Changing epidemiology of invasive fungal infections

Changing epidemiology of invasive fungal infections.

George Petrikkos, MD,

Professor of Internal Medicine and Infectious Diseases

[email protected] National and Kapodistrian University of Athens

ATTIKON Hospital

12th ESCMID Summer School 6 – 13 July 2013, Vravrona, Greece

ESCMID Online Lecture Library

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Transparency Declaration

• I have received research grants from Gilead, Pfizer, Astellas, and Astra-Zeneca

• Acted as paid consultant to MSD and Astellas

• Member of the MSD speaker’ s bureau


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Incidence of Invasive Mycoses Time iC iA

1999 24 3.4

2000 23 4.1

2001 22 3.0

2002 23 2.6

2003 29 2.2

2004 27 2.4

Pfaller, ICAAC M 1805, 2006

Incidence per 100.000 population


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Increasing rate of candidiasis in the US

Martin et al, NEJM 2003;348:1546

+300%

+300%

+600%

+300%


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Increases in the prevalence of systemic Candida infections

Bassetti M, et al. BMC Infect Dis 2006; 6:21

Inci

den

ce o

f ca

nd

idae

mia

(e

pis

od

es/1

0,0

00

pat

ien

t-d

ays/

year

)

Year

1999 2000 2001 2002 2003

0

0.5

1.0

1.5

2.0

2.5

3.0

3.5


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The Incidence of IFIs is increasing

Annual incidence rates for IFIs in patients with haematologic malignancies from 18 centres in Italy between 1999 and 2003

Pagano L et al. Haematologica. 2006;91:1068-1075.

0

1

2

3

4

5

6

1999 2000 2001 2002 2003

Year

Annu

al in

cide

nce

rate

s, %

Aspergillus spp

Other moulds

Candida spp

Other yeasts

All fungal agents

IFI = invasive fungal infection.


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TRANSNET IFI Incidence July 2001-Dec 2005

0

5

1015

20

25

3035

40

45

Jul-Dec2001

Jan-Jun2002

Jul-Dec2002

Jan-Jun2003

Jul-Dec2003

Jan-Jun2004

Jul-Dec2004

Jan-Jun2005

Jul-Dec2005

ApergillosisFusariosisZygomycosis

•Cases/1000 transplants


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Incidence of invasive fungal infections after stem cell transplant, in USA, 2001-2006

(TransNet)

1,6

1,1

0,3

00,20,40,60,8

11,21,41,61,8

Aspergillosis Candidiasis Zygomycosis

12-m

onth

cum

ulat

ive

inci

denc

e (%

)

Kontoyiannis DP. Clin Infect Dis. 2010;50:1091-1100.


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Mortality due to invasive mycoses

0.6

0.4

0.2

0.0

1981 1986 1991 1996

Year

Rate

per

100 0

00 p

opulation

candidiasis

Other mycoses

aspergillosis

McNeil et al., Clin Infect Dis 2001:33


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IFI Neutropenia

Radiation therapy

Cytotoxic chemotherapy

Immunosuppression cyclosporin, steroids

AIDS Damage to integument mucositis, surgery, devices

ICU

Chronic illness renal/liver failure

Age extremes

Alteration of microbial flora

Malnutrition

Malignancy

Factors predisposing to development of IFI


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Populations at risk / risk factors

Immunocompromised “Non-immunocompromised” Neonates

Granulocytopenia Broad spectrum Abx In addition to ←

BMT Hemodialysis Gestational age

Mucositis CVC Low APGAR

GVHD IV drug use Length of NICU stay

Type of chemo Severity of illness H2 blockers

Organ transplants TPN Shock

Broad spectrum Abx GI perforation or surgery Intubation

CVC Colonization? GI disease

Colonization? Diabetes

LOS in ICU

Pancreatitis

Congenital malformations

Risk is an important factor when deciding who/when to treat! Blumberg HM et al. Clin Inf Dis 2001;33:177-86 Wenzel RP. Clin Inf Dis 1995; 20:1531-4 Fass RJ et al. J Antimicrob Chemother 1996;38:915-6


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The medically most important opportunistic mycoses in Europe are caused by Aspergillus spp.

and Candida spp.

