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2011/9/9. 1. Nagasaki University Hospital established in September 20, 1861. 2011/9/9. 2. Fungus diseases in literature 150 years ago. Okudaira M, Jpn J Pathology : 74, 61-91, 1985. IUMS 2011,Sapporo, JAPAN. Respiratory Mycoses Pulmonary Aspergillosis: Pathogenesis and Treatment

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2011/9/9

1

Nagasaki University Hospital

established in September 20, 1861


2011/9/9

2

Fungus diseases in literature

150 years ago

Okudaira M, Jpn J Pathology: 74, 61-91, 1985


IUMS 2011,Sapporo, JAPAN

Respiratory Mycoses

Pulmonary Aspergillosis: Pathogenesis and Treatment

Chronic pulmonary aspergillosis

~new treatment evidence and emergence of azole-resistant Aspergillus fumigatus in Japan~

Department of Molecular Microbiology and Immunology

Nagasaki University Graduate School of Biomedical Sciences

Koichi IZUMIKAWA, M.D., Ph.D.


2011/9/9

4

Chronic forms of Pulmonary Aspergillosis

family case, Sasebo, JAPAN

54 years old, male, SON

82 years old, male, father

slowly progressive inflammatory pulmonary syndrome due to Aspergillus spp.


2011/9/9

5

Chronic forms of Pulmonary Aspergillosis

family case, Sasebo, JAPAN

investigation of circumstances

over 50 years old wooden house

humid and old


Systemic Mycosis in Japan from Autopsy Data

6

Total number of Mycosis

Candidiasis

Aspergillosis

Cryptococcosis

Mucor

5

4

3

2

1

0

FLCZ 1989

F-FLCZ 2004

MCZ 1980

ITCZ 1993

VRCZ 2005

5-FC 1979

MCFG 2002

AMPH-B 1962

L-AMB 2006

(%)

?

Frequency (%)

1960

1970

1980

1990

2000

2007

Year

Kume et al. Med Mycol J 52: 117-127, 2011


Proposed classification and pathogenesis of chronic pulmonary aspergillosis

Preexisting pulmonary defect, with cavity

Aspergillus exposure

Colonization of pulmonary cavity

Generalized immuno-compromised state (e.g. diabetes, AIDS, alcoholism)

Subtle generalized or pulmonary defense defect

Immune dysregulation

No local generalized defect

Nodular or consolidation, w/ or w/o cavitations:

subacute invasive pulmonary aspergillosis (subacute IPA)

or

chronic necrotizing pulmonary aspergillosis (CNPA)

Multiple cavities w/ surrounding inflamation ±aspergilloma:

chronic cavitary pulmonary aspergillosis (CCPA)

or

complex aspergilloma

Resolution of infection or asymptomatic, stable single aspergilloma:

simple aspergilloma

normal/weak fibrosis response

strong fibrosis response

continuing cavity formations and local inflamation

Extensive pluero/pulmonary fibrosis:

chronic fibrosing pulmonary aspergillosis (CFPA)

Denning et al: Clin Infect Dis 37 Suppl 3: S265-80, 2003


Clinical features of CPA patients pulmonary aspergillosis

(%)


Reported tb cases new and relapse cases per 100 000 population
Reported TB cases pulmonary aspergillosisNew and relapse cases (per 100 000 population)

60

50

France

Germany

40

Italy

Japan

30

Netherlands

Portugal

Spain

20

Sweden

United Kingdom of Great

10

Britain and Northern Ireland

United States of America

0

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

WHO, Communicable Diseases Report


CPA case pulmonary aspergillosis

[case]65 Y, Male

[CC] hemosputum, cough

[PH] n.p.

[PI]

1998:right upper lobectomy (Tbc)

2005~:cough, hemosputum

2006~: hemosputum increased

chest CT:fungus ball like shadows in right lower lung.

