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Invasive aspergillosis in patients taking steroids Alessandro C. Pasqualotto Santa Casa de Porto Alegre.

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Presentation on theme: "Invasive aspergillosis in patients taking steroids Alessandro C. Pasqualotto Santa Casa de Porto Alegre."— Presentation transcript:

1 Invasive aspergillosis in patients taking steroids Alessandro C. Pasqualotto Santa Casa de Porto Alegre

2 Potential conflicts of interest Research GrantsResearch Grants Myconostica, Pfizer, Merck, Sigma-Tau, CAPES, CNPq,Fungal Research Trust Myconostica, Pfizer, Merck, Sigma-Tau, CAPES, CNPq, Fungal Research Trust Travel GrantsTravel Grants Pfizer, United Medical, Schering (now Merck), Bagó, Merck Pfizer, United Medical, Schering (now Merck), Bagó, Merck Speaker honorariaSpeaker honoraria Pfizer, United Medical, Merck, Schering (now Merck), Biometrix 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:

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:

6 Steroids enhance Aspergillus growth Ng TTC, et al. Microbiology 1994; 140: % increase in growth rate

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:

10 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: 230-8

11 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:

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

13 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:

14 Meersseman W, et al. Am J Respir Crit Care Med 2008; 177: Aspergillus causing VAP

15 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)

16 IA and inhaled steroids Case reports only (rare)Case reports only (rare) –Fluticasone –COPD / asthma Peter E, et al. Clin Infect Dis 2002; 35: Leav BA, et al. N Engl J Med 2000; 343: 586

17 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:

18 IFD definitions - Host factors Neutropenia >3 weeks steroids Treatment with other recognized T-cell immune suppressants Inherited severe immunodeficiency Allogeneic HSCT Donnelly JP Neutropenia > 4 days unexplained fever despite antibiotics GVHD >3 weeks steroids 38 o C and: - Prior mycosis - AIDS - Immunosuppressive drugs - >10 days neutropenia 38 o C and: - Prior mycosis - AIDS - Immunosuppressive drugs - >10 days neutropenia

19 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: Lionakis MS, Kontoyiannis DP. Lancet 2003; 362:

20 Clinical features Identical to what is observed for neutropenic patients?

21 Clinical features Diagnosis is often delayedDiagnosis is often delayed Low index of suspicionLow index of suspicion Lewis RE, Kontoyiannis DP. Med Mycol 2008: S1-11

22 Clinical 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 pain –Co-infections are frequent Lewis RE, Kontoyiannis DP. Med Mycol 2008: S1-11

23 Differences in pathogenesis?

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

25 Steroids vs. neutropenia Balloy V, et al. Infect Immun 2005; 73: Chamilos, et al. Haematologica 2006; 91: 986 SteroidsChemotherapy BAL fluid Rapid PMN influxNo PMN influx

26 Steroids vs. neutropenia Balloy V, et al. Infect Immun 2005; 73: Chamilos, et al. Haematologica 2006; 91: 986 SteroidsChemotherapy BAL fluid Rapid PMN influxNo PMN influx Pathology Neutrophil infiltration No angioinvasion Pyogranulomatous reaction No neutrophil infiltration Angioinvasion Coagulative necrosis Haemorrhagic infarction

27 Steroids vs. neutropenia Balloy V, et al. Infect Immun 2005; 73: Chamilos, et al. Haematologica 2006; 91: 986 SteroidsChemotherapy BAL fluid Rapid PMN influxNo 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

28 Steroids vs. neutropenia Balloy V, et al. Infect Immun 2005; 73: Chamilos, et al. Haematologica 2006; 91: 986 SteroidsChemotherapy BAL fluid Rapid PMN influxNo 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 lowHigh

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

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

31 Day 0: Halo Day 4: nodule, halo Day 7: Air crescent Caillot, et al. J Clin Oncol 1997; 15: Typical CT findings in IA

32 Nodules in IA NoduleNodule with halo Neutropenia97%82% Non-haematological disorder 82%24% 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: Singh N, Husain S. J Heart Lung Transplant 2003; 22: Bulpa P, et al. Eur Resp J 2007: 30:

34 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: Singh N, Husain S. J Heart Lung Transplant 2003; 22: Bulpa P, et al. Eur Resp J 2007: 30: Lung transplant recipients No specific sign at chest CT IA in COPD Non-specific consolidation

35 Yield of other dx methods Lower sensitivity of respiratory culturesLower sensitivity of respiratory cultures –Lower fungal burden Lower PPVLower PPV –Haematological patient 77% –Steroid-treated patient 58% Horvath JA, Dummer S. Am JMed 1996; 100: 171-8

36 Pfeiffer CD, et al. Clin Infect Dis 2006; 42: Proven or probable IA SensitivitySpecificity 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

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 BAL –H. influenzae –Negative for fungi Clinical case Meersseman W. In: Aspergillosis: from diagnosis to prevention. Pasqualotto AC, ed. Springer

39 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

40 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

41 Maertens J. ICAAC 2006 Which patient has neutropenia?

42 35 year old male Relapsed AML > 50 days of neutropenia Persistent fever GM OD index: 2 x > 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?

44 35 year old male Relapsed AML > 50 days of neutropenia Persistent fever GM OD index: 2 x year old male Hypoplastic MDS High dose steroids (aGvHD III) Cough and pleuritic chest pain GM OD index: 2 x 0.5 Max GM: 7.8Max GM: 0.8 Maertens J. ICAAC 2006

45 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

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 guidelinesLatest IDSA guidelines –No distinction regarding underlying disease Walsh TJ, et al. Clin Infect Dis 2008; 46:

49 Dominant mechanisms Berenguer J, et al. Am J Resp Crit Care Med 1995; 152: Steroid-induced IA –Adverse host response Neutropenia –Fungal development

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

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: Lewis RE, et al. Antimicrob Agents Chemother 2007; 51:

53 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:

54 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:

55 Drug-drug interactions Itraconazole and steroids –3-4x in steroid AUC –15-30% in t ½ Voriconazole – prednisolone C max and AUC by 11% and 34%, respectivelly Lewis RE. AAA 2006

56 Any influence on disease prognosis?

57 Non-myeloablative allo HSCT Steroid dose to treat GVHD Fukuda T, et al. Blood 2003; 102: Overall survival after diagnosis of invasive mould disease

58 Conclusions Steroids are important risk factors for IA

59 Steroid-induced changes in immunobiology of IA mandate different approaches to diagnosis and management compared to neutropenia- associated Conclusions

60 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

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


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