Aspergillus spp. A.fumigatus is the most common etiologic agent (80-90%), other species are A.flavus (10-15%), A.terreus (2-5%), A.niger (1-2%).

Candida spp. C. albicans, with an increasing incidence of

C. glabrata , C. tropicalis and C. krusei.

Kullberg et al. Epidemiology of opportunistic invasive mycosis. Europ. J Med. Research, 2002 ESCMID Online Lectu

re Library

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Candidiasis C. albicans is a member of the indigenous microbial flora of humans. 1. Found in the gastrointestinal tract, upper respiratory tract, buccal

cavity, and vaginal tract. 2. Growth is normally suppressed by other microorganisms found in

these areas. 3. Alterations of gastrointestinal flora by broad spectrum antibiotics or

mucosal injury can lead to gastrointestinal tract invasion. 4. Skin and mucus membranes are normally an effective barrier but

damage by introduction of catheters or intravascular devices can permit Candida to enter the bloodstream. In vitro (25o C): mostly yeast;

In vivo (37o C): Yeast, hyphae and pseudohyphae


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Exogenous transmission of Candida includes:

use of contaminated irrigation solutions

parenteral nutrition fluids

vascular pressure transducers

cardiac valves

corneas.

Transmission of Candida spp. from health care workers to patients and from patient to patient has been well documented, especially in ICU.

The hands of health care workers serve as potential reservoirs for nosocomial transmission of Candida spp.


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Incidence of Candida bloodstream infections (per 10,000 hospital

admissions)

Canada 4.0

United States 8.0

Brazil 24.9

Australia 2.1

Spain 5.3

Sweden 3.2

France 2.0

Italy 3.8

Almirante et al. 2005; Colombo et al. 2005; Chen et al. 2006; Hajjeh et al. 2004; Laupland et al. 2005; Tortorano et al. 2004;


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Candidaemia – Incidences Europe

Almirante 2005, Krcméry 2000, Kibbler , Boo 2005, Presterl 2007, Richet 2002, Marchetti 2004, Verduyn Lunel Neth 2006, Tortorano 2002, Odds 2007, Sandven 2006

0.19/1,000 FCE 6 Mixed hosp UK 1997-1999

4.3/100,000 Barcelona ES 2002-2003

0.34/1,000 adm Multi-centre CH 1991-2000

0.75/1,000 adm 5 Univ hosp NL 1996-2001

0.48/1,000 adm Multi-centre IR 1992-2003

0.29/1,000 adm 25 Mixed hosp FR 1998-2001

6.4/100,000 Lombardy IT 1997-1999

0.77/1,000 adm 1 Univ hosp AU 2006

1.2/100,000 National SK 1997-1998

4.8/100,000 Scotland 2006

3/100,000 Norway 2001-3


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Nosocomial bloodstream infections in US hospitals: 1995-2002

(SCOPE study of 24,179 cases of nosocomial BSI in the US)

Rank

Pathogen

BSI per 10,000

admissions

% BSI % Crude mortality

Total n=20,978

ICU n=10,515

Non-ICU n=10,515

Total ICU Non-ICU

1. CoNS 15.8 31.3 35.9 26.6 20.7 25.7 13.8

2. S aureus 10.3 20.2 16.8 23.7 25.4 34.4 18.9

3. Enterococcus spp 4.8 9.4 9.8 9.0 33.9 43.0 24.0

4. Candida spp 4.6 9.0 10.1 7.9 39.2 47.1 29.0

5. E coli 2.8 5.6 3.7 7.6 22.4 33.9 16.9

6. Klebsiella spp 2.4 4.8 4.0 5.5 27.6 37.4 20.3

7. P aeruginosa 2.1 4.3 4.7 3.8 38.7 47.9 27.6

8. Enterobacter spp 1.9 3.9 4.7 3.1 26.7 32.5 18.0

9. Serratia spp 0.9 1.7 2.1 1.3 27.4 33.9 17.1

10. A baumannii 0.6 1.3 1.6 0.9 34.0 43.4 16.3

BSI=blood stream infection. Surveillance and Control of Pathogens of Epidemiologic Importance (SCOPE) study.


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Evolution of Isolation of Candida Species in Relation to Fluconazole Consumption

0

20

40

60

80

100

1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003Year

Spe

cies

dis

trib

utio

n

Sendid B et al. BMC Infectious Diseases 2006:61-9.

