50%), followed by solid-organ transplant (SOT) [3 ,16 ]. COPD is broadly recognized as a major risk factor for IPA [17,18 –20 ]. A recent study concluded that in the ICU, Aspergillus isolation carries a similar IPA risk in COPD and immunocompromised patients [19 ]. Another study claimed that Aspergillus isolation in all COPD patients should raise suspicion for IPA, not just in GOLD III and IV patients [20 ]. Independent risk factors for IPA in COPD include systemic steroids use in the stable phase, treatment with at least three antibiotics during hospitalization, and antibiotic treatment for at least 10 days [21 ]. Finally, the fact that many COPD patients are chronically colonized with Aspergillus (16.3 cases per 1000 admissions) along with the nonspecific clinical presentation of IPA may lead to delayed or missed diagnosis [2 ,22]. Decompensated liver disease represents another condition depicted as a risk factor for IPA [23,24,25 ,26 ]. In a series of 94 biopsy-proven severe alcoholic hepatitis episodes, 16% were diagnosed with aspergillosis after a median of 26 days after the alcoholic hepatitis diagnosis. Baseline disease severity and ICU admission were independent risk factors for invasive aspergillosis development [25 ]. In another study, 5% of 787 patients with acute or chronic liver failure developed IPA [26 ]. Independent risk factors included older age, encephalopathy, and steroid use [26 ]. Construction, renovation, or demolition works in the hospital or the environment are environmental and iatrogenic risk factors for invasive aspergillosis. They are reported as a probable or possible source in almost half of nosocomial aspergillosis outbreaks [27]. It was suggested that in the ICU setting the indoor air concentration of Aspergillus spp. conidia might be a potential determinant of the frequency of IPA [28 ]. Meersseman et al. [9] classified the risk factors for invasive aspergillosis among ICU patients in three categories: high risk, intermediate risk, and low risk. The low-risk group, however, is very broad and a vast majority will never develop invasive &&

&&

&

&&

&

&

Serologic and molecular diagnostic tests have been developed to detect surrogate markers for Aspergillus spp. Consideration of IPA as a potential cause in ICU patients, timely diagnosis, and prompt administration of appropriate treatment are crucial in order to improve the generally poor prognosis.

&

&&

Intravenous voriconazole (treatment of choice) and liposomal amphotericin B are the primary treatment options in critically ill patients.

&&

This variability may be attributed to the nonspecific clinical presentation and the problematic diagnosis of IPA in ICU patients, as well as to the differences in the case mix of the studied populations [2 ,9]. For instance, the lowest rate (0.017%) was reported by a study that focused on the ‘emerging’ ICU population at risk, excluding ICU patients with the classic risk factors for invasive aspergillosis [5 ]. The rate of Aspergillus isolation from the lower respiratory tract (LRT) of mechanically ventilated patients was 1–2% in previous reports [7,8,10]. &&

&&

RISK FACTORS The European Organization for the Research and Treatment of Cancer/Mycosis Study Group (EORTC/ MSG) has defined a set of host factors for the diagnosis of invasive fungal disease [11,12]. These factors represent a status of profound immunosuppression and are considered as the ‘classic’ risk factors for invasive fungal disease, including IPA. However, these factors comprise only a part of the broad spectrum of immunosuppression and there are several other patients at risk for invasive aspergillosis, including patients with AIDS and

0951-7375 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins

&&

&

&&

&

&

&


175


Respiratory infections &&

&&

&&

&&

aspergillosis [2 ]. Table 1 [2 ,3 ,9,11–15,16 ,17, 18 –20 ,21 ,22–24,25 ,26 ,27,28 –30 ] details the EORTC/MSG ‘classic’ host risk factors for IPA, additional risk factors, and the classification of risk factors proposed by Meersseman et al. [9]. &

&

&&

&&

&

&

&

DIAGNOSIS Early recognition of IPA represents an opportunity to improve outcome. However, the diagnosis of IPA in the ICU setting is difficult because of the nonspecific clinical presentation of IPA in the mechanically ventilated critically ill patients [2 ,7]. IPA may be one of the most frequently missed conditions in the ICU [2 ,9,31 ]. The strict EORTC/MSG criteria (Table 2) [12] fail to diagnose IPA in patients without the ‘classic’ host factors’ [2 ,11,12,32,33]. It should

be noted that EORTC/MSG guidelines were designed for patients with cancer and bone marrow transplant recipients [2 ,11,12]. In the ICU setting, the diagnosis of proven IPA is very rare because of the frequent contraindications for lung biopsy [2 ]. Furthermore, the radiological findings of IPA in mechanically ventilated patients are neither specific nor is the computed tomography (CT) scan always feasible [2 ,7]. Finally, current definitions of probable or possible IPA have been validated only in immunocompromised patients [2 ,3 ,7]. &&

&&

&&

&&

&&

&&

&&

&

&&

‘Putative invasive pulmonary aspergillosis’: a new diagnostic category for ICU patients The lack of specific diagnostic criteria of IPA in critically ill patients hinders prompt diagnosis and

Table 1. Risk factors for IPA and classification of the severity of risk factors Risk factors for IPA ‘Classic’ host risk factors (EORTC/MSG) [11,12] Recent history of severe neutropenia (10 days Allogeneic stem cell transplant recipient Prolonged corticosteroids use (>0.3 mg/kg/day prednisone equivalent >3 weeks) T-cell immunosuppressant treatment during the previous 3 months (e.g. cyclosporine, TNF-a blockers, specific monoclonal antibodies, or nucleoside analogs) Inherited severe immunodeficiency ‘Additional risk’ factors [2 ,3 ,13–15,16 ,17,18 –20 ,21 ,22–24,25 ,26 ,29 ,30 ] &&

&&

&&

&

&

&&

&&

&

&

&

Chronic obstructive pulmonary disease (COPD) Acquired immunodeficiency syndrome (AIDS) Solid-organ transplant (SOT) recipient Decompensated liver disease Severe alcoholic hepatitis Critically ill patients with severe sepsis H1N1 critically ill patients Critically ill patients with ECMO support ‘Environmental’ risk factors (‘Iatrogenic’) [2 ,27,28 ] &&

&

Fungal contamination of indoor air: construction or demolition works in the hospital or its environment Classification of the severity of the risk factors for IPA (ICU patients) [9] High risk

Intermediate risk

Low risk

Neutropenia (neutrophils 7 days)

Prolonged ICU stay (>21 days)

Solid-organ cancer

Postcardiac surgery status

HIV infection

Malnutrition

Lung transplantation Systemic diseases requiring immunosuppressive therapy ECMO, extracorporeal membrane oxygenation; IPA, invasive pulmonary aspergillosis. Data from [2 & & & 26 ,27,28 –30 ].

