Invasive Invasive aspergillosis aspergillosis in patients taking in patients taking steroids steroids Alessandro C. Alessandro C. Pasqualotto Pasqualotto [email protected][email protected].br .br Santa Casa de Santa Casa de Porto Porto Alegre Alegre
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Invasive aspergillosis in patients taking steroids Alessandro C. Pasqualotto [email protected] Santa Casa de Porto Alegre.
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Pfeiffer CD, et al. Clin Infect Dis 2006; 42: 1417-27
Proven or probable IA
Sensitivity Specificity
Haematological malignancies
0.58 (52-64) 0.95 (94-96)
Solid organ transplantation
0.41 (21-64) 0.85 (80-89)
Meta-analysis of GM testing
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
• BAL
– H. influenzae
– Negative for fungi
Clinical case
Meersseman W. In: Aspergillosis: from diagnosis to prevention. Pasqualotto AC, ed. Springer
• BAL
– H. influenzae
– Negative for fungi
• Galactomannan
– Serum was negative
– 2.6 ng/ml in BAL
• Died despite caspofungin
Clinical case
Meersseman W. In: Aspergillosis: from diagnosis to prevention. Pasqualotto AC, ed. Springer
• BAL
– H. influenzae
– Negative for fungi
• Galactomannan
– Serum was negative
– 2.6 ng/ml in BAL
• Died despite caspofungin
• Necropsy confirmed IPA
Clinical case
Meersseman W. In: Aspergillosis: from diagnosis to prevention. Pasqualotto AC, ed. Springer
Maertens J. ICAAC 2006
Which patient has neutropenia?Which patient has neutropenia?
35 year old maleRelapsed AML
> 50 days of neutropeniaPersistent fever
GM OD index: 2 x >0.5
64 year old maleHypoplastic MDS
High dose steroids (aGvHD III)Cough and pleuritic chest pain
GM OD index: 2 x >0.5Maertens J. ICAAC 2006
Maertens J. ICAAC 2006
Which patient has higher serum GM levels?
Which patient has higher serum GM levels?
35 year old maleRelapsed AML
> 50 days of neutropeniaPersistent fever
GM OD index: 2 x ≥ 0.5
64 year old maleHypoplastic MDS
High dose steroids (aGvHD III)Cough and pleuritic chest pain
GM OD index: 2 x ≥ 0.5
Max GM: 7.8 Max GM: 0.8
Maertens J. ICAAC 2006
• 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
• 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 neutropenic patient
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
• 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 toSame response to
antifungal drugs?antifungal drugs?
Antifungal treatmentAntifungal treatment
• Latest IDSA guidelinesLatest IDSA guidelines
– No distinction regarding underlying diseaseNo distinction regarding underlying disease
Walsh TJ, et al. Clin Infect Dis 2008; 46: 327-60
Dominant mechanisms
Berenguer J, et al. Am J Resp Crit Care Med 1995; 152: 1079-86
• Steroid-induced IA
– Adverse host response
• Neutropenia
– Fungal development
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 steroid-treated 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: 494503Lewis 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 onAny influence ondisease prognosis?disease prognosis?
Non-myeloablative allo HSCTSteroid dose to treat GVHD