C. albicans C. glabrata C. tropicalis C. parapsilosis C. krusei Other species


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Candidemia in Bone Marrow Transplantation

30 patients with Candidemia

585 patients received Fluconazole prophylaxis 400 mg/d X 75 days

Colonization: 256 (44%)

Non-albicans in 53%

Rate of candidemia decreased: 11.4% to 4.6%

2/2 C. albicans Flu-R

Attributable mortality: 20%

Marr et al, JID, 2000


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NEMIS Surveillance Hand Cultures

C. parapsilosis

59%

C. albicans

19%

C. lusitaniae

9.5%

C. guillermondii

6.3%

C. glabrata

2.9%

C. tropicalis

1.8%

Other Candida spp.

2.3%

C. krusei

0.6%

Species

% of total

N=2787 isolates

Rangel-Frausto/NEMIS. CID 1999;29:253


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Biofilms and Candida parapsilosis

• 2nd most common species in blood, related to catheters and glucose solutions

• Causes biofilms which usually require removal of catheters etc, as antifungal drugs are ineffective in eradicating biofilms

Pfaller 2006, Pfaller 2007


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Distribution of principal Candida species in Europe

Tortorano AM, et al. Eur J Clin Microbiol Infect Dis 2004; 23:317–22

C. albicans

C. glabrata

C. parapsilosis

C. tropicalis

C. krusei

C. guilliermondii

C. lusitaniae

C. kefyr

Other species

Unidentified Candida sp.

> 1 Candida spp.

Most common species: Candida albicans (44 – 62%, N. America, Europe)

C. glabrata is the 2ndor 3d (according to country )

most commonly isolated Candida species in Europe


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In European countries : C. albicans (61 % of isolates)

U.Binder and C. Lass-Flörl. Mediterr J Hematol Infect Dis 2011; 3:

Region 1st 2nd 3d 4th

Switzerland, UK C. albicans C. glabrata

C. parapsilosis

C. tropicalis

South

C. albicans C. parapsilosis C. glabrata C. tropicalis

Spain

C. albicans C. parapsilosis C.tropicalis C. glabrata

Distribution of principal Candida species in Europe


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1- Tortorano A.M., Peman J., Bernhardt H., Klingspor L., Kibbler C.C., Faure O., Biraghi E., Canton E., Zimmermann K., Seaton S., Grillot R. CMM Working Group on Candidaemia. Epidemiology of candidaemia in Europe: results of 28-month European Confederation of Medical Mycology (ECMM) hospital-based surveillance study. Eur J Clin Microbiol Infect Dis. 2004; 23(4):317-22.

Epidemiology of Candida species is complex and varies among different patient care units1

Causative Candida species by hospital care unit

Clinicians must consider their own units’ epidemiologic trends

Pathogens


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Underlying conditions in patients with candidaemia

Underlying condition* Number of patients (%) Surgery 933 (44.7) Intensive care 839 (40.2)

Solid tumour 471 (22.5)

Haematological malignancy 257 (12.3) Premature birth 125 (6.0) Solid organ transplantation 74 (3.5) HIV infection 63 (3.0) Burns 29 (1.4) A total of 2,089 cases of candidaemia were documented by 106 institutions in the seven participating countries during the 28-month study period *364 (17.4%) were treated with steroids

Tortorano AM et al. Eur J Clin Microb Infect Dis 2004; 23: 317


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Epidemiology of Candida species by underlying condition and age group

Category (n) Candida species

C. albicans C. glabrata C.

parapsilosis

C. tropicalis

Underlying condition Surgery (933) 58.0 16.3 12.6 6.1 Intensive care (839) 60.5 11.9 12.9 6.1 Solid tumour (471) 58.0 15.9 10.6 8.3 Haematological malignancy (257) 34.6* 9.7 14.8 17.9*

Foetal immaturity (125) 60.8 4.8* 28.8* 2.4 HIV infection (63) 65.1 9.5 6.3 6.3 Age group < 1 year (158) 59.6 3.1* 27.9* 3.1 1–19 years (144) 47.9 3.6* 32.9* 5.7 20–69 years (1,189) 57.1 14.0 11.2 8.3 ≥ 70 years (590) 60.0 19.3* 6.9* 7.1 Total population 56.4 13.6 13.3 7.2

Tortorano AM, et al. Eur J Clin Microbiol Infect Dis 2004; 23:317–22 *p ≤ 0.01 versus percentage in total

population.