176


&&

,3

&&

,9,11–15,16

&&

&

&

,17,18 –20 ,21

&&

,22–24,25

&&

,

Volume 27 Number 2 April 2014


Invasive pulmonary aspergillosis Koulenti et al. Table 2. EORTC/MSG diagnostic criteria for IPA Proven IPA

Histopathologic evidence of fungal invasion

Probable IPA

‘Classic’ host factors (profound immunodeficiency – see Table 1) and Clinical features [presence of >1 of 3 suggestive signs of fungal infection on CT scan (dense, well circumscribed lesions, with or without a halo-sign, air crescent sign, or cavity)] and Presence of mycological criteria [direct test (cytology, direct microscopy, or culture) on any respiratory tract aspirate, or galactomannan antigen detection on BAL fluid or serum]

Possible IPA

‘Classic’ host factors (profound immunodeficiency – see Table 1) and Clinical features [presence of >1 of 3 suggestive signs of fungal infection on CT (dense, well circumscribed lesions, with or without a halo-sign, air crescent sign, or cavity)] and Absence of mycological criteria (negative or not done)

BAL, broncho-alveolar lavage fluid; CT, computed tomography; IPA, invasive pulmonary aspergillosis. Adapted with permission from [12].

&&

&&

&

delays treatment [2 ,34 ,35 ]. A clinical dilemma in the ICU is to discriminate colonization from IPA in patients with Aspergillus-positive respiratory tract cultures and to decide to either initiate or withhold antifungal treatment [2 ]. On the basis of a single-center cohort of 172 ICU patients with Aspergillus-positive endotracheal aspirate cultures, a clinical diagnostic algorithm was developed in order to discriminate Aspergillus respiratory colonization from IPA: a case with Aspergillus-positive endotracheal aspirate culture in the presence of compatible signs, abnormal thoracic medical imaging, and either host factors or broncho-alveolar lavage (BAL) fluid positive for Aspergillus on direct microscopy and culture is considered as ‘putative’ IPA (Table 3) [7]. This clinical algorithm was externally validated in a multicenter study including 524 ICU patients with Aspergilluspositive respiratory tract aspirates [16 ]. The algorithm had specificity 61%, sensitivity 92%, and for an assumed prevalence of 20–50% the positive and negative predictive values ranged from 20 to 50% and 94 to 87%, respectively [16 ]. According to the EORTC/MSG criteria, 15% had proven IPA, 6% probable, and 79% of patients were unclassifiable, whereas the algorithm judged 38% of patients to have ‘putative’ IPA and 47% colonization, achieving a 32% higher diagnosis rate and hence probably encompassing a broader proportion of the true IPA burden in the ICU [16 ]. A recent multicenter retrospective study, which included 245 nonneutropenic, nontransplant recipient patients with repeated isolation (2 times) of Aspergillus from LRT samples, reported that 56.7% had proven or probable aspergillosis [36 ].

Biomarkers In the last decade, several serological and molecular diagnostic tests have been developed to detect the surrogate markers for Aspergillus spp.

&&

&&

&&

&&

&&

Galactomannan antigen detection Galactomannan is a component of the cell wall of Aspergillus that is released during tissue invasion and can be detected in serum. The most common technique uses the monoclonal antibody EBA-2 (Platelia Aspergillus EIA; BioRad, Hercules, California, USA). Assay results are reported as optical density index (ODI), which represents the ratio of the optical density of the patient sample compared with the optical density for a threshold serum provided in the assay kit. Positivity is considered when the index is greater than 0.7 in a single sample or greater than 0.5 in two consecutive determinations [37 ]. Diverse factors can produce false-positive results in serum galactomannan: treatment with a b-lactam (e.g. piperacillin–tazobactam and amoxicillin– clavulanate), presence of other invasive mycoses (e.g., Penicillium, histoplasmosis, or blastomycosis), or patients with intestinal mucositis [38 ,39 ]. Validity of the diagnosis depends on the type of patient, being highest in the neutropenic patient: 85% sensitivity and 95% specificity [3 ]. In ICU patients admitted with acute exacerbation of COPD and concomitant IPA, serum galactomannan was detected only in 62% of the patients [22]. In another study, the positivity of two serum determinations presented a sensitivity of 41.7% and a specificity of 93.5% [40]. Galactomannan can also be detected in BAL fluid. Quantification of galactomannan in BAL fluid


&

&&

&

&&


177


Respiratory infections Table 3. Diagnostic criteria for ‘putative’ invasive pulmonary aspergillosis in critically ill patients 1.

Aspergillus-positive respiratory tract specimen culture

2.

Compatible signs and symptoms (one of the following) Fever refractory to at least three days of appropriate antibiotic therapy Recrudescent fever after a period of defervescence of at least 48 h while still on antibiotics and without other apparent cause Pleuritic chest pain Pleuritic rub Dyspnoea Hemoptysis Worsening respiratory insufficiency in spite of appropriate antibiotic therapy and ventilatory support

3.

Abnormal medical imaging by portable chest X-ray or CT scan of the lungs

4.

Either 4a or 4b 4a. Host risk factors (one of the following conditions) Neutropenia (absolute neutrophil count lessthen 500/mm3) preceding or at the time of ICU admission Underlying haematological or oncological malignancy treated with cytotoxic agents Glucocorticoid treatment (prednisone or equivalent, >20 mg/day) Congenital or acquired immunodeficiency 4b. Semiquantitative Aspergillus-positive culture of broncho-alveolar lavage fluid (þ or þþ), without bacterial growth, together with a positive cytological smear showing branching hyphae

A diagnosis of putative invasive pulmonary aspergillosis requires all criteria to be fulfilled (1 þ 2 þ 3 þ either 4a or 4b). Adapted from [7].

