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Invasive aspergillosis
in patients taking steroids
Alessandro C. Pasqualotto
[email protected]
Santa Casa de Porto Alegre
Potential conflicts of interest
• Research Grants
 Myconostica, Pfizer, Merck, Sigma-Tau, CAPES,
CNPq, Fungal Research Trust
• Travel Grants
 Pfizer, United Medical, Schering (now Merck), Bagó,
Merck
• Speaker honoraria
 Pfizer, United Medical, Merck, Schering (now Merck),
Biometrix
A fact:
Aspergillus love steroids
Steroids and Aspergillus
• Lymphocytes
– Lymphopenia, decreased lymphokine production
(e.g, TNF, -INF),Th1/Th2 dysregulation
• Neutrophils
– Defective chemotaxis, phagocytosis,
degranulation, NO production, adherence
Lionakis M, Kontoyiannis DP. Lancet 2003; 362: 1828-38
Steroids and Aspergillus
• Monocytes / macrophages
– Monocytopenia
– Inhibition of pro-inflammatory cytokine production
– Decreased chemotaxis
– Impaired phagocytosis
– Impaired antigen-presenting capacity by DC
Lionakis M, Kontoyiannis DP. Lancet 2003; 362: 1828-38
Steroids enhance
Aspergillus growth
30-40%
increase in
growth rate
Ng TTC, et al. Microbiology 1994; 140: 2475-9
Neutrophil-
mediated damage
of A. fumigatus
hyphae is reduced
after exposure to
dexamethasone
Lewis RE, Kontoyiannis DP. Med Mycology 2008; S1-11
What about clinical data?
IA in allogeneic HSCT
Marr K, et al. Blood 2002; 100: 4358-66
IA in SOT recipients
• Renal transplantation
– Risk correlates with steroid dosage
– Prednisone >1.25 mg/kg/d
Gustafson TL, et al. J Infect Dis 1983; 148: 230-8
IA in SOT recipients
• Renal transplantation
– Risk correlates with steroid dosage
– Prednisone >1.25 mg/kg/d
• Liver, heart and lung tx recipients
– Peri-operative steroid administration and
boluses given to prevent rejection
Patterson JE. Transpl Infect Dis 1999; 1: 2292-36
IA after neurosurgery
• n=25
• Steroids: 52.0%
Pasqualotto AC, Denning DW. Clin Microbiol Infect 2006; 12: 1060-76
IA in patients with solid tumours
• Series with 13 patients
– Only 1 was neutropenic
• 46% received steroids within 30 days
– Median total cumulative dose 695 mg
Ohmagari N, et al. Cancer 2004; 10: 2300-2
Aspergillus causing VAP
Meersseman W, et al. Am J Respir Crit Care Med 2008; 177: 27-34
IA, COPD and steroids
• 57 cases over a decade in Madrid
• 98% taking steroids
– Cumulative dosage >700 mg in 73.6%
• GOLD staging
– III (63.2%); IV (33.8%)
• Overall mortality was 72%
Guinea J, et al. ICAAC 2008 (Abstract M-2161)
IA and inhaled steroids
• Case reports only (rare)
– Fluticasone
– COPD / asthma
Peter E, et al. Clin Infect Dis 2002; 35: 54-56
Leav BA, et al. N Engl J Med 2000; 343: 586
Emerging groups
• Chronic GVHD
• SOT
• Multiple myeloma
• Solid tumours / lymphoma
• SLE / Wegener disease
• AIDS
Nedel WL, Kontoyiannis DP, Pasqualotto AC. Rev Iberoamer Micol 2009; 26: 175-83
IFD definitions - Host factors
Neutropenia
Neutropenia
>3 weeks steroids
>3 weeks steroids
Treatment with other
recognized T-cell
immune suppressants
> 4 days unexplained fever
despite antibiotics
Inherited severe
immunodeficiency
GVHD
Donnelly JP
A ‘threshold dose’?
• Not properly defined
• Overall risk for infection increases if:
– Prednisone >20 mg/daily
– Cumulative dose >700 mg
• Largely variable
Stuck AE, et al. Rev Infect Dis 1989; 11: 954-63
Lionakis MS, Kontoyiannis DP. Lancet 2003; 362: 1828-38
Clinical features
Identical to what is observed for
neutropenic patients?
Clinical features
• Diagnosis is often delayed
• Low index of suspicion
Lewis RE, Kontoyiannis DP. Med Mycol 2008: S1-11
Clinical features
• Diagnosis is often delayed
• Low index of suspicion
• Non-specific signs and symptoms
– Suppression of fever / cough / chest pain
– Co-infections are frequent
Lewis RE, Kontoyiannis DP. Med Mycol 2008: S1-11
Differences in pathogenesis?