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1- Bille J.,Curr Opin Infect Dis. 2005;18(4):314-9. 2- Pfaller M.A., Diekema D.J. Clin Microbiol Infect. 2004;10 Suppl 1:11-23.

Epidemiology of Candida spp infection in Europe and USA

Candida spp. isolated in Europe2 (1992-2001; N = 775)

Candida spp. isolated in the U.S.2 (1992-2001; N = 3,683)

13%

C. glabrata

C. parapsilosis

C. tropicalis

C. glabrata

C. parapsilosis

C. tropicalis

Other non-albicans spp

14%

8%

5%

C. albicans 58%

18%

13%

10%

Other non-albicans spp

C. albicans 54%

C. krusei

3%

C. krusei

2%

Crit Care Med 2009; 37: 1612-18 IJAA 2009; 554:e1-7

2%


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Pt Groups and Host Factors

No of cases 1,143 569 314 1,093

CVC 78% - <91% 73%

Surgery 50% 45% 56% 37%

ICU 36% 40% 51% 25%

SO Tumour 24% 23% 23% 16%

Haematological M. 11% 12% 9% 16%

Premature/Neonate 5% 6% 2.5% 3.3%

SO Transplant 5%* 3.5% 2.5% 2.2%

Burn - 1.4% 0% -

30 Days Mortality 36% 38% 38% 28%

Hajjeh JCM 2004, Tortorano Eur J Clin Micro Inf Dis 2004, Chen Emerg J Dis 2006


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Distribution of principal Candida species in Europe Summary

• The epidemiology of Candida infections is changing so that the proportion of infections caused by C. albicans is decreasing while non-albicans species are becoming more common.1

• The largest increases have been seen in species that show acquired or intrinsic resistance to fluconazole, such as C. glabrata and C. krusei. In many studies, C. glabrata is now the second most commonly isolated Candida species after C. albicans.2

• These changes may be explained by increased fluconazole use and subsequent increases in colonisation by fluconazole-resistant species and may have significant clinical implications.3

• Fluconazole is the most commonly used antifungal agent, despite as many as 10–15% of C. glabrata and almost 75% of C. krusei infection-causing isolates being partially or completely resistant to it.2,4

1.Bassetti M, et al. BMC Infect Dis 2006; 6:21. 2.Tortorano AM, et al.. Eur J Clin Microbiol Infect Dis 2004; 23:317–322. 3.Trick WE, et al.. Clin Infect Dis 2002; 35:627–630. 4.Messer SA, et al. J Clin Microbiol 2006; 44:1782–1787.


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Resistance to fluconazole in Candida spp.

Species

Fluconazole MIC (µg/ml)

Percentage of isolates

50% 90% Range Susceptible

Susceptible–dose-

dependent* Resistant

Candida spp. 0.5 16 ≤ 0.12–256

88.5 7.3 4.2

C. albicans ≤ 0.25

0.5 ≤ 0.12–128

99.4 0.1 0.4

C. glabrata 8 64 1–128 52.1 35.8 12.1 C.

parapsilosis

1 2 0.25–64 98.8 0.8 0.4

C. tropicalis 1 2 ≤ 0.12–128

98.0 0.7 1.3

C. krusei 64 128 16–256 0.0 25.9 74.1

Messer SA, et al. J Clin Microbiol 2006; 44:1782–1787 *Refers to isolates with reduced susceptibility that

can be overcome by increasing the dose.


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Candida glabrata

• Sub-optimal fluconazole dosing

• Pan-azole resistance

• Over 10 years, the frequency of C. glabrata increased in

– Canada, 13-24%

– Europe, 11-13%

– USA, 14-28%

• Least common in Latin America (7.5%)

Pfaller 2006, Bhatti 2006, Pfaller 2007


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Aspergillus & other moulds


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Aspergillus

•Ubiquitous mould:

•Soil, water, decaying vegetation

•Sources

•Unfiltered air/ventilation systems •Dust from renovation/construction •Environmental sources •Food/plants


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Environment as a Risk Factor Fungus at Home

• Hospital construction is known to increase cases of IA

• HEPA filtration is known to decrease cases of IA

• Aspergillus may be found in patient showers… genetically identical to the one from the patient!

