1. Invasive Aspergillosis in Critically Ill Patients A New 21th Century Problem?
Koenraad Vandewoude, MD
Intensive Care Dpt. – Solid Organ Transplant Centre
Ghent University Hospital
Ghent, Belgium

2. Invasive Aspergillosis
Extensive data available in distinct high-risk patient populations:
Hemato-oncological patients
Allogeneic SCT, graft-vs.-host disease
Persistant neutropenia
Solid organ transplant patients, >> lung
Immunosuppressive therapy
Chronic granulomatous disease
Severe combined immunodeficiency
HIV …

3. Aspergillus spp. Underestimated Pathogen in the ICU?
Epidemiological data on incidence and outcome of Invasive Aspergillosis in Critically Ill patients are scarce …
Low index of suspicion
Positive cultures often discarded as colonization or contamination
Absence of feasible diagnostic reference standard
Now, the question addressed in this lecture, is whether Aspergillus is an underestimated pathogen in critically ill patients?
What we know for sure, is that reliable data on the incidence of invasive aspergillosis in this setting are scarce.
Several factors may explain this lack of data.
First, the index of suspicion of this opportunistic infection is still low amongst critical care practioners. Respiratory tract samples positive for Aspergillus are often discarded as colonization or contamination, and are not taken into account for treatment.
Moreover, in contrast to immunocompromised host, there is no feasible and reliable diagnostic reference standard.
And finally, in order to have a good estimate of incidence of this disease, a per protocol necropsy policy is necessary in patients dying with unexplained pneumonia.

4. Invasive Pulmonary Aspergillosis in Critically Ill patients
Differentiate between
Pts referred to the ICU with IPA
e.g. pt. from Bone Marrow Transplant Unit with proven/probable IPA and respiratory failure
100% mortality? 1
Pts. with IPA diagnosed in the ICU
community acquired
nosocomial
ICU acquired
grim prognosis 2
Of course, one should make a difference between patients, admitted to the ICU, referred from the bone marrow transplant unit with an established diagnosis of aspergillosis. It is known that when such a patient develops respiratory insufficiency, death is impending, and mortality is nearly 100%.
On the other hand, there are group of critically ill patients, in whom the diagnosis of invasive pulmonary aspergillosis is made during their ICU stay. They may have acquired the disease in the community, or during there stay in other wards of the hospital, including in the intensive care; studies about health care associated pneumonia have demonstrated that also in this group of patients, the outcome of nosocomially acquired IA is very poor, with a mortality of about 80%.
Janssen JJ. Outcome of ICU treatment in Invasive Aspergillosis. Intens Care Med 1996; 22:
Vallés J. A 7 year Study of Severe Hospital Acquired Pneumonia requiring ICU Admission. Intens Care Med 2003; 29:

5. Pulmonary Aspergillosis A Spectrum of Clinical Entities
Depending on patient immune status
With tissue invasion 1,2
Acute invasive aspergillosis
Subacute invasive aspergillosis
Chronic cavitary and fibrosing pleuropulmonary aspergillosis
Acute Tracheobronchitis with tissue invasion
Without tissue invasion
Tracheobronchial colonization
Tracheobronchitis
Pulmonary Aspergilloma
The term invasive aspergillosis, refers to several categories of disease; the severity of disease is mainly dependent upon the host immune defence.
Aspergillosis may present as an acute pneumonia, with hefty tissue invasion, leading to demise in 7 to 10 days, even when treated appropriately. However, there also exist more indolent forms of aspergillosis, that evolve over weeks and even months, and that are accompanied with less or more severe systemic and respiratory signs and symptoms.
A special entity of invasive pulmonary aspergillosis is acute invasive aspergillus tracheobronchitis. This form of the disease is chararacterized by ulcerative lesions in the tracheobronchial tree, and by the formations of membranes – these membranes may ultimately obstruct the airways, leading to respiratory insufficiency; most patients have severe bronchoconstriction, and mechanical ventilation is very difficult with high ventilatory pressures.
On the other end of the disease spectrum, are entities without evidence of tissue invasion: such as innocent colonization of the airways (frequently seen in COPD patients and smokers, non invasive bronchits, and the pulmonary aspergilloma, developing in a pre-existing cavity, with the development of hyphae in that cavity, but without evidence of tissue invasion.
Clinical entity may change due immune defence alteration
1 Denning DW.
Chronic cavitary and fibrosing pulmonary and pleural aspergillosis. Clin Infect Dis 2003
2 Paterson DL.
New clinical presentations of invasive pulmonary aspergillosis in non-conventional hosts. Clin Microbiol Infect 2004