Pathogenesis of IA
Dagenais TRT, Keller NP. Clin Microbiol Rev 2009; 447-65
Steroids vs. neutropenia
BAL fluid
Steroids
Chemotherapy
Rapid PMN influx
No PMN influx
Balloy V, et al. Infect Immun 2005; 73: 494-503
Chamilos, et al. Haematologica 2006; 91: 986
Steroids vs. neutropenia
Steroids
Chemotherapy
BAL fluid
Rapid PMN influx
No PMN influx
Pathology
Neutrophil infiltration No neutrophil infiltration
No angioinvasion
Angioinvasion
Pyogranulomatous
reaction
Coagulative necrosis
Haemorrhagic infarction
Balloy V, et al. Infect Immun 2005; 73: 494-503
Chamilos, et al. Haematologica 2006; 91: 986
Steroids vs. neutropenia
Steroids
Chemotherapy
BAL fluid
Rapid PMN influx
No PMN influx
Pathology
Neutrophil infiltration No neutrophil infiltration
Fungal
development
No angioinvasion
Angioinvasion
Pyogranulomatous
reaction
Coagulative necrosis
Haemorrhagic infarction
Small numbers
Large numbers
of conidia
of hyphae
Balloy V, et al. Infect Immun 2005; 73: 494-503
Chamilos, et al. Haematologica 2006; 91: 986
Steroids vs. neutropenia
Steroids
Chemotherapy
BAL fluid
Rapid PMN influx
No PMN influx
Pathology
Neutrophil infiltration No neutrophil infiltration
Fungal
development
GM
No angioinvasion
Angioinvasion
Pyogranulomatous
reaction
Coagulative necrosis
Haemorrhagic infarction
Small numbers
Large numbers
of conidia
of hyphae
Very low
High
Balloy V, et al. Infect Immun 2005; 73: 494-503
Chamilos, et al. Haematologica 2006; 91: 986
Steroids
Neutropenia
H&E
x100
GMS
x100
Chamilos G, et al. Haematologica 2006; 91: 986-9
Does that have any impact
on the performance
of diagnostic tests?
Typical CT findings in IA
Day 0:
Halo
Day 4:
Day 7:
 nodule,
halo
Air crescent
Caillot, et al. J Clin Oncol 1997; 15: 139-47
The ‘Halo sign’
Nodules
in IA
Nodule
Nodule
with halo
Neutropenia
97%
82%
Non-haematological
disorder
82%
24%
Maertens J. ICAAC 2006
Can we rely on the ‘halo sign’?
• Aspergillus causing VAP (ICU)
Halo sign: 0%
Meersseman W, et al. Am J Respir Crit Care Med 2008; 177: 27-34
Singh N, Husain S. J Heart Lung Transplant 2003; 22: 258-66
Bulpa P, et al. Eur Resp J 2007: 30: 782-800
Can we rely on the ‘halo sign’?
• Aspergillus causing VAP (ICU)
Halo sign: 0%
• Lung transplant recipients
 No specific sign at chest CT
• IA in COPD
 Non-specific consolidation
Meersseman W, et al. Am J Respir Crit Care Med 2008; 177: 27-34
Singh N, Husain S. J Heart Lung Transplant 2003; 22: 258-66
Bulpa P, et al. Eur Resp J 2007: 30: 782-800
Yield of other dx methods
• Lower sensitivity of respiratory cultures
– Lower fungal burden
• Lower PPV
– Haematological patient 77%
– Steroid-treated patient 58%
Horvath JA, Dummer S. Am JMed 1996; 100: 171-8
Meta-analysis of GM testing
Proven or probable IA
Haematological
malignancies
Solid organ
transplantation
Sensitivity
Specificity
0.58 (52-64)
0.95 (94-96)
0.41 (21-64)
0.85 (80-89)
Pfeiffer CD, et al. Clin Infect Dis 2006; 42: 1417-27
Clinical case
• 56 year-old
• COPD on steroids
• ICU for respiratory
tract infection
• CRX: diffuse
infiltrate
Meersseman W. In: Aspergillosis: from diagnosis to prevention. Pasqualotto AC, ed. Springer
Clinical case
• BAL
– H. influenzae
– Negative for fungi
Meersseman W. In: Aspergillosis: from diagnosis to prevention. Pasqualotto AC, ed. Springer
Clinical case
• BAL
– H. influenzae
– Negative for fungi
• Galactomannan
– Serum was negative
– 2.6 ng/ml in BAL
• Died despite caspofungin
Meersseman W. In: Aspergillosis: from diagnosis to prevention. Pasqualotto AC, ed. Springer
Clinical case
• BAL
– H. influenzae
– Negative for fungi
• Galactomannan
– Serum was negative
– 2.6 ng/ml in BAL
• Died despite caspofungin
• Necropsy confirmed IPA
Meersseman W. In: Aspergillosis: from diagnosis to prevention. Pasqualotto AC, ed. Springer
Which patient has neutropenia?
