Invasive aspergillosis in patients taking steroids Alessandro C. Pasqualotto [email protected] Santa Casa de Porto Alegre

Invasive aspergillosis Invasive aspergillosis in patients taking steroidsin patients taking steroids

Alessandro C. PasqualottoAlessandro C. Pasqualotto

[email protected]@santacasa.tche.br

Santa Casa de Santa Casa de Porto AlegrePorto Alegre

Potential conflicts of interest

• Research GrantsResearch Grants Myconostica, Pfizer, Merck, Sigma-Tau, CAPES, Myconostica, Pfizer, Merck, Sigma-Tau, CAPES,

CNPq,CNPq, Fungal Research TrustFungal Research Trust

• Travel GrantsTravel Grants Pfizer, United Medical, Schering (now Merck), Bagó, Pfizer, United Medical, Schering (now Merck), Bagó,

Merck Merck

• Speaker honorariaSpeaker honoraria Pfizer, United Medical, Merck, Schering (now Merck), Pfizer, United Medical, Merck, Schering (now Merck),

BiometrixBiometrix

A fact:A fact:AspergillusAspergillus love steroids love steroids

Steroids and Steroids and AspergillusAspergillus• 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 Steroids and AspergillusAspergillus• 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 Steroids enhance Aspergillus Aspergillus growthgrowth

Ng TTC, et al. Microbiology 1994; 140: 2475-9

30-40%

increase in

growth rate

30-40%

increase in

growth rate

Neutrophil-

mediated damage

of A. fumigatus

hyphae is reduced

after exposure to

dexamethasone

Neutrophil-

mediated damage

of A. fumigatus

hyphae is reduced

after exposure to

dexamethasone

Lewis RE, Kontoyiannis DP. Med Mycology 2008; S1-11

What about clinical data?What about clinical data?

IA in allogeneic HSCTIA in allogeneic HSCT

Marr K, et al. Blood 2002; 100: 4358-66

• 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: 230-8Gustafson TL, et al. J Infect Dis 1983; 148: 230-8

• 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: 2292-36Patterson JE. Transpl Infect Dis 1999; 1: 2292-36

• n=25

• Steroids: 52.0%

IA after neurosurgery

Pasqualotto AC, Denning DW. Clin Microbiol Infect 2006; 12: 1060-76

• 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: 2300-2Ohmagari N, et al. Cancer 2004; 10: 2300-2

Meersseman W, et al. Am J Respir Crit Care Med 2008; 177: 27-34

Aspergillus causing VAP

• 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)

IA and inhaled steroidsIA and inhaled steroids

• Case reports only Case reports only (rare)(rare)

– FluticasoneFluticasone

– COPD / asthmaCOPD / asthma

Peter E, et al. Clin Infect Dis 2002; 35: 54-56Leav BA, et al. N Engl J Med 2000; 343: 586

• 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: 175-83

IFD definitions - Host factors

NeutropeniaNeutropenia

>3 weeks steroids >3 weeks steroids

Treatment with other recognized T-cell immune suppressants

Treatment with other recognized T-cell immune suppressants

Inherited severe immunodeficiency

Inherited severe immunodeficiency

Allogeneic HSCTAllogeneic HSCT

Donnelly JP

NeutropeniaNeutropenia

> 4 days unexplained fever despite antibiotics

> 4 days unexplained fever despite antibiotics

GVHDGVHD

>3 weeks steroids>3 weeks steroids

<36oC or >38oC and:- Prior mycosis- AIDS- Immunosuppressive drugs- >10 days neutropenia

<36oC or >38oC and:- Prior mycosis- AIDS- Immunosuppressive drugs- >10 days neutropenia

• 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: 954-63Lionakis MS, Kontoyiannis DP. Lancet 2003; 362: 1828-38

Stuck AE, et al. Rev Infect Dis 1989; 11: 954-63Lionakis MS, Kontoyiannis DP. Lancet 2003; 362: 1828-38

Clinical featuresClinical featuresIdentical to what is observed for Identical to what is observed for

neutropenic patients?neutropenic patients?

Clinical featuresClinical features

• Diagnosis is often delayedDiagnosis is often delayed

• Low index of suspicionLow index of suspicion

Lewis RE, Kontoyiannis DP. Med Mycol 2008: S1-11

Clinical featuresClinical 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 painSuppression of fever / cough / chest pain

– Co-infections are frequentCo-infections are frequent

Lewis RE, Kontoyiannis DP. Med Mycol 2008: S1-11

Differences in pathogenesis?Differences in pathogenesis?