Platelia EIA: positive, Aspergillus Ab: positive

β-D-gulucan 35.0pg/ml

admission for further treatment

[PE] Height 161cm, Weight 44.3kg, BMI 17.1,

Body temp. 36.8℃, pulse 68/min, regular rhythm


8700 pulmonary aspergillosis

6700

5700

5300

6500

8000

7500

7500

1.65

5.70

0.19

0.20

0.93

1.46

3.24

0.72

39.5

117.8

90.9

68.2

47.4

25.9

28.9

0.65

0.976

0.985

1.025

0.441

0.461

0.591

0.517

CPA caseITCZ oral solution treatment

2/16

2/22

3/19

10/4

10/11

6 months

BIPM 0.6g/day

BIPM 0.6g/day

MCFG 150mg/day

VRCZ 200mg/day

ITCZ 400mg/day

ITCZ 200mg/day

BALF: A. fumigatus

A. niger

A. versicolor

A. terreus

BALF: A. fumigatus

sputum:A. terreus

37℃

hemosputum

WBC(/μl)

CRP(mg/dl)

β-D-glucan(pg/ml)

Aspergillus antigen (EIA)


12 pulmonary aspergillosis

  • Evidence of CPA treatment


NO RCT existed !!

P.O. first and I.V. is optional

Clin Infect Dis 2008; 46:327-360


Kohno, Izumikawa et al: J Infect, 2010


New evidence of cpa treatment overall efficacy mcfg v s vrcz
New Evidence of CPA treatment pulmonary aspergillosisOverall efficacy MCFG v.s. VRCZ

15

(%)

P=0.543*

100

60.0%

(30/50)

53.2%

(25/47)

efficacy

50

0

MCFG

VRCZ

Kohno, Izumikawa et al: J Infect, 2010


New Evidence of CPA treatment pulmonary aspergillosis Frequency of side effect MCFG v.s. VRCZ

16

P=0.0004*

(%)

61.1%

(33/54)

70

60

50

frequency

40

26.4%

(14/53)

30

20

10

0

MCFG

VRCZ

Kohno, Izumikawa et al: J Infect, 2010


New Evidence of CPA treatment pulmonary aspergillosis Frequency of side effect MCFG v.s. VRCZ

Visual disturbance & hepatic dysfunction

17

70

70

70

60

60

60

50

50

50

40

40

40

30

30

30

20

20

20

10

10

10

0

0

0

P=0.012*

P<0.0001*

(%)

(%)

(%)

P=0.025*

50.0%

(27/54)

frequency

frequency

frequency

35.2%

(19/54)

29.6%

(16/54)

26.4%

(14/53)

15.1%

(8/53)

0.0%

(0/53)

MCFG

VRCZ

MCFG

VRCZ

MCFG

VRCZ

Adverse effects except visual related events

Hepatic events

Visual

events

Kohno, Izumikawa et al: J Infect, 2010


2011/9/9 pulmonary aspergillosis

18

Day1~5

Day-2

Day0

Inoculum(i.t.)

immunosupression

L-AMB inhalation

ICR,♀,8weeks

Another route of antifungal administration

nebulized L-AMB & MCFG IPA murine model

Day-2,0:Cyclophosphamide200mg/kg i.p.+CortisoneAcetate250mg/kg s.c.

Day0: MF-13 conidia 1×108/ml:50μl intratracheal inoculation

Day1~5: L-AMB1.2mg/ml:8ml nebulize once/day

MCFG 1mg/kg/day intraperitoneal

Group1: nL-AMB + MCFG

Group2: nL-AMB

Group3: MCFG

Group4: Control

and/ or MCFG i.p.

Takazono, Izumikawa: AAC 53: 3508-3510, 2009


Another route of antifungal administration pulmonary aspergillosis

nebulized L-AMB & MCFG IPA murine model

2011/9/9

19

1

n L-AMB+MCFG

.8

survival rate

N L-AMB

.6

MCFG

.4

control

.2

0

Time (DAYS)

0

2

4

6

8

10

12

14

16

Control

MCFG (i.p.)