Maertens J. ICAAC 2006
35 year old male
Relapsed AML
> 50 days of neutropenia
Persistent fever
GM OD index: 2 x >0.5
64 year old male
Hypoplastic MDS
High dose steroids (aGvHD III)
Cough and pleuritic chest pain
GM OD index: 2 x >0.5
Maertens J. ICAAC 2006
Which patient
has higher serum GM levels?
Maertens J. ICAAC 2006
Max GM: 7.8
35 year old male
Relapsed AML
> 50 days of neutropenia
Persistent fever
GM OD index: 2 x ≥ 0.5
Max GM: 0.8
64 year old male
Hypoplastic MDS
High dose steroids (aGvHD III)
Cough and pleuritic chest pain
GM OD index: 2 x ≥ 0.5
Maertens J. ICAAC 2006
IA in a neutropenic patient
• 50-yo male
• AML on cycle 2, D27 of
clofarbine/idarubicin
• ANC of 0
• High fever
• R-sided pleuritic chest
pain (2 days duration)
• Serum GM 1.2
Lewis RE, Kontoyiannis DP. Med Mycology 2008; S1-11
IA in a steroid-treated patient
• 52-yo female
• D45 allo HSCT (AML)
• ANC of 1800
• GVHD on tacrolimus
and steroids
• No fever
• BAL: A. fumigatus
and P. aeruginosa
• Negative serum GM
Lewis RE, Kontoyiannis DP. Med Mycology 2008; S1-11
Same response to
antifungal drugs?
Antifungal treatment
• Latest IDSA guidelines
– No distinction regarding underlying disease
Walsh TJ, et al. Clin Infect Dis 2008; 46: 327-60
Dominant mechanisms
• Steroid-induced IA
– Adverse host response
• Neutropenia
– Fungal development
Berenguer J, et al. Am J Resp Crit Care Med 1995; 152: 1079-86
Effects on the immune system
• d-AmB
– Pronounced pro-inflammatory activity
– Release of inflammatory cytokines,
chemokines, NO, prostaglandins and others
– Fever, chills, myalgias and rigors
Lewis RE, Kontoyiannis DP. Med Mycology 2008; S1-11
Effects on the immune system
• d-AmB
– Pronounced pro-inflammatory activity
– Release of inflammatory cytokines,
chemokines, NO, prostaglandins and others
– Fever, chills, myalgias and rigors
• Potential deleterious effects in steroidtreated hosts with IA
Lewis RE, Kontoyiannis DP. Med Mycology 2008; S1-11
Effects on the immune system
• Animal models
– d-AmB reduces mortality and fungal burden in
neutropenic mice with IA
– Ineffective in steroid-immunosuppressed mice
Balloy V, et al. Infect Immun 2005; 73: 494503
Lewis RE, et al. Antimicrob Agents Chemother 2007; 51: 1078-81
Empty liposomes
• Potent immunomodulating effects
• Pre-treatment of steroid-immunosup. mice with
empty liposomes
– Reduces inflammatory pathology
– Improves fungal clearance and survival
– Similar efficacy than 10 mg/kg L-AmB and 1 mg/kg of
d-AmB
Lewis RE, et al. Antimicrob Agents Chemother 2007; 51: 1078-81
Other antifungal drugs
• Echinocandins
– Immunostimulatory effects
– β-glucan unmasking
• Triazoles
– Few direct effects on mononuclear and PMN
Lewis RE, et al. Antimicrob Agents Chemother 2007; 51: 1078-81
Drug-drug interactions
• Itraconazole and steroids
– 3-4x  in steroid AUC
– 15-30%  in t½
• Voriconazole
–  prednisolone Cmax and AUC by 11% and 34%,
respectivelly
Lewis RE. AAA 2006
Any influence on
disease prognosis?
Non-myeloablative allo HSCT
Steroid dose to treat GVHD
Overall survival
after diagnosis
of invasive
mould disease
Fukuda T, et al. Blood 2003; 102: 827-33
Conclusions
• Steroids are important risk factors for IA
Conclusions
• Steroids are important risk factors for IA
• Steroid-induced changes in immunobiology of
IA mandate different approaches to diagnosis
and management compared to neutropeniaassociated
Conclusions
• Steroids are important risk factors for IA
• Steroid-induced changes in immunobiology of
IA mandate different approaches to diagnosis
and management compared to neutropeniaassociated
• Prognostic importance
Acknowledgments
• CNPq
• Teresa Sukiennik
• Luiz Carlos Severo
• Arnaldo L Colombo / Infocus scientific
committee