• Highest concentration of Aspergillus fumigatus is at home

• Protective environment for pts with allo-BMT now included in the new draft CDC guidelines for isolation

Williamson, Thorax 1997;52:229.

Taskinen, Acta Paediatr 1999; 88:1373.

Oren, Am J Hematol 2001; Anaissie, CID 2002.


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Environment as a risk factor

• Hospital construction is known to increase cases of IA

• HEPA filtration is known to decrease cases of IA

• Aspergillus may be found in patient showers… genetically identical to the one from the patient!

• Protective environment for pts with allo-BMT now included in the new draft CDC guidelines for isolation

Oren, Am J Hematol 2001; Anaissie, CID 2002.

Invasive Aspergillosis


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Aspergillus and Construction

•Association between aspergillosis outbreaks and construction •Environmental controls associated with decreased risk

•Maintain positive pressure

•Install appropriate barriers •Control traffic in construction areas •Monitoring of airborne spore count

Arnow 1991; Wald 1997; Cornet 1999; Patterson 2000


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Dust Control - Contractor Issues


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Dust Control - Maintenance Issues


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ADMISSION TO THE HUMAN BODY

•Aspergillus is clearly mainly an airborne infection, the spores in the air will enter the body through the airways and they will arrive CLIK in nasal sinuses and bronchi where the first lesions are usually found.


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Classic risk factors for aspergillosis

• Hematological malignancies

– Leukemia

– MDS

– SCT

– GVHD

– Prolonged neutropenia

– Induction chemo

• Critically ill?

• Immunosuppression, Steroids

• HIV/AIDS?

• Transplant patients:

– Lung, liver, heart, renal

– Liver transplant

– Acute/ chronic rejection

– Steroids

– Tacrolimus

– OKT3

– Renal failure

– CMV

Muhlemann K, Leukemia. 2005 Feb 24; Sole A, Clin Microbiol Infect. 2005 May;11(5):359-65; Nina Singh N, Clin Microbiol Rev. 2005 Jan;18(1):44-69; Thursky K, Bone Marrow Transplant. 2004 Jul;34(2):115-21.


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Invasive Aspergillosis in Transplant Recipients

Type of Transplant Incidence Range, % (Mean) Mortality (%)

Lung 3-14% (6%) 68%

Liver 1-8 (2) 87

Heart 1-15 (5) 78

Kidney 0-4 (1) 77

Small bowel 0-10 (2) 66

Allogeneic stem cell 5-26 (10) 78-92

Autologous stem cell 2-6 (5) 78-92

Nonmyeloblative stem cell 8-23 (11) 63-67

Singh & Paterson. Clin Microbiol Rev. 2005 18:44-69.


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TRANSNET Aspergillus Isolates 2001-2004

A.terreus9%Other*

5%

A.niger10%

A.flavus13%

A. Fumigatus63%

*Other includes A versicolor, A ustus, A glaucus, A nidulans, and A ilacinus.

Adapted from Baddley JW, et al. IDSA . 2004. Abstract 673.


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The Changing Landscape of Fungal Infections: Increasing Apergillosis and Other Molds

• An increase in aspergillosis and decrease in candidiasis has been observed:

– 2 large autopsy studies

– Study of bone marrow transplant recipients

• A similar pattern has been reported in a pediatric cancer population

Groll A et al. J Infect 1996:23-32. Yamazaki T et al. J Clin Microbiol 1999;1732-1737. van Burik J et al. Medicine 1998:246-254. Rosen G et al. J Pediatr Hematol Oncol 2005:135-140.


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Invasive Aspergillosis Continues to Pose a Significant Threat

• In Germany, a review of 11,000 autopsy cases from 1978 through 1992 demonstrated a 17-60% proportional increase in cases of invasive aspergillosis.

• In the US, the number of deaths due to aspergillosis increased almost 4-fold between 1980 and 1997.