L-AMB

L-AMB+ MCFG (i.p.)

Day3

pathology

GMS stain×400

Takazono, Izumikawa: AAC 53: 3508-3510, 2009


Another route of antifungal administration pulmonary aspergillosis

nebulized L-AMB & MCFG IPA murine model

2011/9/9

20

AMPH-Bconcentration

L-AMB inhalation conc.

Lung (mg/kg)

serum (μg/ml)

control

0.1

<0.02

L-AMB 1.2mg/ml

35.5±4.2

0.02

L-AMB 2.6mg/ml

73.2±15.8

0.06

L-AMB 4.0mg/ml

94.2±20.2

0.06

Takazono, Izumikawa: AAC 53: 3508-3510, 2009


250 pulmonary aspergillosis

6

5

200

4

150

3

100

2

50

1

0

0

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

ITCZ resistant A. fumigatus

Nijmegen, Netherland

number

%

PLoS Med. 2008 November; 5(11): e219


Multi-azole pulmonary aspergillosis

ITCZ & POSA

VRCZ

ITCZ

Susceptible

AzoleresistantA. fumigatus

Manchester, U.K.

100

%

20

90

80

70

5

14

60

Number of patient cases

17

50

7

5

3

40

0

0

30

5

20

7

0

0

10

0

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

Year

Bueid et al. JAC 65: 2116-2118, 2010


Mechanism of action pulmonary aspergillosis

azole antifungals

Ergosterol

Toxic sterol

Azoles

Ergosterol

Ergosterol

P450

Erg3

P450

Erg3

14DM

14DM

Toxic sterol

Erg3

ー Triazole

+ Triazole

Cowen LE. Eukaryotic Cell 2008 7:747-764


Mechanism of resistance pulmonary aspergillosis

azole antifungals

Traizoles

Triazoles

Ergosterol

Ergosterol

Erg 3

Erg 3

P450 14DM

P450 14DM

Alternate sterol

Triazoles

Ergosterol

P450 14DM

Erg 3

Mutation

Toxic sterol

Erg 3

Alternation of synthesis

Mutation of Erg 3

Overexpression of

Efflux pumps

Alternation, mutation and over expression of P45014DM

Cowen LE. Eukaryotic Cell 2008 7:747-764


TR pulmonary aspergillosis

TR

G54

Promoter

G138

ITCZ resistance

POSA resistance

Multi-azole resistance

Multi-azole resistance

Membrane-anchoring region

Mechanism of azoleresistant A. fumigatusCyp51Amutation hot spot, Netherland & U.K.

Multi-azole resistance

(%)

L98H

M220

G448

F-helix

G-helix

Cyp51A

Membrane-anchoring region

Verweij PE, et al. Lancet Infect Dis 9: 789-795, 2009


Drug susceptibility of pulmonary aspergillosisAspergillus fumigatus

Nagasaki University Hospital Clinical Isolates (196 strains)

Strains:

Clinical isolated A. fumigatus between 1994 and 2010

Method of identification:

microscopic morphology

ability to grow at 48˚C

molecular confirmation (sequence of ITS and D1/D2)

Drug susceptibility test:

CLSI M38 A-2

Tested antifungals:

FLCZ, ITCZ, VRCZ, POSA, MCFG, AMPH-B

Molecular epidemiology

STR/microsatellite analysis


Drug susceptibility of pulmonary aspergillosisAspergillus fumigatus

Nagasaki University Hospital Clinical Isolates (196 strains)

frequency of non-WT isolates

Itraconazole ≧2 μg/ml (14/196)

7.1 %

Voriconazole ≧2 μg/ml (8/196)

4.1%

Posaconazole ≧1 μg/ml (5/196)

2.6 %


Drug susceptibility of pulmonary aspergillosisAspergillus fumigatus

Nagasaki University Hospital Clinical Isolates (196 strains)

frequency of non-WT isolates and cross resistance

POSA

VRCZ

ITCZ


Drug susceptibility of pulmonary aspergillosisAspergillus fumigatus

Nagasaki University Hospital Clinical Isolates (196 strains)