6. IPA diagnosis in ICU patients
EORTC/MSG Case Definitions 1
Difficult to apply outside high risk populations
Not useful to guide therapy
One of the major problems in ICU patients, is the absence of a reliable diagnostic reference frame. One can argue that is would be feasible to use the EORTC/MSG diagnostic criteria for invasive mould infections – but in fact these guidelines are not applicable outside the severely immunocompromised population; furthermore, these guidelines should not be used to guide therapy and clinical practice – if so, antifungal treatment would be instituted late in the course of the disease, or would not even be considered.
1 Ascioglu S. Defining opportunistic invasive fungal infections in immunocompromised
patients with cancer and hematopoietic stem cell transplants. Clin Infect Dis 2002

7. Consensus Definitions
Proven IPA
Histopathology + culture
Probable IPA
1 host + 1 microbiological +1 clinical
Host: neutropenia, fever, immunosuppressive therapy, steroids, GVHD
Microbiological:
positive culture sputum, BAL
Non-invasive test: galactomannan, -D-glucan
CT: halo, air-crescent, cavity within area of consolidation
Possible IPA
1 host + 1 microbiological OR 1 clinical
More specific signs / symptoms
CT: halo, air-crescent, cavity
New infiltrate + specific pulmonary: pleural rub; pleural pain; hemoptysis
The consensus definitions are well known, and are based upon host risk factors, the results of microbiological examination, and the clinical picture, including the results of medical imaging. Non-invasive markers, such as the galactomannan and glucan, and PCR, in blood or bronchial lavage fluids, can also be used to substantiate the diagnosis. Probable and possible aspergillosis are the most frequent clinical categories of diagnosis in routine practice.

8. Particular Issues in ICU patients
Interpretation of Host Factors:
not always clearly detectable …
(combination of) underlying disease and/or critical illness induced immunosuppression with low or intermediate probability of invasive disease 1, 2
Impaired phagocytic function
Organ dysfunctions, metabolic derangements
Corticosteroids 3, 4:
difficult assessment of treshold dose/duration of exposure*
However, one should consider some particular issues in the critical care setting.
Firstly, the interpretation of host factors is not evident in ICU patiens. These can be easily appreciated in patients referred by the hematology ward, but how should we appreciate the temporary immune deficiency, or immunoparalysis, that can occur after sepsis and during severe critical illness? This immunocompromised state is characterized by deficient phagocytosis, and both innate and acquired immune dysfunctions; a patient immune defence may be further weakenen by multiple organ dysfunction, and metabolic derangements, such as uremia, liver dysfunction, and hyperglycemia
Furthermore, corticosteroid therapy is frequently given to septic patients and in case of COPD exacerbations. It not clear at what dose this kind of treatment should be considered as a major host risk factor – it also known that hydrocortisone enhances the growth of Aspergillus fumigatus in vitro.
1 Hartemink KJ. Immunoparalysis as a cause for invasive aspergillosis? Intensive Care
Med 2003
2 Engelich G. Acquired disorders of phagocyte function complicating medical and surgical illnesses. Clin Infect Dis 2001
3 Lionakis M. Glucocorticoids and Invasive Fungal Infections. Lancet 2003; 362:
4 Palmer LB. Corticosteroid Treatment as a Risk Factor for Invasive Aspergillosis in Patients with Lung Disease. Thorax 1991; 46: 15-20

9. Particular Issues in ICU patients
Signs and symptoms difficult to appreciate
cough, chest pain, pleural rub, hemoptysis, dyspnea
non specific
evaluation difficult or impossible
fever?
clinical examination hampered by mechanical ventilation
A second problematic issue is the assessment of clinical signs and symptoms; in patients that are intubated and sedated. One can not rely on fever, as a warning symptom as in the setting of neutropenia; furthermore, clinical examination is hampered by the supportive treatment patients receive on the ICU.