• When stratified by underlying disease, patients with bone marrow transplants have a case mortality of 87-90%, the highest rate observed for any group.

Kullberg B, Lashof O. European J Med Res. 2002;7:183-191.


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Aspergillosis at Autopsy - Sites of Infection

Disseminated

Lungs only

CNS only

Disseminated (not lungs)

Vogeser et al Eur J Clin Microbiol Infect Dis 1999;18; 42-45


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0

10

20

30

40

50

60

70

80

90

Underlying condition Site of infection

Overall BMT Leukaemia lymphoma

Pulmonary CNS Disseminated

Crude mortality for invasive aspergillosis Review of the literature - 1941 patients from 50 studies

(1118/1941)

(247/285)

(142/288)

(74/84)

(97/161)

Lin et al


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Author Year Type of study Patient category N. Incidence Mortality

Lewis 1985 Case series IPA complicating influenza pneumonia

Case report and literature review 6 - 100%

Karam 1986 Cases series Non-neutropenic patients - 10 structural lung disease

7 steroid treatment

32 - 100%

Janssen JJWM

1996 Monocentric

Retrospective Medical ICU pts with hematological malignancy, immunosuppression for mixed connective tissue disease, ARDS

25 - 92%

Pittet 1996 COPD patients in MICU

Acquisition of IPA during mechanical ventilation due to high grade airborne inoculation

2 - 100%

Rello 1998 Monocentric Series of COPD patients and literature review

24 - 100%

Valles 2002 Two centres

Observational, prospective study

Hospital acquired pneumonia requiring ICI admission

Aspergillus spp. identified in 17% of pts Mainly COPD pts

77%

Bulpa 2001 Monocentric

Case series COPD patients admitted to ICU diagnosed with IPA

23 - 100%

Epidemiological studies on Aspergillosis in ICU


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Author Year Type of study Patient category N. Incidence Mortality

Meersseman 2004 Monocentric

Retrospective Medical ICU

70% cases without malignancy

5 pts with IA without known predisposing condition (of whom 3 Child C cirrhosis)

107 5.8% 91%

Garnacho-Montero

2005 Multicentric

Prospective 73 ICU’s in Spain

patients with LOS > 7 days 20 1.1% 80%

Vandewoude 2006 Retrospective Mixed ICU 40% haematological pts

83 3.3/ 1000

77%

Epidemiological studies on Aspergillosis in ICU


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Cryptococcosis


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Epidemiology of Cryptococcosis Mainly: Cryptococcus neoformans (associated with HIV or other immunosuppression, cosmopolitan, pigeon excrement)

Cryptococcus gattii (previous name C. neoformans var. gattii, associated with recent epidemics in immunocompetent in British Columbia, Canada and the Pacific Northwest, tropical and subtropical climates, eucalyptus trees)


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Epidemiology of Cryptococcosis

Cryptococcosis is usually acquired by inhaling aerosolized cells of C. neoformans from the environment, disseminate from lungs to CNS.

pathogenic for immune-competent individuals, but most often encountered as “opportunistic pathogen”.

the most common cause of fungal meningitis and tends to occur in patients with defective cellular immunity (HIV).

HIV patients with CD4+ T less than 200/mm3 are at high risk for CNS and disseminated cryptococcosis.


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Western & Central Europe

500

North Africa & Middle East

6,500 Sub-Saharan

Africa 720,000

Eastern Europe & Central Asia

27,200

South & South-East Asia

120,000 Oceania

100

North America 7,800 Caribbean

7,800 Latin America

54,400

East Asia 13,600

Global total: 957,900 cases (range: 371,700 – 1,544,000)

Estimated annual cases of HIV-associated cryptococcosis

Park et al. AIDS 2009; 23: 525-30


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Western & Central Europe

45

North Africa & Middle East

3,600 Sub-Saharan

Africa 504,000

Eastern Europe & Central Asia

15,000

South & South-East Asia

66,000 Oceania

10

North America 700 Caribbean

4,300 Latin America

29,900

East Asia 1,200

Global total: 624,700 deaths (range: 125,000 – 1,124,900)

