Download Fungal lung infections in critically ill patients

Fungal lung infections in critically ill patients
Prof. Dr. Stijn Blot
Dept. of Internal Medicine
Faculty of Medicine & Health Sciences
Ghent University
De Pintelaan 185
9000 Ghent
BELGIUM
Burns, Trauma & Critical Care Research Centre
The University of Queensland, Brisbane, Queensland
AUSTRALIA
[email protected]
AIMS
At the conclusion of this activity, learner will have insights in
 Criteria and categories for diagnosing invasive fungal disease in severely
immunocompromized hosts
 Risk profile for invasive pulmonary aspergillosis (IPA) in immunocompetent ICU patients
 Approach to diagnose IPA in ICU patients, including discrimination of Aspergillus
colonization from IPA
 Therapeutic options for IPA
SUMMARY
Introduction
Most frequently isolated fungal pathogens in ICU patients are Candida spp. and Aspergillus spp., with
Candida being much more involved in critical illness. While Aspergillus is mostly isolated from
respiratory tract samples, Candida is frequently cultured from urinary tract samples, intra-abdominal
drains, wounds, as well as the respiratory tract, especially in mechanically ventilated patients with
exposure to antibiotics. In contrast with Aspergillus of which >90% of isolates are cultured from the
lung, Candida spp isolated from the respiratory tract are only rarely pathogenic and therefore of minor
clinical relevance. Suggested reading includes the following references: [1-5]. For that reason the
accent of this course will be on invasive pulmonary aspergillosis (IPA).
Aspergillus spp.
Aspergillus is a filamentous fungus and widespread in the environment. Over 90% of the nosocomial
aspergillosis cases are caused A. fumigatus [6]. The mechanism of pathogenesis is through the
inhalation of conidia that may be followed by haematogenous spread. As such, Aspergillus may affect
any organ system, albeit that the lung is responsible for >90% of all cases of invasive aspergillosis.
Also in case of disseminated aspergillosis, the lung is often among the affected organs [7, 8].
Incidence of invasive pulmonary aspergillosis
Studies reporting on the incidence of IPA and invasive aspergillosis are scarce but in general rates
range from 1% to 6.5%. These numbers should be interpreted cautiously as estimates are biased due
to the problematic diagnosis and very case-mix depending [9-11].
Outcomes
IPA in ICU patients is associated with very mortality ranging 70-95%, and an attributable mortality of
about 20% [9, 12-14]. The disease is absolutely lethal if left untreated. In non-ICU patients, diagnosis
at an early stage of the disease and prompt initiation of appropriate antifungal therapy is associated
with improved outcomes [15].
Risk profile for IPA
Classic risk factors for IPA include those reflecting profound immunodeficiency as defined by the
EORTC/MSG and generally called ‘host factors’ (i.e. allogeneic BMT, neutropenia, prolonged
corticosteroid therapy, therapy with T cell immunosuppressants, and inherited immunodeficiency). In
the past 15 years the spectrum of recognized risk factors has been enlarged beyond these classic host
factors. In ICUs, the patient at risk for IPA can be characterized by (i) being mechanically ventilated,
(ii) a high severity of acute illness with substantial organ derangements, (iii) sepsis and or respiratory
distress, and (iv) underlying conditions including but limited to liver cirrhosis, COPD, and renal
failure [16, 17].
Aspergillus-positive endotracheal aspirates… What does it mean?
The finding of an Aspergillus-positive ETA initiates a clinical dilemma. Very often the diagnostic
criteria as defined by the EORTC/MSG cannot help to discriminate IPA from Aspergillus colonization
as the diagnosis of proven IPA requires positive histopathological findings. Besides the Aspergilluspositive culture, the diagnosis of probable IPA additionally requires host factors and medical imaging
findings on CT scan that are very suggestive for invasive fungal disease (i.e. (i) dense, wellcircumscribed lesions +/- halo sign, (ii) air-crescent sign, or (iii) cavitation). Unfortunately such
findings are rarely observed in mechanically ventilated patients. Furthermore the diagnosis of possible
IPA according to the EORTC/MSG criteria is based on a combination of host factors and medical
imaging, and as such of no use to discriminate colonization from IPA.