(but not in more accessible respiratory samples such as tracheal aspirate) is becoming of great utility for the diagnosis of IPA, with an adequate diagnostic value in nonneutropenic critically ill patients. In 110 critically ill patients, using a cutoff value of 0.5, sensitivity and specificity in BAL was 88 and 87%, respectively, whereas sensitivity of galactomannan determination in serum was only 42% [41]. In 11 of 26 cases with proven IPA, both BAL culture and galactomannan in serum were negative, whereas the galactomannan in BAL fluid was positive [41]. Similarly, in a Spanish study including 51 critically ill patients, the most adequate cut-off value was at least 1, with 100% sensitivity and 89.36% specificity for proven IPA [42]. In addition, galactomannan positivity preceded the positivity of culture for Aspergillus spp. Importantly, galactomannan levels in BAL fluid for the control neutropenic patients were not different from the mean value of the control nonneutropenic patient [42]. 1,3 b-D-glucan b-D-Glucan is a component of the cell wall of most fungi (with the exception of Cryptococcus spp. and Zygomycetes) [3 ]. Its detection provides diagnostic information for IPA in oncohematological patients with neutropenia [43,44]. In nonneutropenic critically ill patients, the diagnostic accuracy

of galactomannan and b-D-glucan in serum was similar [45 ]. However, its utility for the diagnosis of IPA in critical patients is lower than that of the galactomannan determination in BAL [42,46]. It is important to highlight that this test is timeconsuming and not user-friendly [38 ]. False positives have been described in patients under hemodialysis, in those treated with amoxicillin/ clavulanic acid, azithromycin, immunoglobulins, albumin, or glucans, with the use of cellulose filters for intravenous administration and in Grampositive bacteremia [3 ]. In addition, it is also positive in infections by other fungi containing b-D-glucan in the cell wall such as Candida spp. [47]. &&

&&

&&

Nucleic acids Detection of nucleic acids by polymerase chain reaction presents 88% sensitivity and 75% specificity for IPA diagnosis [3 ]. The lack of a standardized method is the reason for discrepancies in the literature [3 ]. The performance of Aspergillus DNA detection by polymerase chain reaction has not been specifically tested in critically ill patients [3 ]. &&

&&

&&

&&

178


Immunological parameters A prospective study of critically ill immunocompromised patients with pulmonary infection evaluated



Invasive pulmonary aspergillosis Koulenti et al.

the quantitative changes of key immunological parameters on day 1, 3, and 10 after ICU admission [48 ]. CD8þ and CD28þCD8þ T-cell counts were lower in patients with IPA compared with those without IPA [48 ]. Among IPA patients, lower counts were associated with early mortality [48 ]. These results suggest a potential for CD8þ and CD28þCD8þ T-cell counts in timely risk identification [48 ]. &&

&&

&&

&&

THERAPEUTIC APPROACH Prompt initiation of appropriate antifungal treatment has well documented benefits in terms of mortality and healthcare costs [5 ,9,49]. Initiation of treatment is warranted upon suspicion of IPA while diagnostic evaluation is conducted, without the need of definitive proof [2 ,3 ,50]. The antifungal agents that are active against Aspergillus spp. are: from the class of triazoles, itraconazole, voriconazole, and posaconazole; amphotericin B; and echinocandins, caspofungin, micafungin, and anidulafungin [2 ,3 ]. The severity of critical illness combined with the poor prognosis of IPA, especially if appropriate treatment is delayed, does not justify the risk of insufficient treatment by oral solutions, so intravenous voriconazole or liposomal amphotericin B are the suggested initial treatment options [2 ]. Voriconazole is recommended as the first-choice IPA treatment by current guidelines [49–51]. However, it should be noted that the indication was based on clinical trials that did not include ICU patients and transplant recipients [9]. Voriconazole is associated with higher response rates and lower mortality compared with amphotericin B in the treatment of ‘probable’ or ‘proven’ invasive aspergillosis [49,52]. The PATH Alliance study, a North American large prospective surveillance study of invasive fungal infections (IFIs), reported that voriconazole was the main antifungal agent for invasive aspergillosis (45.5%) [53]. A recent observational multicenter study confirmed the clinical utility of voriconazole [54 ]. Voriconazole’s serum concentrations present great variability, and drug monitoring is advocated [3 ]. A recent randomized trial concluded that routine therapeutic drug monitoring (TDM) of voriconazole vs. non-TDM might reduce both drug discontinuation rates because of adverse events (4 vs. 17%) and improve treatment response in IFIs (81 vs. 57%) [55 ]. Liposomal amphotericin B has also demonstrated utility in the treatment of IPA with the same efficacy but improved safety profile compared with classic amphotericin B and the other lipid formulations [3 ,56,57]. Caspofungin has been &&

&&

&&

&&

&&

&&

&

&&

&&

&&

shown effective as salvage therapy in IPA [58]. A very recent multicenter, prospective, noncomparative, observational study that aimed to assess the effectiveness and safety of caspofungin in hematological patients with IFI concluded that caspofungin either alone or in combination is an effective and well tolerated option (79% complete or partial response; 1.7% nonserious adverse events) [59 ]. Regarding the role of combination therapy in IPA, there are insufficient data to support combination as primary therapy and the current guidelines recommend it as salvage therapy (in breakthrough or refractory invasive aspergillosis) [2 ,3 ]. A recent systematic review concluded that the cumulative evidence for use of combination therapy in invasive aspergillosis is conflicting and has moderate strength [60 ]. Nevertheless, it should be noted that up to 30% of ICU patients require salvage therapy for IPA [3 ]. Finally, although bioavailability and toxicity issues seriously complicate antifungal treatment, the data on the pharmacokinetic and pharmacodynamic characteristics of antifungals in critically ill patients are rather limited. Future pharmacokinetic and pharmacodynamic studies that will optimize the drug choices and dosing regimens, facilitating a more effective utilization of the available antifungal agents, are warranted [2 ,9, 61,62]. Detailed information on IPA antifungal treatment is shown in Table 4 [2 ,3 ,49–60 ,63–69]. &&