Estimated annual deaths from HIV-associated cryptococcosis

Park et al. AIDS 2009; 23: 525-30


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0

200.000

400.000

600.000

800.000

1.000.000

1.200.000

Malaria

Diarrhe

al dis

ease

s

Childh

ood-c

luster

dise

ases

Cryptoc

occo

sis

Tuberc

ulosis

STDs exc

luding

HIV

Tropica

l-clus

ter di

seas

es

Hepati

tis B

Non-C

rypto

Mening

itis

Hepati

tis C

Estimated deaths in Sub-Saharan Africa from cryptococcosis and other infectious

diseases*

WHO estimates

* Excluding HIV AIDS


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“The Others…”


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Rare fungal infections Changing epidemiology


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Rare fungi increasingly encountered as causing disease:

Zygomycetes (mucorales) Hyaline filamentous fungi: Fusarium spp., Pseudallescheria boydii /Scedosporium Acremonium spp. Paecilomyces spp. Dematiaceous filamentous fungi: Bipolaris spp., Cladophialophora bantiana, Exophiala species Alternaria

mucormycosis

pheohyphomycosis

hyalohyphomycosis


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Non-aspergillus moulds in SCT; FHCRC, Seattle

Marr KA, et al. Clin Infect Dis. 2002;34:909-917

Fusarium species 16

14

12

10

8

6

4

2

0

1985-1989 1990-1994 1995-1999

Time period

Zygomycetes

Scedosporium species

Inf

ect

ions

, n


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Kaplan-Meier curve showing probability of survival for 53 transplant recipients with various types of mold infections

(Pp.153, by the Mantel-Cox test).


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Epidemiology of Mucormycosis


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Mode of transmission

Spores-Conidia

Trauma /inoculation

Respiration


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Zygomycosis: Epidemiology

• The incidence of Zygomycosis is approximately 1.7 cases per 1 000 000 inhabitants per year, which means 500 patients per year in the USA.1

• Post-mortem evaluation shows that zygomycosis is 10- to 50-fold less frequent than candidiasis or aspergillosis, and it appears one to five cases per 10 000 autopsies.2-4

• In patients undergoing allogenic bone marrow transplantation the incidence may be 2-3%.5,6

1. Ree JR et al. Clin Infect Dis ; 27:1138-1147;1998. 2. Hotchi M et al. Am J Clin Pathol ;74:410-416;1980. 3. Tietz HJ et al. Mycosis (suppl 2); 81-85;1998. 4.Yamazaki T et al. J Clin Microbiol ; 37: 1732-1738;1999. 5. Maertens J et al. Bone Marrow Transplant ; 24:307-312;1999. 6. Marty FM et al . N Eng J Med ; 350:950-952


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Changing Spectrum of Invasive Molds

Invasive Aspergillosis

64%

Fusariosis16%

Zygomycosis20%

Incidence per 1000 Patient Days

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

2000 2001 2002 2003 200

Year

Rat

e of

asp

ergi

llosi

s

0

0,03

0,06

0,09

0,12

0,15

0,18

0,21

Rat

e of

Zyg

omyc

osis

Aspergillus

Zygomycetes

Kontoyiannis DP, et al. J Infect Dis. 2005;191:1350-1360.


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0%

20%

40%

60%

80%

100%

1940s 1950s 1960s 1970s 1980s 1990s 2000s

Per

cen

tag

e o

f zyg

om

yco

sis

case

s d

ocu

men

ted

by

cultu

re

Roden M, et al. Clinical Infectious Diseases 2005; 41:634–53

Mucormycosis has emerged as an increasingly important infection with high mortality.

Introduction


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Patterns of Zygomycosis

4%10%

5%

60%

12%

3% 6%

Roden M, et al. Clinical Infectious Diseases 2005; 41:634–53

Malignancy

Rhinocerebral Sinus Sino-orbital Pulmonary Cutaneous Gastrointestinal Other

40%

8%14%

15%

9%

8%6%

Diabetes

7%9%

5%

8%

50%

9%

8% 4%

No Underlying Condition

Most of zygomycotic infections occur in patients with underlying diseases.

In a review of 929 zygomycosis cases, approximately 20% occurred in healthy individuals, but the most common reported cases were in those with diabetes, followed by cancer and bone marrow transplantation.