A clinical algorithm can be used to distinguish colonization from IPA. A diagnosis of putative IPA is
achieved when the Aspergillus-positive ETA sample (=entry criterion) is additionally accompanied by
(i) compatible signs and symptoms, (ii) any radiologic abnormality either on chest x-ray or CT-scan,
and (iii) either (iiia) the presence of a host factor or (iiib) a BAL fluid positive on culture and
cytological examination (branching hyphae)[11]. If one of the additional criteria is not fulfilled, the
case is considered Aspergillus colonization. This algorithm demonstrated favorable operating
characteristics and allows detecting a broader proportion of the true burden of disease compared with
the EORTC/MSG diagnostic criteria [18].
IPA in the absence of Aspergillus-positive respiratory tract cultures.
A main limitation of the clinical algorithm is that it requires an Aspergillus-positive culture as entry
criterion. IPA might occur in the absence of positive cultures [19]. This is probably the main reason
why invasive aspergillosis is frequently found as a missed diagnosis in autopsy series in ICU patients
[20, 21]. Galactomannan antigen detection on serum is a standard approach to diagnose invasive
aspergillosis in neutropenic patients. However, the antigen is cleared by circulating neutrophils and as
such of little value in non-neutropenic critically ill patients. Galactomannan detection on BAL fluid
however appeared to have strong operating characteristics to diagnose IPA in ICU patients [19]. A
recent study successfully demonstrated that the clinical algorithm works equally well when the entry
criterion (Aspergillus-positive culture) is replaced by a positive galactomannan test on BAL fluid
[22]. The challenge is to organize the laboratory for frequent galactomannan detection analyses and to
identify the patients at risk for IPA (preferably at an early stage) that might benefit from (regular)
BAL procedures. Recently a lateral-flow device test has been developed to diagnose IPA [23]. The
test is easily executed (no need for BAL fluid pre-treatment) and the result is rapidly ready (10-15
min.). In ICU patients this test demonstrated to have a high negative predictive value while the
positive predictive value was moderate.
To treat or not treat?
A proven diagnosis is difficult to achieve in a critically ill patient and if so, in many cases too late to
secure a favorable outcome. In order to keep a realistic chance for survival it seems crucial to start
appropriate antifungal therapy at an early stage, i.e. when there exists a “substantial degree of
suspicion for IPA”. Therefore, the clinician should balance the following elements that contribute to a
reasonable degree of diagnostic certainty:

Risk profile
o ICU patients at risk IPA are on mechanical ventilation and experience severe acute
illness as evidence by organ failure.
Severe respiratory distress and sepsis are very common admission diagnoses.
In case the patient has presence of host factors (i.e. being severely
immunocompromized) the risk profile for invasive fungal disease is obvious.
Very often the patients has one or more severe underlying conditions such as severe
liver cirrhosis, COPD, or chronic renal insufficiency.

Medical imaging
o
o

Any abnormality on medical imaging (either on chest x-ray or CT scan) may hide
Aspergillus involvement.
In case medical imaging reveals robust sings of invasive fungal disease (cf. the
EORTC/MSG ‘clinical features’) appropriate antifungal therapy must be considered.
Mycology
o
o
o
o
Galactomannan antigen detection on BAL fluid is a strong indicator for IPA in nonneutropenic patients (cut-off value OD ≥0.5).
Aspergillus-positive respiratory tract cultures are equivocal but should never be
discarded. Especially, repeatedly positive cultures should awake suspicion for
invasive disease.
Also a cytological smear demonstrating fungal elements might be an important sign,
particularly with branching hyphae as this is an indication for tissue invasion.
Finally a positive lateral-flow test also contributes to the diagnosis of IPA.
Antifungal agents
Voriconazole is the drug of choice for IPA [24]. The drug is preferably administered intravenously as
absorption might be disturbed due to critical illness [25]. Monitoring of the renal function is
recommended as the IV vehicle (SBECD) may accumulate. In case of moderate hepatic insufficiency
(Child Pugh A & B) the maintenance dose can be halved (use identical loading dose). In case of
severe liver cirrhosis the benefits of the drug must outweigh the risks. Substantial pharmacokinetic
variability with voriconazole is observed. Therefore, therapeutic drug monitoring (TDM) is
recommended in order to ensure adequate drug concentrations. The use of TDM for voriconazole has
been associated with improved efficacy and outcomes in non-ICU patients [26].