&&

&&

&&

&&

&&

&&

&&

&&

OUTCOMES Despite the availability of potent antifungal agents, mortality in IPA remains dramatically high. Mortality rates of IPA in ICU patients vary from 70 to 95% [6–8,13,70,71]. The high mortality can, at least in part, be attributed to the difficult and delayed diagnosis [33]. A recent study of nonneutropenic, nontransplant recipient patients with aspergillosis reported a 78.6% mortality in proven and 41.6% in probable cases, with mortality being positively associated with radiographic signs worsening, number of postculture antibiotics and the Acute Physiology and Chronic Health Evaluation-II score [36 ]. In invasive aspergillosis complicating severe alcoholic hepatitis, the 3-month transplantfree survival was 0% compared to 53% of those without alcoholic hepatitis, and this despite antifungal treatment [25 ]. In COPD patients, mortality was substantially higher among IPA compared with colonized patients (58.3 vs. 10.0%) [20 ]. In cases in which initial pulmonary involvement leads to infliction of other organs, mortality is even


&&

&&

&


179


Respiratory infections Table 4. Treatment options for invasive pulmonary aspergillosis [2 ,3 ,49–60 ,63–69] &&

&&

&&

Antifungals for IPA Triazoles (voriconazole, itraconazole, posaconazole) Drawbacks of triazoles include drug-related hepatotoxicity and hazardous drug interactions Voriconazole Active against Aspergillus including A.terreus Recommended treatment of choice: primary treatment (IDSA: A-I ATS: A-II, ECIL: A-I) Metabolized by and inhibiting enzymes of cytochrome P450 (CYP2C19, CYP2C9, CYP3A4) resulting in considerable drug interactions (including midazolam and several drugs of critical importance for the transplant recipients and patients with AIDS) Intravenous form with considerable renal and liver toxicity because of cyclodextrin (the solvent vehicle); no adequate clearance by renal replacement therapy Oral form with risk of inadequate absorption and subtherapeutic levels in critically ill patients Great inter-subject variability in serum concentrations in relation to CYP2C19 polymorphism, age, dose, underlying disases, hepatic function Serum concentrations < 1mg/l are associated with therapeutic failure while> 5.5 mg/l with toxicity Paucity of PK studies describing weight-based dosing of IV voriconazole in obese patients Routine serum level monitoring suggested to decrease discontinuations due to adverse events and improve response to treatment Itraconazole Active against Aspergillus including A.terreus Resistant strains of A. fumigatus described Oral formulation ‘attractive’ for long-term therapy Posaconazole Significant efficacy for invasive aspergillosis Prophylaxis, treatment or salvage therapy Less applicable in critically ill patients because only oral form available Polyenes (amphotericin B) A.terreus resistant to amphotericin B both in vitro and in animal models Liposomal amphotericin B : alternative treatment (IDSA: A-I); primary treatment (ATS: A-II, ECIL: B-I) Ampotericin B lipid complex : alternative treatment (IDSA: A-II); primary treatment (ECIL: B-II) Lipid formulations: similar efficacy with lower toxicity than classic amphotericin B Liposomal amphotericin is the best tolerated, with lower transfusion related reactions (fever, chills) and lower renal failure Liposomal amphotericin B with improved PK/PD profile compared with other lipid formulations No informatiom on the utility of nebulized amphotericin is available Echinocandins (caspofungin, anidulafungin, micafungin) Caspofungin, anidulafungin, micafungin have in-vitro and in-vivo activity against Aspergillus spp. Caspofungin: alternative treatment (IDSA: B-II ATS: C-II, ECIL: C-II) Caspofungin is the only echinocandin approved in Europe for patients with proven or probable invasive aspergillosis refractory to or intolerant of conventional antifungal treatment In an observational study, 79% of adult hematological patients with IFI had complete or partial response with caspofungin and it was generally well tolerated Caspofungin showed good tolerance and similar clinical cure rate to voriconazole or liposomal amphotericin B in the treatment of IPA in a recent dose-escalation study Limited data on anidulafungin and micafungin use for invasive aspergillosis Micafungin: alternative treatment (IDSA: B-II) Clinical trials on echinocandins in critically ill patients lacking Combination of antifungals Recommendation: salvage treatment (IDSA: B-II, ATS: C-II, ECIL: C-II); primary treatment (ECIL: D-III) Up to 30% of ICU patients require salvage therapy for IPA According to data of observational studies, in 14–50% of cases a combination was administered Cumulative evidence conflicting and of moderate strength (systematic review of 1 randomized controlled trial and 7 cohort studies in hemato-oncological patients) Voriconazole and caspofungin combination: synergistic interaction against Aspergillus (simultaneous inhibition of cell membrane and fungal cell wall biosynthesis); report for improved 3-month survival of combination vs. voriconazole alone

180




Invasive pulmonary aspergillosis Koulenti et al. Caspofungin and liposomal amphotericin B for invasive aspergillosis: a favourable response in 60%; more successful as a primary than salvage therapy; trends toward higher favorable responses in IPA than extrapulmonary invasive aspergillosis and in neutropenic patients Studies do not support the combination of voriconazole with amphotericin B (antagonistic effect) Well designed, large-scale randomized controlled trials needed to determine antifungal combinations’ usefulness Duration of antifungal treatment Duration of treatment not well defined Individualization of treatment duration according to clinical/radiological (usually CT) evolution Generally: For nonneutropenic patients a minimum of 6-12 weeks of treatment; longer for neutropenic patients (should be continued throughout the period of immunosuppression and until lesions resolve) In cases of antifungal combinations: one of the drugs to be withdrawn when clinical situation improves and (reversible) risk factors no longer present (mainly steroids or neutropenia) If possible, when clinical situation improves (critical illness diminished) and (reversible) risk factors no longer present, switch to oral form Resolution of galactomannan antigenemia to a normal level is not sufficient as a sole criterion for discontinuation of antifungal therapy (IDSA B-III) ATS, American Thoracic Society; ECIL, European Conference on Infections in Leukemia; IDSA, Infectious Diseases Society of America; IFI, invasive fungal infections; IPA, invasive pulmonary aspergillosis.

