Invasive aspergillosis in patients taking steroids Alessandro C. Pasqualotto...
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Invasive aspergillosis Invasive aspergillosis in patients taking steroidsin patients taking steroids
Alessandro C. PasqualottoAlessandro C. Pasqualotto
[email protected]@santacasa.tche.br
Santa Casa de Santa Casa de Porto AlegrePorto Alegre
Potential conflicts of interest
• Research GrantsResearch Grants Myconostica, Pfizer, Merck, Sigma-Tau, CAPES, Myconostica, Pfizer, Merck, Sigma-Tau, CAPES,
CNPq,CNPq, Fungal Research TrustFungal Research Trust
• Travel GrantsTravel Grants Pfizer, United Medical, Schering (now Merck), Bagó, Pfizer, United Medical, Schering (now Merck), Bagó,
Merck Merck
• Speaker honorariaSpeaker honoraria Pfizer, United Medical, Merck, Schering (now Merck), Pfizer, United Medical, Merck, Schering (now Merck),
BiometrixBiometrix
A fact:A fact:AspergillusAspergillus love steroids love steroids
Steroids and Steroids and AspergillusAspergillus• 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 Steroids and AspergillusAspergillus• 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 Steroids enhance Aspergillus Aspergillus growthgrowth
Ng TTC, et al. Microbiology 1994; 140: 2475-9
30-40%
increase in
growth rate
30-40%
increase in
growth rate
Neutrophil-
mediated damage
of A. fumigatus
hyphae is reduced
after exposure to
dexamethasone
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?What about clinical data?
IA in allogeneic HSCTIA in allogeneic HSCT
Marr K, et al. Blood 2002; 100: 4358-66
• Renal transplantation
– Risk correlates with steroid dosage
– Prednisone >1.25 mg/kg/d
IA in SOT recipients
Gustafson TL, et al. J Infect Dis 1983; 148: 230-8Gustafson TL, et al. J Infect Dis 1983; 148: 230-8
• 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
IA in SOT recipients
Patterson JE. Transpl Infect Dis 1999; 1: 2292-36Patterson JE. Transpl Infect Dis 1999; 1: 2292-36
• n=25
• Steroids: 52.0%
IA after neurosurgery
Pasqualotto AC, Denning DW. Clin Microbiol Infect 2006; 12: 1060-76
• Series with 13 patients
– Only 1 was neutropenic
• 46% received steroids within 30 days
– Median total cumulative dose 695 mg
IA in patients with solid tumours
Ohmagari N, et al. Cancer 2004; 10: 2300-2Ohmagari N, et al. Cancer 2004; 10: 2300-2
Meersseman W, et al. Am J Respir Crit Care Med 2008; 177: 27-34
Aspergillus causing VAP
• 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%
IA, COPD and steroids
Guinea J, et al. ICAAC 2008 (Abstract M-2161)
IA and inhaled steroidsIA and inhaled steroids
• Case reports only Case reports only (rare)(rare)
– FluticasoneFluticasone
– COPD / asthmaCOPD / asthma
Peter E, et al. Clin Infect Dis 2002; 35: 54-56Leav BA, et al. N Engl J Med 2000; 343: 586
• Chronic GVHD
• SOT
• Multiple myeloma
• Solid tumours / lymphoma
• SLE / Wegener disease
• AIDS
Emerging groups
Nedel WL, Kontoyiannis DP, Pasqualotto AC. Rev Iberoamer Micol 2009; 26: 175-83
IFD definitions - Host factors
NeutropeniaNeutropenia
>3 weeks steroids >3 weeks steroids
Treatment with other recognized T-cell immune suppressants
Treatment with other recognized T-cell immune suppressants
Inherited severe immunodeficiency
Inherited severe immunodeficiency
Allogeneic HSCTAllogeneic HSCT
Donnelly JP
NeutropeniaNeutropenia
> 4 days unexplained fever despite antibiotics
> 4 days unexplained fever despite antibiotics
GVHDGVHD
>3 weeks steroids>3 weeks steroids
<36oC or >38oC and:- Prior mycosis- AIDS- Immunosuppressive drugs- >10 days neutropenia
<36oC or >38oC and:- Prior mycosis- AIDS- Immunosuppressive drugs- >10 days neutropenia
• Not properly defined
• Overall risk for infection increases if:
– Prednisone >20 mg/daily
– Cumulative dose >700 mg
• Largely variable
A ‘threshold dose’?
Stuck AE, et al. Rev Infect Dis 1989; 11: 954-63Lionakis MS, Kontoyiannis DP. Lancet 2003; 362: 1828-38
Stuck AE, et al. Rev Infect Dis 1989; 11: 954-63Lionakis MS, Kontoyiannis DP. Lancet 2003; 362: 1828-38
Clinical featuresClinical featuresIdentical to what is observed for Identical to what is observed for
neutropenic patients?neutropenic patients?
