Invasive aspergillosis in patients taking steroids Alessandro C

Invasive aspergillosis in patients taking steroids Alessandro C. Pasqualotto pasqualotto@santacasa. tche. br Santa Casa de Porto Alegre

Potential conflicts of interest • Research Grants ü Myconostica, Pfizer, Merck, Sigma-Tau, CAPES, CNPq, Fungal Research Trust • Travel Grants ü Pfizer, United Medical, Schering (now Merck), Bagó, Merck • Speaker honoraria ü 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), Th 1/Th 2 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

Neutrophilmediated damage of A. fumigatus hyphae is reduced after exposure to dexamethasone Lewis RE, Kontoyiannis DP. Med Mycology 2008; S 1 -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 >3 weeks steroids Allogeneic HSCT <36 o. C or >38 o. C 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: S 1 -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: S 1 -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 x 100 GMS x 100 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 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) üHalo 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) üHalo sign: 0% • Lung transplant recipients ü No specific sign at chest CT • IA in COPD ü 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 (a. Gv. HD 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 (a. Gv. HD 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, D 27 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; S 1 -11

IA in a steroid-treated patient • 52 -yo female • D 45 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; S 1 -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-Am. B – 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; S 1 -11

Effects on the immune system • d-Am. B – 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; S 1 -11

Effects on the immune system • Animal models – d-Am. B 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-Am. B and 1 mg/kg of d. Am. B 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 -4 x 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