10. Particular Issues in ICU patients
Medical Imaging:
Concurrent pulmonary injury hampers interpretation
residual infiltrates, atelectasis, ARDS, …
CT scan feasible in case of high-grade ventilatory and inotropic dependency?
Typical lesions: Halo, Air-crescent …
low incidence in non-neutropenic patients
Another problem is the value of medical imaging. There are so many confounding factors in the interpretation of radiological data, such as residual infiltrates after bacterial pneumonia, atelectasis, pleural fluid effusion, ;
Specific features such as the halo sign and the air crescent sign are infrequently seen in ICU patients, moreover it has been shown that this radiological features ar far less common in patients with other immune deficiencies than neutropenia;
Greene RA. Radiologic findings in acute invasive pulmonary aspergillosis: utility
of the halo and air-crescent sign for diagnosis and treatment of invasive pulmonary
aspergillosis in high-risk patients. 13th ECCMID, 2002, Glasgow

11. Microbiological sampling …
>> lower respiratory tract samples
BAL not always feasible
Direct microscopy is mandatory!*
Serology
Aspergillus galactomannan? **
validation in neutropenic pts
sensitive/significant in other patients
ß-glucan: ? ***
Biopsy procedures …
transbronchial biopsy not possible
thoracoscopic procedure preferred
caveats:
ventilator and pressor dependency
coagulation disorders …
The interpretation of microbiological data is also difficult.
Broncho-alveolar lavage is not always feasible
An important point is always to require for an urgent direct microscopic examination: the demonstration of septate hyphae may be a key indicator for the diagnosis.
There is a lot of experience with non-invasive diagnostics such as the galactomannan test, and the demonstration of the beta D glucan, in patients after stem cell transplantation, but the sensitivity and specificity of these test in other patient groups should be further explored.
Finally, one could argue to be more aggressive in diagnostic procedures and to have a lung tissue biopsy in case of diagnostic incertitude, however, such quite invasive procedures are often not possible in patients with high grade ventilatory and inotropic support, and in the presence of coagulation abnormalities. Moreover, biopsy can be falsely negative due to sampling error, or after exposure to antifungals.
* Uffredi ML. Significance of aspergillus fumigatus isolation from respiratory specimens in non-granulocytopenic patients. Eur J Clin Microbiol Infect Dis 2003
* * Maertens J. Screening for circulating galactomannan as a non-invasive diagnostic tool for invasive aspergillosis in prolonged neutropenic patients and stem cell transplantation recipients. Blood 2001; 97:
** *Ostrosky-Zeichner L. Multicenter clinical evaluation of the (1-3) beta-D-glucan assay as an aid in diagnosis of fungal infections in humans. Clin Infect Dis 2005; 41: 654-9

12. Invasive Aspergillosis in ICU Patients Fact or Fiction?
Isolation of Aspergillus spp. in ‘immunocompetent host’ is often/always interpreted as colonization ….
Assessment of clinical signifance most difficult in patient groups with intermediate risk of invasive disease
Literature data
Variable diagnostic criteria
When you have a positive culture in a patient, a major problem is to estimate the clinical significance of this finding, in patients with an intermediate or low probability of acquiring invasive pulmonary aspergillosis. Differentiating between colonization and infection is a major challenge for the clinician.
When reviewing the available literature, there is also some differences in the diagnostic assessment of patients.

13. of Aspergillosis. Clin Infect Diseases 2001
In the setting of stem cell transplantation, it is quite evident to state that a positive culture is clinically relevant, because more then 60 % of these patients do have invasive disease,
But the problem is an accurate interpretation of a culture in patients with intermediate risk for aspergillosis, certainly when it concerns patients with non hematological disease, such ase malnutrition, diabetes, chronic lung disease.
This has been nicely demonstrated in this paper by Perfect.
Perfect J. Impact of culture isolation of Aspergillus species: a hospital-based survey
of Aspergillosis. Clin Infect Diseases 2001

14. Author
Year
Type of study
Patient category N.
Incidence
Mortality
Lewis
1985
Case series
IPA complicating influenza pneumonia
Case report and literature review 6 -
100%
Karam
1986
Cases series
Non-neutropenic patients - 10 structural lung disease
7 steroid treatment 32
Janssen JJWM
1996
Monocentric
Retrospective
Medical ICU pts with hematological malignancy, immunosuppression for mixed connective tissue disease, ARDS 25
92%
Pittet
COPD patients in MICU
Acquisition of IPA during mechanical ventilation due to high grade airborne inoculation 2
Rello
1998
Series of COPD patients and literature review 24
Valles
2002
Two centres
Observational, prospective study
Hospital acquired pneumonia requiring ICI admission
Aspergillus spp. identified in 17% of pts
Mainly COPD pts
77%
Bulpa
2001
COPD patients admitted to ICU diagnosed with IPA 23
Meersseman
2004
Medical ICU
70% cases without malignancy
5 pts with IA without known predisposing condition (of whom 3 Child C cirrhosis)
107
5.8%
91%
Garnacho-Montero
2005
Multicentric
Prospective
73 ICU’s in Spain
patients with LOS > 7 days 20
1.1%
80%
Vandewoude
2006
Mixed ICU
40% haematological pts 83
3.3/1000
Now, what about the available literature on invasive aspergillosis in ICU patients?
This form of the disease has already been identified more than twenty years ago, as a major complication in patients with existing structural lung disease, and as a complication of influenza pneumonia, as described by Karam and Lewis in the eighties.
Case series have also indicated that Aspergillus must be considered as pathogenic in patients with COPD, one should be very alert in these patients if they had exposure to corticosteroid treatment even in low doses and for short courses.
In a Dutch study, ICU treatment for hematological patients with invasive aspergillosis was considered futile, because of the high mortality.
Bulpa described a series of COPD patients with invasive disease, and also raised the question of therapeutic futility because of poor outcome of these patients.
Finally, there are three studies in intensive care, adressing epidemiologic features of pts with IA.

