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Delve into the relationship between steroids and Aspergillus infections, exploring the impact on immune responses and clinical outcomes in patients. Learn about the increased growth rate of Aspergillus with steroid use, risk factors, and diagnostic challenges.
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Invasive aspergillosis in patients taking steroids Alessandro C. Pasqualottopasqualotto@santacasa.tche.brSanta 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
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 Med2000; 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 Allogeneic HSCT <36oC or >38oC and: - Prior mycosis - AIDS - Immunosuppressive drugs - >10 days neutropenia 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
Pathogenesis of IA Dagenais TRT, Keller NP. Clin Microbiol Rev 2009; 447-65
Steroids vs. neutropenia Balloy V, et al. Infect Immun 2005; 73: 494-503 Chamilos, et al. Haematologica 2006; 91: 986
Steroids vs. neutropenia Balloy V, et al. Infect Immun 2005; 73: 494-503 Chamilos, et al. Haematologica 2006; 91: 986
Steroids vs. neutropenia Balloy V, et al. Infect Immun 2005; 73: 494-503 Chamilos, et al. Haematologica 2006; 91: 986
Steroids vs. neutropenia Balloy V, et al. Infect Immun 2005; 73: 494-503 Chamilos, et al. Haematologica 2006; 91: 986
Neutropenia Steroids 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?
Day 0: Halo Day 7: Air crescent Day 4: nodule, halo Typical CT findings in IA Caillot, et al. J ClinOncol 1997; 15: 139-47
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: 27-34 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 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 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 > 50 days of neutropenia Persistent fever 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