worse. In a series of 10 cases of cerebral aspergillosis, following pulmonary involvement, observed mortality rates were 90% [72]. IPA not only carries a poor prognosis, but it is also associated with considerable morbidity and healthcare costs. Invasive aspergillosis has been reported to increase the ICU length of stay (LOS) by 12 days, the duration of mechanical ventilation by 9 days and the overall hospital LOS by 10 days (increase ranging from 3 to 16 days depending on the underlying disease) [71,73]. A large retrospective cohort of U.S. hospitals that included 1603 patients with aspergillosis reported a median hospital cost of $52 803 [74]. Interestingly, intravenous antifungals accounted for only 7.2% of aspergillosis-related hospitalization cost, and the initial antifungal choice was not independently associated with crude mortality. Notwithstanding, initial treatment with voriconazole was associated with reduced total hospitalization costs and hospital LOS, whereas treatment with amphotericin B lipid complex or caspofungin was also independently associated with a reduced LOS in hospital [74]. Another study of invasive aspergillosis patients without the ‘classic’ risk factors reported in-hospital mortality of 46%, mean hospital and ICU LOS of 26.9 and 15.8 days, respectively, and the total hospital cost was $76 235 per patient, with the majority of the cost related to room and board [5 ]. Each 1 day delay in starting antifungal therapy was associated with 1.28 days longer hospital stay and 3.5% increase in costs [5 ]. Also, patients who received fluconazole as initial treatment compared with those who received voriconazole had an average increased LOS by 6 days and a 33% increase in hospital costs [5 ]. &&

&&

&&

CONCLUSION IPA has been increasingly recognized as an emerging opportunistic infection in critically ill patients. Putative IPA is a recently established diagnostic category following a diagnostic algorithm for critically ill patients with Aspergilluspositive LRT samples. Timely diagnosis and prompt administration of appropriate antifungal treatment may improve the unacceptably high mortality of IPA. Future research is warranted to improve the speed and accuracy of noninvasive diagnostic techniques and to optimize the dosing regimens. Acknowledgements None. Conflicts of interest D.K. has no competing interests. J.G.-M. received speaker fees from MSD and Astellas. S.B. has received grant support from Pfizer and received speaker fees from Pfizer and Gilead.

REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Marr KA, Patterson T, Denning D. Aspergillosis. Pathogenesis, clinical manifestations, and therapy. Infect Dis Clin North Am 2002; 16:875– 894. 2. Blot S, Koulenti D, Dimopoulos G. Invasive pulmonary aspergillosis && in critically ill patients. In: Jean-Louis V, editor. Annual update in intensive care and emergency medicine. Springer Berlin Heidelberg; 2013; 63–75. A comprehensive review on the current epidemiology, diagnosis, and treatment options for IPA in the ICU setting.



181


Respiratory infections 3. Garnacho-Montero J, Olaechea P, Alvarez-Lerma F, et al. Epidemiology, diagnosis and treatment of fungal respiratory infections in the critically ill patient. Rev Esp Quimioter 2013; 26:173–188. Practical recommendation based on the clinical evidence or expert opinions elaborated by The Spanish Society of Chemotherapy and The Spanish Society of Intensive Care and Coronary Units. 4. Vandewoude K, Vogelaers D, Blot S. Aspergillosis in the ICU – the new 21st century problem. Med Mycol 2006; 44:71–76. 5. Baddley JW, Stephens JM, Ji X, et al. Aspergillosis in intensive care unit (ICU) && patients: epidemiology and economic outcomes. BMC Infect Dis 2013; 13:29. A large retrospective cohort study that included 6424 patients with aspergillosis (excluding patients with classic host risk factors) from a U.S. hospital administrative database (2005–2008) and described epidemiology, antifungal treatment, and economic outcome of ICU patients with aspergillosis. 6. Meersseman W, Vandecasteele SJ, Wilmer A, et al. Invasive aspergillosis in critically ill patients without malignancy. Am J Respir Crit Care Med 2004; 170:621–625. 7. Vandewoude KH, Blot SI, Depuydt P, et al. Clinical relevance of Aspergillus isolation from respiratory tract samples in critically ill patients. Crit Care 2006; 10:R31. 8. Garnacho-Montero J, Amaya-Villar R, Ortiz-Leyba C, et al. Isolation of Aspergillus spp. from the respiratory tract in critically ill patients: risk factors, clinical presentation and outcome. Crit Care 2005; 9:R191–R199. 9. Meersseman W, Lagrou K, Maertens J, Van Wijngaerden E. Invasive aspergillosis in the intensive care unit. Clin Infect Dis 2007; 45:205–216. 10. Bassetti M, Mikulska M, Repetto E, et al. Invasive pulmonary aspergillosis in intensive care units: is it a real problem? J Hosp Infect 2010; 74:186–187. 11. Ascioglu S, Rex JH, de Pauw B, et al. Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus. Clin Infect Dis 2002; 34: 7–14. 12. De Pauw B, Walsh TJ, Donnelly JP, et al. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/ MSG) Consensus Group. Clin Infect Dis 2008; 46:1813–1821. 13. Vandewoude K, Blot S, Benoit D, et al. Invasive aspergillosis in critically ill patients: analysis of risk factors for acquisition and mortality. Acta Clin Belg 2004; 59:251–257. 14. Hartemink KJ, Paul MA, Spijkstra JJ, et al. Immunoparalysis as a cause for invasive aspergillosis? Intensive Care Med 2003; 29:2068–2071. 15. Blot S, Rello J, Dimopoulos G, et al. Risk factors and outcome in critically ill patients with invasive pulmonary aspergillosis [abstract]. Abstracts of the Interscience Conference on Antimicrobial Agents and Chemotherapy American Society for Microbiology, San Francisco 2012; abstr. K-951. 16. Blot SI, Taccone FS, Van den Abeele AM, et al. A clinical algorithm to && diagnose invasive pulmonary aspergillosis in critically ill patients. Am J Respir Crit Care Med 2012; 186:56–64. A large international multicenter study of ICU patients with IPA that validated a previously created algorithm [7] for the diagnosis of IPA in ICU patients and concluded that the algorithm achieved a 32% higher diagnosis rate and probably encompasses a larger proportion of the true IPA burden in the ICUs. 17. Bulpa P, Dive A, Sibille Y. Invasive pulmonary aspergillosis in patients with chronic obstructive pulmonary disease. Eur Respir J 2007; 30:782–800. 18. Tutar N, Metan G, Koç A, et al. Invasive pulmonary aspergillosis in patients & with chronic obstructive pulmonary disease. Multidiscip Respir Med 2013; 8:59. A single-center retrospective study that included patients with positive LRT culture for Aspergillus, which aimed to investigate the clinical and demographic features of IPA patients with COPD. 19. He HY, Chang S, Ding L, et al. Significance of Aspergillus spp. isolation from & lower respiratory tract samples for the diagnosis and prognosis of invasive pulmonary aspergillosis in chronic obstructive pulmonary disease. Chin Med J (Engl) 2012; 125:2973–2978. A single-center large study that aimed to investigate the significance of Aspergillus isolation from LRT samples for the diagnosis and prognosis of IPA in the COPD population. 20. Barberan J, Sanz F, Hernandez JL, et al. Clinical features of invasive pulmonary & aspergillosis vs. colonization in COPD patients distributed by GOLD stage. J Infect 2012; 65:447–452. A retrospective study that aimed to explore the clinical features of IPA vs. colonization among hospitalized COPD patients. 21. Xu H, Li L, Huang WJ, et al. Invasive pulmonary aspergillosis in patients with && chronic obstructive pulmonary disease: a case control study from China. Clin Microbiol Infect 2012; 18:403–408. A hospital-based, retrospective, case–control study of 30 COPD patients with IPA and 60 COPD control patients without IPA that concluded that the possibility of IPA should be considered in COPD patients with obvious dyspnea, antibioticresistant LRT infection, and repeated detection of Aspergillus in sputum. 22. Guinea J, Torres-Narbona M, Gijon P, et al. Pulmonary aspergillosis in patients with chronic obstructive pulmonary disease: incidence, risk factors, and outcome. Clin Microbiol Infect 2010; 16:870–877. &&