15. Invasive pulmonary aspergillosis in non-immunocompromised, non-neutropenic hosts*
Review of 32 cases
Underlying diseases: lung fibrosis, COPD, Influenza A, diabetes mellitus, alcoholism, ‘short’ course of steroids, …
… IPA should be considered when Aspergillus spp. is isolated in resp. secretions and presence of pneumonia ….
* Karam G. Invasive pulmonary aspergillosis in non-immunocompromised, non-neutropenic hosts. Reviews of infectious diseases 1986; 8:

16. COPD patients with IPA: benefits of ICU? *
23 pts, 16 proven, 7 probable (repeated isolation)
recent steroid treatment, or intensification of steroid treatment
severe bronchospasm (12/23)
all required mechanical ventilation
Mortality 100%
This slide refers to the paper of Bulpa, describing a series op 23 patients with COPD and invasive aspergillosis;
All these pts developed respiratory insufficiency requiring mechanical ventilation, and all of them died.
* Bulpa P. COPD patients with invasive pulmonary aspergillosis: benefits of intensive care? Intens Care Med 2001; 27: 59-67

17. Invasive pulmonary aspergillosis in COPD patients: an emerging fungal pathogen*
13 cases of IPA in COPD pts admitted to ICU
bronchospasm ++
steroid treatment often continued in spite of isolation of Aspergillus spp.
Mortality 100% - proven IPA by autopsy
In a recent paper by Ader, the importance of Aspergillus as a lethal pathogen in COPD was highlighted; it was stressed Aspergillus isolation should be considered relevant, after steroid treatment
An important observation in this study, and also in the previous study , is the presence of severe bronchoconstriction, impeding mechanical ventilation in these patients.
* Ader F. Invasive pulmonary aspergillosis in COPD patients: an emerging fungal pathogen.
Clin Microbiol Infec 2005: Jun;11:427-9.

18. Retrospective cohort study based on prospectively gathered microbiology and autopsy data – UZ KULeuven: 127/1850 ptn
An excellent study from Leuven has learned us important data about invasive aspergillosis in patients in a medical ICU
In this study, EORTC guidelines were strictly applied, and they performed autopsy in 76 patients out of 127 patients with suspicion of invasive aspergillosis.
The diagnosis of invasive aspergillosis was made in 107 patients, representing an incidence of more than 5%; the majority of the patients did not suffer from hematologic disease.
The mortality of more than eighty percent, and exceeded the mortality as derived from the SAPS score upon admission of these patients, indicating the serious impact of aspergillosis on patient outcome.
5.8% van aantal opgenomen ptn!!! met IPA
Meersseman W. Invasive Aspergillosis in Critically Ill patients without Malignancy
Am J Respir Crit Care Med 2004

19. In a Spanisch multicenter study, the incidence of Invasive disease was about 1.1 % of admissions;
Only 10 % of patients had neutropenia as predisposing factor
COPD was the major underlying illness in these patients, and most of them received corticosteroid treatment; Mortality was 80%

20. Clinical relevance of Aspergillus isolation from respiratory tract samples in critically ill patients. Critical Care 2006
Retrospective study
Sole entry criterion = positive lower respiratory tract specimen
Adapted criteria to discriminate colonization vs. clinical relevant ‘infection’ (i.e. : relevant to start antifungal treatment)
Incidence 3.3/1000 admission