Dagenais TRT, Keller NP. Clin Microbiol Rev 2009; 447-65

Pathogenesis of IAPathogenesis of IA

Steroids vs. neutropenia

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

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






No angioinvasion



Angioinvasion



Fungal development

Small numbers

of conidia

Large numbers

of hyphae






No angioinvasion



Angioinvasion



Fungal development

Small numbers

of conidia

Large numbers

of hyphae

GM Very low High

Chamilos G, et al. Haematologica 2006; 91: 986-9

H&Ex100

Steroids Neutropenia

GMSx100

Does that have any impactDoes that have any impact

on the performanceon the performance

of diagnostic tests?of diagnostic tests?

Day 0: Halo

Day 4: nodule,

halo

Day 7: Air crescent

Caillot, et al. J Clin Oncol 1997; 15: 139-47

Typical CT findings in IATypical CT findings in IA

Nodules

in IA

Nodule Nodule with halo

Neutropenia 97% 82%

Non-haematological disorder

82% 24%

The ‘Halo sign’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: 27-34Singh 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%

Meersseman W, et al. Am J Respir Crit Care Med 2008; 177: 27-34Singh N, Husain S. J Heart Lung Transplant 2003; 22: 258-66

Bulpa P, et al. Eur Resp J 2007: 30: 782-800

• Lung transplant recipients

No specific sign at chest CT

• IA in COPD

Non-specific consolidation

Yield of other dx methodsYield of other dx methods• Lower sensitivity of respiratory culturesLower sensitivity of respiratory cultures

– Lower fungal burdenLower fungal burden

• Lower PPVLower PPV

– Haematological patient 77%Haematological patient 77%

– Steroid-treated patient 58%Steroid-treated patient 58%

Horvath JA, Dummer S. Am JMed 1996; 100: 171-8

Pfeiffer CD, et al. Clin Infect Dis 2006; 42: 1417-27

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)

Meta-analysis of GM testing

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

• BAL

– H. influenzae

– Negative for fungi

Clinical case


• BAL

– H. influenzae


• Galactomannan

– Serum was negative

– 2.6 ng/ml in BAL

• Died despite caspofungin

Clinical case


• BAL

– H. influenzae


• Galactomannan

– Serum was negative

– 2.6 ng/ml in BAL

• Died despite caspofungin

• Necropsy confirmed IPA

Clinical case



Which patient has neutropenia?Which patient has neutropenia?

35 year old maleRelapsed AML

> 50 days of neutropeniaPersistent fever

GM OD index: 2 x >0.5

64 year old maleHypoplastic MDS

High dose steroids (aGvHD III)Cough and pleuritic chest pain

GM OD index: 2 x >0.5Maertens J. ICAAC 2006


Which patient has higher serum GM levels?

Which patient has higher serum GM levels?

35 year old maleRelapsed AML

> 50 days of neutropeniaPersistent fever

GM OD index: 2 x ≥ 0.5

64 year old maleHypoplastic MDS

High dose steroids (aGvHD III)Cough and pleuritic chest pain

GM OD index: 2 x ≥ 0.5

Max GM: 7.8 Max GM: 0.8


• 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

• 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


IA in a neutropenic patient

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

• 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


Same response toSame response to

antifungal drugs?antifungal drugs?

Antifungal treatmentAntifungal treatment

• Latest IDSA guidelinesLatest IDSA guidelines

– No distinction regarding underlying diseaseNo distinction regarding underlying disease

Walsh TJ, et al. Clin Infect Dis 2008; 46: 327-60

Dominant mechanisms

Berenguer J, et al. Am J Resp Crit Care Med 1995; 152: 1079-86

• Steroid-induced IA

– Adverse host response

• Neutropenia

– Fungal development

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


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


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: 494503Lewis 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-AmB and 1 mg/kg of d-AmB

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

– 3-4x in steroid AUC

– 15-30% in t½

• Voriconazole

prednisolone Cmax and AUC by 11% and 34%, respectivelly

Lewis RE. AAA 2006

Any influence onAny influence ondisease prognosis?disease prognosis?

Non-myeloablative allo HSCTSteroid dose to treat GVHD

Fukuda T, et al. Blood 2003; 102: 827-33

Overall survival

after diagnosis

of invasive

mould disease

Overall survival

after diagnosis

of invasive

mould disease

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

Conclusions


• Steroid-induced changes in immunobiology of

IA mandate different approaches to diagnosis

and management compared to neutropenia-

associated

• Prognostic importance

Conclusions

Acknowledgments

• CNPq

• Teresa Sukiennik

• Luiz Carlos Severo

• Arnaldo L Colombo / Infocus scientific

committee

Documents

Invasive aspergillosis in patients taking steroids Alessandro C. Pasqualotto [email protected] Santa Casa de Porto Alegre