Alternatives for voriconazole include lipid-associated amphotericin B, caspofungin, micafungin, and
posaconazole. Combination therapy can be considered for salvage therapy.
REFERENCES
1. el-Ebiary M, Torres A, Fàbregas N, la Bellacasa de JP, González J, Ramirez J, del Baño D,
Hernández C, Jiménez de Anta MT. Significance of the isolation of Candida species from
respiratory samples in critically ill, non-neutropenic patients. An immediate postmortem
histologic study. Am. J. Respir. Crit. Care Med.; 1997; 156: 583–590.
2. Krause R, Halwachs B, Thallinger GG, Klymiuk I, Gorkiewicz G, Hoenigl M, Prattes J,
Valentin T, Heidrich K, Buzina W, Salzer HJF, Rabensteiner J, Prüller F, Raggam RB,
Meinitzer A, Moissl-Eichinger C, Högenauer C, Quehenberger F, Kashofer K, ZollnerSchwetz I. Characterisation of Candida within the Mycobiome/Microbiome of the Lower
Respiratory Tract of ICU Patients. Jacobsen ID, editor. PLoS ONE; 2016; 11: e0155033.
3. Terraneo S, Ferrer M, Martin-Loeches I, Esperatti M, Di Pasquale M, Giunta V, Rinaudo M,
de Rosa F, Li Bassi G, Centanni S, Torres A. Impact of Candida spp. isolation in the
respiratory tract in patients with intensive care unit-acquired pneumonia. Clin. Microbiol.
Infect. 2016; 22: 94.e1–.e8.
4. Meersseman W, Lagrou K, Spriet I, Maertens J, Verbeken E, Peetermans WE, Van
Wijngaerden E. Significance of the isolation of Candida species from airway samples in
critically ill patients: a prospective, autopsy study. Intensive Care Med; 2009; 35: 1526–1531.
5. Blot S, Dimopoulos G, Rello J, Vogelaers D. Is Candida really a threat in the ICU? Curr Opin
Crit Care 2008; 14: 600–604.
6. Kosmidis C, Denning DW. The clinical spectrum of pulmonary aspergillosis. Thorax; 2014; :
thoraxjnl–2014–206291.
7. Spapen H, Spapen J, Taccone FS, Meersseman W, Rello J, Dimopoulos G, Charles P-E, Rao
R, Pérez M, Martin C, Vogelaers D, Blot SI, AspICU Study Investigators. 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.
8. Koulenti D, Garnacho-Montero J, Blot S. Approach to invasive pulmonary aspergillosis in
critically ill patients. Curr. Opin. Infect. Dis. 2014; 27: 174–183.
9. Meersseman W, Vandecasteele SJ, Wilmer A, Verbeken E, Peetermans WE, Van
Wijngaerden E. Invasive aspergillosis in critically ill patients without malignancy. Am. J.
Respir. Crit. Care Med. 2004; 170: 621–625.
10. Garnacho-Montero J, Amaya-Villar R, Ortiz-Leyba C, León C, Alvarez-Lerma F, Nolla-Salas
J, Iruretagoyena JR, Barcenilla F. Isolation of Aspergillus spp. from the respiratory tract in
critically ill patients: risk factors, clinical presentation and outcome. Crit Care; 2005; 9:
R191–R199.
11. Vandewoude KH, Blot SI, Depuydt P, Benoit D, Temmerman W, Colardyn F, Vogelaers D.
Clinical relevance of Aspergillus isolation from respiratory tract samples in critically ill
patients. Crit Care 2006; 10: R31.
12. Vandewoude K, Blot S, Benoit D, Depuydt P, Vogelaers D, Colardyn F. Invasive
aspergillosis in critically ill patients: analysis of risk factors for acquisition and mortality.
Acta Clin Belg; 2004; 59: 251–257.
