Invasive Aspergillosis in Critically Ill PatientsA New 21th Century Problem?

Koenraad Vandewoude, MDIntensive Care Dpt. – Solid Organ Transplant Centre

Ghent University HospitalGhent, Belgium

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– …

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

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

1. Janssen JJ. Outcome of ICU treatment in Invasive Aspergillosis. Intens Care Med 1996; 22: 1291-93

2. Vallés J. A 7 year Study of Severe Hospital Acquired Pneumonia requiring ICU Admission. Intens Care Med 2003; 29: 1981-88

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

Clinical entity may change due immune defence alteration

1 Denning DW. Chronic cavitary and fibrosing pulmonary and pleural aspergillosis. Clin Infect Dis 20032 Paterson DL. New clinical presentations of invasive pulmonary aspergillosis in non-conventional hosts. Clin Microbiol Infect 2004

IPA diagnosis in ICU patients

• EORTC/MSG Case Definitions 1

– Difficult to apply outside high risk populations– Not useful to guide therapy

1 Ascioglu S. Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants. Clin Infect Dis 2002

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

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*

1 Hartemink KJ. Immunoparalysis as a cause for invasive aspergillosis? Intensive CareMed 20032 Engelich G. Acquired disorders of phagocyte function complicating medical and surgical illnesses. Clin Infect Dis 20013 Lionakis M. Glucocorticoids and Invasive Fungal Infections. Lancet 2003; 362: 1828-384 Palmer LB. Corticosteroid Treatment as a Risk Factor for Invasive Aspergillosis in Patients with Lung Disease. Thorax 1991; 46: 15-20

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

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

Greene RA. Radiologic findings in acute invasive pulmonary aspergillosis: utilityof the halo and air-crescent sign for diagnosis and treatment of invasive pulmonaryaspergillosis in high-risk patients. 13th ECCMID, 2002, Glasgow

• 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 …

* 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: 1604-10** *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

Invasive Aspergillosis in ICU PatientsFact 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

Perfect J. Impact of culture isolation of Aspergillus species: a hospital-based surveyof Aspergillosis. Clin Infect Diseases 2001

Author Year Type of study Patient category N. Incidence Mortality

Lewis 1985 Case series IPA complicating influenza pneumoniaCase report and literature review

6 - 100%

Karam 1986 Cases series Non-neutropenic patients - 10 structural lung disease7 steroid treatment

32 - 100%

Janssen JJWM 1996 MonocentricRetrospective

Medical ICU pts with hematological malignancy, immunosuppression for mixed connective tissue disease, ARDS

25 - 92%

Pittet 1996 COPD patients in MICUAcquisition of IPA during mechanical ventilation due to high grade airborne inoculation

2 - 100%

Rello 1998 Monocentric Series of COPD patients and literature review 24 - 100%

Valles 2002 Two centresObservational, prospective study

Hospital acquired pneumonia requiring ICI admissionAspergillus spp. identified in 17% of pts Mainly COPD pts

77%

Bulpa 2001 MonocentricCase series

COPD patients admitted to ICU diagnosed with IPA 23 - 100%

Meersseman 2004 MonocentricRetrospective

Medical ICU70% cases without malignancy5 pts with IA without known predisposing condition (of whom 3 Child C cirrhosis)

107 5.8% 91%

Garnacho-Montero

2005 MulticentricProspective

73 ICU’s in Spainpatients with LOS > 7 days

20 1.1% 80%

Vandewoude 2006 Retrospective Mixed ICU 40% haematological pts

83 3.3/1000 77%

• 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: 357-63

• 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%

* Bulpa P. COPD patients with invasive pulmonary aspergillosis: benefits of intensive care? Intens Care Med 2001; 27: 59-67

• 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

* Ader F. Invasive pulmonary aspergillosis in COPD patients: an emerging fungal pathogen.

Clin Microbiol Infec 2005: Jun;11:427-9.

• Retrospective cohort study based on prospectively gathered microbiology and autopsy data – UZ KULeuven: 127/1850 ptn

Meersseman W. Invasive Aspergillosis in Critically Ill patients without MalignancyAm J Respir Crit Care Med 2004

Clinical relevance of Aspergillus isolation from respiratory tract samples in critically ill patients. Critical Care 2006

– Retrospective study– 1997-2003– 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

Adapted Diagnostic Criteria …

• Definite IPA– positive histology (+culture) of lung tissue– positive culture from normally sterile site

• Probable IPA1. Lower resp tract sample pos for Aspergillus 2. Compatible signs and symptoms3. Abnormal medical imaging of chest4. Either

A. host risk factors: neutropenia, hemato-oncologic malignancy treated with cytostatics, steroid treatment > 20 mg/day, immunodeficiency

B. BAL:– semiquantitative positive culture +/++and– cytologic exam positive (branching hyhae)

Vandewoude K. Clinical relevance of Aspergillus isolation from respiratory tract samples in critically ill patients. Critical Care 2006

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

• 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

Vandewoude K. Invasive aspergillosis in critically ill patients: attributable mortality and excesses in length of stay and ventilator dependence. J Hosp Infection 2004

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 … ?

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

?

• 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