21. Adapted Diagnostic Criteria …
Definite IPA
positive histology (+culture) of lung tissue
positive culture from normally sterile site
Probable IPA
Lower resp tract sample pos for Aspergillus
Compatible signs and symptoms
Abnormal medical imaging of chest
Either
host risk factors: neutropenia, hemato-oncologic malignancy treated with cytostatics, steroid treatment > 20 mg/day, immunodeficiency
BAL:
semiquantitative positive culture +/++
and
cytologic exam positive (branching hyhae)
We performed a retrospective study in ICU patients, with as sole entry criterion a positive culture of Aspergillus in a respiratory specimen, and we used adapted criteria to discriminate colonization from infection
The criteria were adapted, in a way that we took any evidence of pneumonia into account, and that we considered to presence of a clearly positive microscopic evidence, with septate hyphae, as an information that corroborates the clinical relevance.
Vandewoude K. Clinical relevance of Aspergillus isolation from respiratory tract samples in critically ill patients. Critical Care 2006

22. We had 172 pts with a positive culture, and according to the diagnostic algoritm, we could separated two groups of patients, group of pts with IA and another considered as colonization, because of the absence of pneumonia, host risk factors, and because the positive culture was not supported with a positive direct microscopic examination.
We identified 83 patients with invasive disease
An important fact is that we had 17 patients with suspicion of invasive aspergillosis, and that was ultimately confirmed by histologic examination; the speculation of colonization was confirmed by histology in another 9 pts
These findings support the positive predictive value of the diagnostic algorithm

23. An important observation was that the majority of patients did have any hematological underlying disease.
Underlying diseases were COPD, malnutrition, liver cirrhosis,…

24. When comparing both patient groups, we found that pts with invasive disease had a higher APACHE II score upon admission, that they experienced more hemodynamic instability and acute renal failure than pts considered colonized.
An important difference between both pt groups in the outcome, with an in-hospital mortality of 77% in IA pts and 40% in colonized pts

25. Survival curves for ICU patients with IPA vs Aspergillus spp
Survival curves for ICU patients with IPA vs Aspergillus spp. colonization …

26. Does Invasive Aspergillosis has an impact on ICU patient outcome?
i.e.: is there an attributable mortality?
Case-control study
1:2 matching
Matching criteria
APACHE II (admission)
Diagnostic category
Age
Two cohorts of pts with same ‘expected mortality’
Vandewoude K. Invasive aspergillosis in critically ill patients: attributable mortality and
excesses in length of stay and ventilator dependence. J Hosp Infection 2004

27. An important question is whether invasive aspergillosis had an impact on outcome in terms of attributable mortality
We tried to adress this issue a matched cohort study
Pts were matched upon APACHE II score, age, and upon diagnostic category upon admission
We found that hospital mortality was higher in the patient group with invasive disease, this was not significantly different,
An important observation however is that the mortality in pts with IA was clearly higher than mortality as expected upon APACHE II score, in contrast to the data for the colonized pts.
We also demonstrated that the use of ICU resources as significantly higher in pts with IA, as indicated by the difference in length of stay and ventilator dependence.
Vandewoude K. Invasive aspergillosis in critically ill patients: attributable mortality and
excesses in length of stay and ventilator dependence. J Hosp Infection 2004

28. Conclusion Invasive Aspergillosis in ICU patient is a Fact …
Incidence …
0.33 – 5.8%
Depending on patient mix: MICU > SICU
Limited patient groups, precluding firm conclusions …
Underestimated?
Delayed diagnosis
Diagnosis post mortem …
Grim prognosis
Mortality exceeding 77%
Observed mortality >> predicted mortality
Attributable mortality … ?
In conclusion, literature data indicate that invasive aspergillosis is an emerging disease in critically ill patients
Data on incidence vary considerably, and are also influenced by type of hospital and type of ICU
Proven IA is often an autopsy finding, indicating that diagnosis is delayed in most pts

29. Conclusion
Do not discard an Aspergillus spp. positive respiratory tract specimen in critically ill patients – consider the clinical significance even in the absence of EORTC/MSG host risk factors

30. ?
Epidemiology: prospective multicenter observational studies needed to estimate incidence
Biopsy if possible?
Protocol based autopsy policy
Validation of clinical diagnostic algorithm,
Useful to guide (pre-emptive) therapy
Development of criteria for pre-emptive treatment
Consideration of additional host risk factors:
COPD, steroid treatment, MOF, ….
Explore and measure immunoparalytic state
Evaluation of non-invasive serologic markers in ICU pts
galactomannan
Beta-D-glucan
PCR