182


23. Li D, Chen L, Ding X, et al. Hospital-acquired invasive pulmonary aspergillosis in patients with hepatic failure. BMC Gastroenterol 2008; 8:32. 24. Prodanovic H, Cracco C, Massard J, et al. Invasive pulmonary aspergillosis in patients with decompensated cirrhosis: case series. BMC Gastroenterol 2007; 7:2. 25. Gustot T, Maillart E, Bocci M, et al. Invasive aspergillosis in patients with && severe alcoholic hepatitis. J Hepatol 2014; 60:267–274. A prospective single-center study that included 94 biopsy-proven severe alcoholic hepatitis episodes, including 15 patients who developed IPA, which concluded that invasive aspergillosis is a frequent complication of alcoholic hepatitis and advocated systematic screening for invasive aspergillosis in this patient group. 26. Chen J, Yang Q, Huang J, Li L. Risk factors for invasive pulmonary & aspergillosis and hospital mortality in acute-on-chronic liver failure patients: a retrospective-cohort study. Int J Med Sci 2013; 10:1625–1631. A large, single-center retrospective study that included 787 patients with acute-onchronic-liver failure including 39 patients who developed IPA, which aimed to identify the clinical characteristics and risk factors for IPA in this patient group. 27. Vonberg RP, Gastmeier P. Nosocomial aspergillosis in outbreak settings. J Hosp Infect 2006; 63:246–254. 28. Boff C, Zoppas BC, Aquino VR, et al. The indoor air as a potential determinant & of the frequency of invasive aspergillosis in the intensive care. Mycoses 2013; 56:527–531. A prospective 2-year study in three ICUs that attempted to correlate the indoor air fungal burden with the frequency of Aspergillus spp. isolation from the samples of ICU patients. 29. Wauters J, Baar I, Meersseman P, et al. Invasive pulmonary aspergillosis is a & frequent complication of critically ill H1N1 patients: a retrospective study. Intensive Care Med 2012; 38:1761–1768. A retrospective study of 40 ICU patients with confirmed H1N1, which reported that IPA was diagnosed in 23% of the cases and suggested the need of increased awareness for IPA in this patients’ group, especially those receiving corticosteroids in the week prior to ICU admission. 30. Garcia X, Mian A, Mendiratta P, et al. Aspergillus infection and extracorporeal & membrane oxygenation support. J Intensive Care Med 2013; 28:178–184. A case report and retrospective analysis of Extracorporeal Life Support Organization (ELSO) registry data, which reported that Aspergillus infection among ECMO-supported patients occurs often in hosts who do not have known immunodeficiencies. 31. Robinett KS, Weiler B, Verceles AC. Invasive aspergillosis masquerading as & catastrophic antiphospholipid syndrome. Am J Crit Care 2013; 22:448–451. A case report illustrating that invasive aspergillosis is a frequently missed diagnosis. 32. Maertens J, Theunissen K, Verbeken E, et al. Prospective clinical evaluation of lower cut-offs for galactomannan detection in adult neutropenic cancer patients and haematological stem cell transplant recipients. Br J Haematol 2004; 126:852–860. 33. Nivoix Y, Velten M, Letscher-Bru V, et al. Factors associated with overall and attributable mortality in invasive aspergillosis. Clin Infect Dis 2008; 47:1176– 1184. 34. Blot S, Charles PE. Fungal sepsis in the ICU: are we doing better? – Trends in && incidence, diagnosis, and outcome. Minerva Anestesiol 2013; 79:1396–1405. An update on the current diagnosis and treatment of fungal sepsis in critically ill patients. 35. Dai Z, Zhao H, Cai S, et al. Invasive pulmonary aspergillosis in nonneutropenic & patients with and without underlying disease: a single-centre retrospective analysis of 52 subjects. Respirology 2013; 18:323–331. A single-center retrospective study of 52 nonneutropenic patients with proven and probable IPA that aimed to explore the clinical differences between nonneutropenic patients with and without underlying disease. 36. Barberan J, Alcazar B, Malmierca E, et al., ASP Investigator Group. Repeated && Aspergillus isolation in respiratory samples from nonimmunocompromised patients not selected based on clinical diagnoses: colonisation or infection? BMC Infect Dis 2012; 12:295. A large, multicenter retrospective study of 29 Spanish hospitals, which included patients with at least 2 respiratory cultures yielding Aspergillus, aimed to explore the implications for the patients’ management of the repeated isolation of Aspergillus in the LRT. 37. Cuenca-Estrella M. Diagno´stico de laboratorio de la enfermedad fuńgica & invasora. Enferm Infecc Microbiol Clin 2012; 30:257–264. A review about the diagnosis of invasive fungal disease, including invasive aspergillosis. 38. Ostrosky-Zeichner L. Invasive mycoses: diagnostic challenges. Am J Med && 2012; 125:S14–S24. An update of the diagnostic techniques available for the diagnosis of invasive fungal infections. 39. Pemań J, Zaragoza R. Combined use of nonculture-based lab techniques in & the diagnosis and management of critically ill patients with invasive fungal infections. Expert Rev Anti Infect Ther 2012; 10:1321–1330. An excellent review about nonculture-based assays for the diagnosis of invasive fungal diseases and their applicability for the management of these infections. 40. He H, Ding L, Li F, Zhan Q. Clinical features of invasive bronchial-pulmonary aspergillosis in critically ill patients with chronic obstructive respiratory diseases: a prospective study. Crit Care 2011; 15:R5.