13. Vandewoude KH, Blot SI, Benoit D, Colardyn F, Vogelaers D. 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.
14. Janssen JJ, Strack van Schijndel RJ, van der Poest Clement EH, Ossenkoppele GJ, Thijs LG,
Huijgens PC. Outcome of ICU treatment in invasive aspergillosis. Intensive Care Med 1996;
22: 1315–1322.
15. Nivoix Y, Velten M, Letscher-Bru V, Moghaddam A, Natarajan-Amé S, Fohrer C, Lioure B,
Bilger K, Lutun P, Marcellin L, Launoy A, Freys G, Bergerat J-P, Herbrecht R. Factors
associated with overall and attributable mortality in invasive aspergillosis. Clin. Infect. Dis.;
2008; 47: 1176–1184.
16. Koulenti D, Vogelaers D, Blot S. What's new in invasive pulmonary aspergillosis in the
critically ill. Intensive Care Med; 2014; 40: 723–726.
17. Meersseman W, Lagrou K, Maertens J, Van Wijngaerden E. Invasive aspergillosis in the
intensive care unit. Clin. Infect. Dis.; 2007; 45: 205–216.
18. Blot SI, Taccone FS, Van den Abeele A-M, Bulpa P, Meersseman W, Brusselaers N,
Dimopoulos G, Paiva JA, Misset B, Rello J, Vandewoude K, Vogelaers D, AspICU Study
Investigators. A clinical algorithm to diagnose invasive pulmonary aspergillosis in critically
ill patients. Am. J. Respir. Crit. Care Med. 2012; 186: 56–64.
19. Meersseman W, Lagrou K, Maertens J, Wilmer A, Hermans G, Vanderschueren S, Spriet I,
Verbeken E, Van Wijngaerden E. Galactomannan in bronchoalveolar lavage fluid: a tool for
diagnosing aspergillosis in intensive care unit patients. Am. J. Respir. Crit. Care Med.; 2008;
177: 27–34.
20. Khawaja O, Khalil M, Zmeili O, Soubani AO. Major discrepancies between clinical and
postmortem diagnoses in critically ill cancer patients: Is autopsy still useful? Avicenna J Med;
2013; 3: 63–67.
21. Tejerina E, Esteban A, Fernández-Segoviano P, María Rodríguez-Barbero J, Gordo F, FrutosVivar F, Aramburu J, Algaba A, Gonzalo Salcedo García O, Lorente JA. Clinical diagnoses
and autopsy findings: discrepancies in critically ill patients*. Crit. Care Med. 2012; 40: 842–
846.
22. Schroeder M, Simon M, Katchanov J, Wijaya C, Rohde H, Christner M, Laqmani A,
Wichmann D, Fuhrmann V, Kluge S. Does galactomannan testing increase diagnostic
accuracy for IPA in the ICU? A prospective observational study. Crit Care; 2016; 20: 139.
23. Eigl S, Prattes J, Lackner M, Willinger B, Spiess B, Reinwald M, Selitsch B, Meilinger M,
Neumeister P, Reischies F, Wölfler A, Raggam RB, Flick H, Eschertzhuber S, Krause R,
Buchheidt D, Thornton CR, Lass-Florl C, Hoenigl M. Multicenter evaluation of a lateral-flow
device test for diagnosing invasive pulmonary aspergillosis in ICU patients. Crit Care; 2015;
19: 178.
24. Walsh TJ, Anaissie EJ, Denning DW, Herbrecht R, Kontoyiannis DP, Marr KA, Morrison
VA, Segal BH, Steinbach WJ, Stevens DA, van Burik J-A, Wingard JR, Patterson TF,
Infectious Diseases Society of America. Treatment of aspergillosis: clinical practice
guidelines of the Infectious Diseases Society of America. Clin. Infect. Dis.; 2008. p. 327–360.
25. Blot SI, Pea F, Lipman J. The effect of pathophysiology on pharmacokinetics in the critically
ill patient--concepts appraised by the example of antimicrobial agents. Adv. Drug Deliv. Rev.
2014; 77: 3–11.
26. Pascual A, Calandra T, Bolay S, Buclin T, Bille J, Marchetti O. Voriconazole therapeutic
drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes.
Clin. Infect. Dis.; 2008; 46: 201–211.