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Invasive aspergillosis in patients taking steroids

Invasive aspergillosis in patients taking steroids. Alessandro C. Pasqualotto pasqualotto@santacasa.tche.br Santa Casa de Porto Alegre. Potential conflicts of interest. Research Grants Myconostica, Pfizer, Merck, Sigma-Tau, CAPES, CNPq, Fungal Research Trust Travel Grants

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Invasive aspergillosis in patients taking steroids

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  1. Invasive aspergillosis in patients taking steroids Alessandro C. Pasqualottopasqualotto@santacasa.tche.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 >1.25 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 >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

  12. IA after neurosurgery • n=25 • Steroids: 52.0% Pasqualotto AC, Denning DW. Clin Microbiol Infect 2006; 12: 1060-76

  13. 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

  14. 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 >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)

  16. 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

  17. 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

  18. 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

  19. 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

  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?

  24. Pathogenesis of IA Dagenais TRT, Keller NP. Clin Microbiol Rev 2009; 447-65

  25. Steroids vs. neutropenia Balloy V, et al. Infect Immun 2005; 73: 494-503 Chamilos, et al. Haematologica 2006; 91: 986

  26. Steroids vs. neutropenia Balloy V, et al. Infect Immun 2005; 73: 494-503 Chamilos, et al. Haematologica 2006; 91: 986

  27. Steroids vs. neutropenia Balloy V, et al. Infect Immun 2005; 73: 494-503 Chamilos, et al. Haematologica 2006; 91: 986

  28. Steroids vs. neutropenia Balloy V, et al. Infect Immun 2005; 73: 494-503 Chamilos, et al. Haematologica 2006; 91: 986

  29. Neutropenia Steroids H&E x100 GMS x100 Chamilos G, et al. Haematologica 2006; 91: 986-9

  30. Does that have any impact on the performance of diagnostic tests?

  31. 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

  32. The ‘Halo sign’ 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

  34. 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

  36. Meta-analysis of GM testing Pfeiffer CD, et al. Clin Infect Dis 2006; 42: 1417-27

  37. 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 > 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

  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 > 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?

  48. Antifungal treatment • Latest IDSA guidelines • No distinction regarding underlying disease Walsh TJ, et al. Clin Infect Dis 2008; 46: 327-60

  49. 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

  50. 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

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