Invasive pulmonary aspergillosis Koulenti et al. 41. Meersseman W, Lagrou K, Maertens J, Wilmer A, et al. Galactomannan in bronchoalveolar lavage fluid: a tool for diagnosing aspergillosis in intensive care unit patients. Respir Crit Care Med 2008; 1:27–34. 42. Acosta J, Catalan M, del Palacio-Pere´z-Medel A, et al. A prospective comparison of galactomannan in bronchoalveolar lavage fluid for the diagnosis of pulmonary invasive aspergillosis in medical patients under intensive care: comparison with the diagnostic performance of galactomannan and of (1!3)-b-D-glucan chromogenic assay in serum samples. Clin Microbiol Infect 2011; 17:1053–1060. 43. Ostrosky-Zeichner L, Alexander BD, Kett DH, et al. Multicenter clinical evaluation of the (1!3) beta-D-glucan assay as an aid to diagnosis of fungal infections in humans. Clin Infect Dis 2005; 41:654–659. 44. Pazos C, Ponton J, Del Palacio A. Contribution of (1!3)-beta-D-glucan chromogenic assay to diagnosis and therapeutic monitoring of invasive aspergillosis in neutropenic adult patients: a comparison with serial screening for circulating galactomannan. J Clin Microbiol 2005; 43:299–305. 45. Acosta J, Catalan M, del Palacio-Pe´rez-Medel A, et al. Prospective study in && critically ill nonneutropenic patients: diagnostic potential of (1,3)-b-D-glucan assay and circulating galactomannan for the diagnosis of invasive fungal disease. Eur J Clin Microbiol Infect Dis 2012; 31:721–731. A prospective study that assessed circulating galactomannan and b-D-glucan levels in critically ill patients at risk of invasive fungal disease and concluded that galactomannan and b-D-glucan had similar diagnostic accuracy for invasive aspergillosis and that galactomannan preceded cultures results in invasive aspergillosis. 46. De Vlieger G, Lagrou K, Maertens J, et al. Beta-D-glucan detection as a diagnostic test for invasive aspergillosis in immunocompromised critically ill patients with symptoms of respiratory infection: an autopsy-based study. J Clin Microbiol 2011; 49:3783–3787. 47. Ayats J, Martıń-Mazuelos E, Pemań J, et al. Recomendaciones sobre el diagno´stico de la enfermedad fuńgica invasora de la Sociedad Espanõla de Enfermedades Infecciosas y Microbiologıá Clıńica (SEIMC). Actualizacioń 2010. Enferm Infecc Microbiol Clin 2011; 29:39.e1–39.e-15. 48. Cui N, Wang H, Long Y, Liu D. CD8þ T-cell counts: an early predictor of risk && and mortality in critically ill immunocompromised patients with invasive pulmonary aspergillosis. Crit Care 2013; 17:R157. A study that evaluated the quantitative changes in key humoral and cellular parameters in critically ill patients with pulmonary infections, and their potential influence on the risk and prognosis of IPA. 49. Walsh TJ, Anaissie EJ, Denning DW, et al., Infectious Diseases Society of America. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis 2008; 46:327–360. 50. Limper AH, Knox KS, Sarosi GA, et al. An official American Thoracic Society Statement: Treatment of fungal infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med 2011; 183:96–128. 51. Maertens J, Marchetti O, Herbrecht R, et al. Third European Conference on Infections in Leukemia. European guidelines for antifungal management in leukemia and hematopoietic stem cell transplant recipients: summary of the ECIL 3 – 2009 update. Bone Marrow Transplant 2011; 46:709–718. 52. Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002; 347:408–415. 53. Azie N, Neofytos D, Pfaller M, et al. The PATH (Prospective Antifungal Therapy) Alliance(R) registry and invasive fungal infections: update. Diagn Microbiol Infect Dis 2012; 73:293–300. 54. Jacobs F, Selleslag D, Aoun M, et al. An observational efficacy and safety & analysis of the treatment of acute invasive aspergillosis using voriconazole. Eur J Clin Microbiol Infect Dis 2012; 31:1173–1179. An observational multicenter study that aimed to evaluate the efficacy and safety of voriconazole in patients with acute invasive aspergillosis in a real-life clinical setting. 55. Park WB, Kim NH, Kim KH, et al. The effect of therapeutic drug && monitoring on safety and efficacy of voriconazole in invasive fungal infections: a randomized controlled trial. Clin Infect Dis 2012; 55:1080–1087. A randomized trial which compared the routine TDM of voriconazole vs. fixed standard treatment concluded that the group with the TDM showed reduced drug discontinuation rates because of adverse events and improved treatment response in IFIs.