Comparison of positive rate of Cyp51A mutation to Europe


Drug susceptibility of pulmonary aspergillosisAspergillus fumigatus

Nagasaki University Hospital Clinical Isolates (196 strains)

Comparison Cyp51A mutation with Netherland

TR

TR

G54

Promoter

G138

ITCZ resistance

POSA resistance

Multi-azole resistance

Multi-azole resistance

Membrane-anchoring region

Multi-azole resistance

(%)

L98H

M220

G448

F-helix

G-helix

Cyp51A

Membrane-anchoring region

AAC. 2010; 54: 2425-30


Azole-resistant pulmonary aspergillosisAspergillus fumigatus

Nagasaki University Hospital Clinical Isolates (196 strains)

Correlation of ITCZ exposure amount and drug susceptibility

180000

150000

120000

Cumulative ITCZ exposure (mg)

90000

r = 0.5916

p <0.0001

60000

30000

0.25

0.125

0.5

1

8

4

2

>8

ITCZ MIC(μg/ml)


Azole-resistant pulmonary aspergillosisA. fumigatus isolated case

59 years old, Male

2011/9/9

32

CC: fever, cough, sputum

PH: surgical for pneumothorax

β-D glucan

Aspergillus Ag

AspergillusAb

Sputum culture (bacteria)

Sputum culture (Tbc)

Sputum culture

53.5

2.9

(+)

(-)

(-)

pg/ml

C.O.I.

A. fumigatus


Azole-resistant pulmonary aspergillosisA. fumigatus isolated case

59 years old, Male

2011/9/9

33

12

10

11

1

2

3

4

5

6

7

8

9

24.0

βD glucan

1999

ITCZ 200mg

53.5

15.7

6.9

Aspergillus Ag

2000

2.9

5.3

2.5

Sputum culture

Serum ITCZ conc. 1.148 μg/ml

MCFG 150mg

1st isolated ITCZ low-sensitive A. fumigatus

2.1

0.6

2001

ITCZ 400mg

ITCZ 200mg

53.4

132.2

87.0

2002

5.1

6.6

9.1

4.9

2.9

1.5

VRCZ 300mg

7.2

2003

0.8

0.6

0.1

ITCZ 200mg

MCFG 300mg


Azole resistant pulmonary aspergillosisA. fumigatus isolated case

59 years old, Male

2011/9/9

34

MCFG

150mg

ITCZ

200mg

ITCZ

400mg

1/23

8/16

12/14

5/16

2001/10/22

2000/08/15

2000/12/14

2001/05/17

2002/01/23

VRCZ

300mg

6/4

8/25

2003/04/14

2002/08/27

2011/08/29

2002/02/27

2002/05/22


Azole-resistant pulmonary aspergillosisA. fumigatus isolated case

59 years old, Male, summary of isolated strains and cases

2011/9/9

35


SUMMARY pulmonary aspergillosis

CPA treatment and drug resistance

Treatment

→New evidence become available by first RCT →Development of newer treatment is required

Azole-resistance

→It is few in Japan

→Cyp51A mutation is common in drug resistant strains

→Resistant may be acquired by exposure of azole


2014/9/11 pulmonary aspergillosis

37

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Annual meeting 2012,

Nagasaki, JAPAN


Acknowledgement pulmonary aspergillosis

  • Nagasaki University

    • Shigeru Kohno

    • Takayoshi Tashiro

    • Katsunori Yanagihara

    • Yoshihiro Yamamoto

    • Hiroshi Kakeya

    • Taiga Miyazaki

    • Yoshifumi Imamura

    • Shigeki Nakamura

    • Takahiro Takazono

    • Masato Tashiro

    • Katsuji Hirano

  • National Institutes of Infectious Diseases

    • Yoshitsugu Miyazaki

    • Hideaki Ohno


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