Clinical featuresClinical features
• Diagnosis is often delayedDiagnosis is often delayed
• Low index of suspicionLow index of suspicion
Lewis RE, Kontoyiannis DP. Med Mycol 2008: S1-11
Clinical featuresClinical features• Diagnosis is often delayedDiagnosis is often delayed
• Low index of suspicionLow index of suspicion
• Non-specific signs and symptomsNon-specific signs and symptoms
– Suppression of fever / cough / chest painSuppression of fever / cough / chest pain
– Co-infections are frequentCo-infections are frequent
Lewis RE, Kontoyiannis DP. Med Mycol 2008: S1-11
Differences in pathogenesis?Differences in pathogenesis?
Dagenais TRT, Keller NP. Clin Microbiol Rev 2009; 447-65
Pathogenesis of IAPathogenesis of IA
Steroids vs. neutropenia
Balloy V, et al. Infect Immun 2005; 73: 494-503Chamilos, et al. Haematologica 2006; 91: 986
Steroids Chemotherapy
BAL fluid Rapid PMN influx No PMN influx
Steroids vs. neutropenia
Balloy V, et al. Infect Immun 2005; 73: 494-503Chamilos, et al. Haematologica 2006; 91: 986
Steroids Chemotherapy
BAL fluid Rapid PMN influx No PMN influx
Pathology Neutrophil infiltration
No angioinvasion
Pyogranulomatous reaction
No neutrophil infiltration
Angioinvasion
Coagulative necrosis
Haemorrhagic infarction
Steroids vs. neutropenia
Balloy V, et al. Infect Immun 2005; 73: 494-503Chamilos, et al. Haematologica 2006; 91: 986
Steroids Chemotherapy
BAL fluid Rapid PMN influx No PMN influx
Pathology Neutrophil infiltration
No angioinvasion
Pyogranulomatous reaction
No neutrophil infiltration
Angioinvasion
Coagulative necrosis
Haemorrhagic infarction
Fungal development
Small numbers
of conidia
Large numbers
of hyphae
Steroids vs. neutropenia
Balloy V, et al. Infect Immun 2005; 73: 494-503Chamilos, et al. Haematologica 2006; 91: 986
Steroids Chemotherapy
BAL fluid Rapid PMN influx No PMN influx
Pathology Neutrophil infiltration
No angioinvasion
Pyogranulomatous reaction
No neutrophil infiltration
Angioinvasion
Coagulative necrosis
Haemorrhagic infarction
Fungal development
Small numbers
of conidia
Large numbers
of hyphae
GM Very low High
Chamilos G, et al. Haematologica 2006; 91: 986-9
H&Ex100
Steroids Neutropenia
GMSx100
Does that have any impactDoes that have any impact
on the performanceon the performance
of diagnostic tests?of diagnostic tests?
Day 0: Halo
Day 4: nodule,
halo
Day 7: Air crescent
Caillot, et al. J Clin Oncol 1997; 15: 139-47
Typical CT findings in IATypical CT findings in IA
Nodules
in IA
Nodule Nodule with halo
Neutropenia 97% 82%
Non-haematological disorder
82% 24%
The ‘Halo sign’The ‘Halo sign’
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: 27-34Singh 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%
Meersseman W, et al. Am J Respir Crit Care Med 2008; 177: 27-34Singh N, Husain S. J Heart Lung Transplant 2003; 22: 258-66
Bulpa P, et al. Eur Resp J 2007: 30: 782-800
• Lung transplant recipients
No specific sign at chest CT
• IA in COPD
Non-specific consolidation
Yield of other dx methodsYield of other dx methods• Lower sensitivity of respiratory culturesLower sensitivity of respiratory cultures
– Lower fungal burdenLower fungal burden
• Lower PPVLower PPV
– Haematological patient 77%Haematological patient 77%
– Steroid-treated patient 58%Steroid-treated patient 58%
Horvath JA, Dummer S. Am JMed 1996; 100: 171-8
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
Fukuda T, et al. Blood 2003; 102: 827-33
Overall survival
after diagnosis
of invasive
mould disease
Overall survival
after diagnosis
of invasive
mould disease
Conclusions
• Steroids are important risk factors for IA
• Steroids are important risk factors for IA
• Steroid-induced changes in immunobiology of
IA mandate different approaches to diagnosis
and management compared to neutropenia-
associated
Conclusions
• Steroids are important risk factors for IA
• Steroid-induced changes in immunobiology of
IA mandate different approaches to diagnosis
and management compared to neutropenia-
associated
• Prognostic importance
Conclusions
Acknowledgments
• CNPq
• Teresa Sukiennik
• Luiz Carlos Severo
• Arnaldo L Colombo / Infocus scientific
committee