56. Cornely OA, Maertens J, Bresnik M, et al. Liposomal amphotericin B as initial therapy for invasive mold infections: a randomized trial comparing a high loading dose regimen with standard dosing (AmbiLoad Trial). Clin Infect Dis 2007; 44:1289–1297. 57. Hachem RY, Boktour MR, Hanna HA, et al. Amphotericin B lipid complex versus liposomal amphotericin monotherapy for invasive aspergillosis in patients with hematologic malignancy. Cancer 2008; 112:1282– 1287. 58. Maertens J, Raad I, Petrikkos G, et al. Efficacy and safety of caspofungin for treatment of invasive aspergillosis in patients refractory to or intolerant of conventional antifungal therapy. Clin Infect Dis 2004; 39: 1563–1571. 59. Jarque I, Tormo M, Bello JL, et al. Caspofungin for the treatment of invasive && fungal disease in hematological patients (ProCAS Study). Med Mycol 2013; 51:150–154. A multicenter, prospective, noncomparative, observational study that assessed the effectiveness and safety of caspofungin in hematological patients with IFI. 60. Garbati MA, Alasmari FA, Al-Tannir MA, Tleyjeh IM. The role of combination && antifungal therapy in the treatment of invasive aspergillosis: a systematic review. Int J Infect Dis 2012; 16:e76–e81. A systematic review (of one randomized controlled trial and seven cohort studies in hemato-oncological patients), which reported that the cumulative evidence for the use of combination therapy in invasive aspergillosis is conflicting and has moderate strength. 61. Lepak AJ, Andes DR. Antifungal PK/PD considerations in fungal pulmonary infections. Semin Respir Crit Care Med 2011; 32:783–794. 62. Lepak A, Andes D. Fungal sepsis: optimizing antifungal therapy in the critical care setting. Crit Care Clin 2011; 2:2011; 7:123–147. 63. Moriyama B, Jarosinski PF, Figg WD, et al. Pharmacokinetics of intravenous voriconazole in obese patients: implications of CYP2C19 homozygous poor metabolizer genotype. Pharmacotherapy 2013; 33:e19–e22. 64. Cornely OA, Vehreschild JJ, Vehreschild MJ, et al. Phase II dose escalation study of caspofungin for invasive aspergillosis. Antimicrob Agents Chemother 2011; 55:5798–5803. 65. Walsh TJ, Raad I, Patterson TF, et al. Treatment of invasive aspergillosis with posaconazole in patients who are refractory to or intolerant of conventional therapy: an externally controlled trial. Clin Infect Dis 2007; 44: 2–12. 66. Traunmu¨ller F, Popovic M, Konz KH, et al. Efficacy and safety of current drug therapies for invasive aspergillosis. Pharmacology 2011; 88:213– 224. 67. Singh N, Limaye AP, Forrest G, et al. Combination of voriconazole and caspofungin as primary therapy for invasive aspergillosis in solid organ transplant recipients: a prospective, multicenter, observational study. Transplantation 2006; 81:320–326. 68. Aliff TB, Maslak PG, Jurcic JG, et al. Refractory Aspergillus pneumonia in patients with acute leukemia: successful therapy with combination caspofungin and liposomal amphotericin. Cancer 2003; 97:1025–1032. 69. Kontoyiannis DP, Hachem R, Lewis RE, et al. Efficacy and toxicity of caspofungin in combination with liposomal amphotericin B as primary or salvage treatment of invasive aspergillosis in patients with hematologic malignancies. Cancer 2003; 98:292–299. 70. Janssen JJ, Strack van Schijndel RJ, van der Poest Clement EH, et al. Outcome of ICU treatment in invasive aspergillosis. Intensive Care Med 1996; 22:1315–1322. 71. Vandewoude KH, Blot SI, Benoit D, et al. Invasive aspergillosis in critically ill patients: attributable mortality and excesses in length of ICU stay and ventilator dependence. J Hosp Infect 2004; 56:269–276. 72. Spapen H, Spapen J, Taccone FS, et al. Cerebral aspergillosis in adult critically ill patients: a descriptive report of 10 patients from the AspICU cohort. Int J Antimicrob Agents 2014; 43:165–169. 73. Tong KB, Lau CJ, Murtagh K, et al. The economic impact of aspergillosis: analysis of hospital expenditures across patient subgroups. Int J Infect Dis 2009; 13:24–36. 74. Kim A, Nicolau DP, Kuti JL. Hospital costs and outcomes among intravenous antifungal therapies for patients with invasive aspergillosis in the United States. Mycoses 2011; 54:e301–e312.



183


What's new in invasive pulmonary aspergillosis in the critically ill.

The role of galactomannan testing to diagnose invasive pulmonary aspergillosis in critically ill patients.

Our 2015 approach to invasive pulmonary aspergillosis.

Putative invasive pulmonary aspergillosis in critically ill patients with chronic obstructive pulmonary disease: a matched cohort study.

Clinical diagnosis of invasive pulmonary aspergillosis in a non-neutropenic critically ill patient.

Epidemiology of invasive aspergillosis in critically ill patients: clinical presentation, underlying conditions, and outcomes.

Invasive pulmonary aspergillosis in non-immunocompromised patients.

Invasive pulmonary aspergillosis in non-immunocompromised patients.

[Invasive pulmonary aspergillosis in patients with chronic obstructive pulmonary disease].

Invasive pulmonary aspergillosis in patients with chronic obstructive pulmonary disease.

Pulmonary arterial hypertension in critically ill elderly patients.

Invasive aspergillosis in immunosuppressed patients.

Glutamine supplementation to critically ill patients?

Tracheoesophageal fistula induced by invasive pulmonary aspergillosis.

Invasive pulmonary aspergillosis with pneumopericardium and pneumothorax.

Hyponatremia in critically ill patients.

Sedation in critically ill patients.

Host biomarkers of invasive pulmonary aspergillosis to monitor therapeutic response.

Comparative Effectiveness of Noninvasive and Invasive Ventilation in Critically Ill Patients With Acute Exacerbation of Chronic Obstructive Pulmonary Disease.

Early diagnosis of invasive pulmonary aspergillosis in hematologic patients: an opportunity to improve the outcome.

Has Stewart approach improved our ability to diagnose acid-base disorders in critically ill patients?

A simplified lung ultrasound approach to detect increased extravascular lung water in critically ill patients.

Intubation of critically ill patients.

Cerebral aspergillosis in adult critically ill patients: a descriptive report of 10 patients from the AspICU cohort.