Invasive aspergillosis

1
Invasive aspergillosis in patients taking
steroids
Alessandro C. Pasqualottopasqualotto_at_santacasa.tc
he.brSanta Casa de Porto Alegre
2
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

3
A fact Aspergillus love steroids
4
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
5
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
6
Steroids enhance Aspergillus growth
30-40 increase in growth rate
Ng TTC, et al. Microbiology 1994 140 2475-9
7
Neutrophil-mediated damage of A. fumigatus hyphae
is reduced after exposure to dexamethasone
Lewis RE, Kontoyiannis DP. Med Mycology 2008
S1-11
8
What about clinical data?
9
IA in allogeneic HSCT
Marr K, et al. Blood 2002 100 4358-66
10
IA in SOT recipients

• Renal transplantation
• Risk correlates with steroid dosage
• Prednisone gt1.25 mg/kg/d

Gustafson TL, et al. J Infect Dis 1983 148 230-8
11
IA in SOT recipients

• Renal transplantation
• Risk correlates with steroid dosage
• Prednisone gt1.25 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
12
IA after neurosurgery

• n25
• Steroids 52.0

Pasqualotto AC, Denning DW. Clin Microbiol Infect
2006 12 1060-76
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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
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Aspergillus causing VAP
Meersseman W, et al. Am J Respir Crit Care Med
2008 177 27-34
15
IA, COPD and steroids

• 57 cases over a decade in Madrid
• 98 taking steroids
• Cumulative dosage gt700 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)
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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
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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
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IFD definitions - Host factors
Neutropenia
Neutropenia
gt3 weeks steroids
gt3 weeks steroids
Allogeneic HSCT
lt36oC or gt38oC and - Prior mycosis - AIDS -
Immunosuppressive drugs - gt10 days neutropenia
Treatment with other recognized T-cell immune
suppressants
gt 4 days unexplained fever despite antibiotics
Inherited severe immunodeficiency
GVHD
Donnelly JP
19
A threshold dose?

• Not properly defined
• Overall risk for infection increases if
• Prednisone gt20 mg/daily
• Cumulative dose gt700 mg
• Largely variable

Stuck AE, et al. Rev Infect Dis 1989 11
954-63 Lionakis MS, Kontoyiannis DP. Lancet 2003
362 1828-38
20
Clinical features Identical to what is observed
for neutropenic patients?
21
Clinical features

• Diagnosis is often delayed
• Low index of suspicion

Lewis RE, Kontoyiannis DP. Med Mycol 2008 S1-11
22
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
23
Differences in pathogenesis?
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Pathogenesis of IA
Dagenais TRT, Keller NP. Clin Microbiol Rev 2009
447-65
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Steroids vs. neutropenia
Steroids Chemotherapy
BAL fluid Rapid PMN influx No PMN influx
Balloy V, et al. Infect Immun 2005 73
494-503 Chamilos, et al. Haematologica 2006 91
986
26
Steroids vs. neutropenia
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
Balloy V, et al. Infect Immun 2005 73
494-503 Chamilos, et al. Haematologica 2006 91
986
27
Steroids vs. neutropenia
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
Balloy V, et al. Infect Immun 2005 73
494-503 Chamilos, et al. Haematologica 2006 91
986
28
Steroids vs. neutropenia
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
Balloy V, et al. Infect Immun 2005 73
494-503 Chamilos, et al. Haematologica 2006 91
986
29
Neutropenia
Steroids
HE x100
GMS x100
Chamilos G, et al. Haematologica 2006 91 986-9
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Does that have any impact on the performance of
diagnostic tests?
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Typical CT findings in IA
Caillot, et al. J Clin Oncol 1997 15 139-47
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The Halo sign
Nodules in IA Nodule Nodule with halo
Neutropenia 97 82
Non-haematological disorder 82 24
Maertens J. ICAAC 2006
33
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
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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
35
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
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Meta-analysis of GM testing
Proven or probable IA 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)
Pfeiffer CD, et al. Clin Infect Dis 2006 42
1417-27
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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
38
Clinical case

• BAL
• H. influenzae
• Negative for fungi

Meersseman W. In Aspergillosis from diagnosis
to prevention. Pasqualotto AC, ed. Springer
39
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
40
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
41
Which patient has neutropenia?
Maertens J. ICAAC 2006
42

• 35 year old male
• Relapsed AML
• gt 50 days of neutropenia
• Persistent fever
• GM OD index 2 x gt0.5

• 64 year old male
• Hypoplastic MDS
• High dose steroids (aGvHD III)
• Cough and pleuritic chest pain
• GM OD index 2 x gt0.5

Maertens J. ICAAC 2006
43
Which patient has higher serum GM levels?
Maertens J. ICAAC 2006
44
Max GM 7.8
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

• 35 year old male
• Relapsed AML
• gt 50 days of neutropenia
• Persistent fever
• GM OD index 2 x 0.5

Maertens J. ICAAC 2006
45
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
46
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
47
Same response to antifungal drugs?
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Antifungal treatment

• Latest IDSA guidelines
• No distinction regarding underlying disease

Walsh TJ, et al. Clin Infect Dis 2008 46 327-60
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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
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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
51
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
52
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
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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
54
Other antifungal drugs

• Echinocandins
• Immunostimulatory effects
• ß-glucan unmasking
• Triazoles
• Few direct effects on mononuclear and PMN

Lewis RE, et al. Antimicrob Agents Chemother
2007 51 1078-81
55
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
56
Any influence on disease prognosis?
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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
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Conclusions

• Steroids are important risk factors for IA

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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

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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

61
Acknowledgments

• CNPq
• Teresa Sukiennik
• Luiz Carlos Severo
• Arnaldo L Colombo / Infocus scientific committee