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REVIEW OF THE LITERATURE (More than 5 Cases in Europe)

1. G.Petrikkos . Eur J. Clin Microbiol. and Inf. Dis. 2003 24 cases. Greece 2. M. Torres Narbona. J. Clin. Microbiol. 2007 6 cases Spain 3. L. Pagano. Journal of Chomother. 2009. 60 cases. Italy 4. D.Bitar. Emerg Infect Dis 2009. 531 cases France 5. M Ruping J . Animicrob. Chemother 2009. 41 cases Germany 6. J. Abrosioni. Int . J. Infect. Dis. 2010. 55 cases Switzerland 7. V. Saegeman Emerg Infect Dis. 2010 31 cases Belgium


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Zygomycosis in Europe: analysis of 230 cases accrued by the registry of the European Confederation of Medical Mycology (ECMM) Working Group on

Zygomycosis between 2005 and 2007

• Skiada A, Pagano L, Groll A, Zimmerli S, Dupont B, Lagrou K, Lass-Florl C, Bouza E, Klimko N, Gaustad P, Richardson M, Hamal P, Akova M, Meis JF, Rodriguez-Tudela JL, Roilides E, Mitrousia-Ziouva A, Petrikkos G; European Confederation of Medical Mycology Working Group on Zygomycosis.

Clin Microbiol Infect. 2011 Dec;17(12):1859-67.


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9

21

60

1

2

2

36

35

6 5

12

16

2

0 1

0

22 0

60

36

35

22

21

16

12

9

6

5

2

2

2

1

1

Italy

Greece

Germany

Switzerland

France

Belgium

Austria

Spain

Russia

Norway

Finland

Czech Republic

Turkey

Netherlands

UK

0



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Sites of infection in relation to underlying disease

Hematological malignancies (102)

p< 0.001

pulmonary34%

rhinocerebral

15%sinusitis

13%

soft tissue10%

disseminated

27%

liver1%

rhinocerebral52%

sinusitis10%

soft tissue14%

pulmonary14%

disseminated10%

soft tissues89%

sinusitis5%

pulmonary6%

Immunocompetent (18)

Diabetes (21)



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RESULTS: Underlying disease in relation to the site of infection

Hem. malignancy correlated with pulmonary disease

– Of the 103 patients with hematological malignancy , 35 had pulmonary zygomycosis (33.98%)

– Of the 67 patients with pulmonary zygomycosis , 35 had an underlying hematological malignancy (52.24%)

Diabetes correlated with rhinocerebral disease

– Of the 21 patients with diabetes, 11 had rhinocerebral disease (52.38%)

– Of the 31 patients with rhinocerebral disease, 11 had diabetes (35.48%)

Pearson chi2 p<0.001



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RESULTS: Underlying Diseases and mortality (%)

0

10

20

30

40

50

60

70

80

Underlying

Mortality



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Mortality rates according to the site of infection

Phinocerebral 40-50%

Pulmonary 80%

Soft tissue Better prognosis


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Mortality Due to Mold Infections

42,0%

64,0%

52,0%

0%

20%

40%

60%

80%

100%

Aspergillus spp Zygomycetes Fusarium spp

% o

f pat

ient

s

Pagano L et al. Haematologica 2006;91:1068-1075.

11,802 patients (18 centers)


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CONCLUSIONS

• In conclusion, this large European study found that zygomycosis continues to be a disease with a dismal prognosis in about half of the cases.

• Clinicians treating patients with diabetes, haematological malignancies or trauma, or patients who are immunosuppressed for any reason, should have a high index of suspicion for the disease and make every effort to obtain tissue for histology, culture and, if possible, PCR.

• A combination of liposomal amphotericin B with surgery offers the best chance of recovery.


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A.Skiada et al. for the European Confederation of Medical Mycology Working Group on Zygomycosis. Clin Microbiol Infect. 2011

Mucormycosis Underling diseases

Differences Between Europe and India

Trauma/no underlying

dis. 18%

Diabetes 15%

Haematol. malignancy

50%

SO Ca/T 8%

DFO 1%

Cortico 6%

HIV 2%

Skiada et al. 2011 Trauma/no underlying

dis. 20%

Diabetes 78%

Haematol. Malignancy

1%

SO Ca/T 1%

Chakrabarti et al. 2006


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Variables that Account for the Current Trends in the Epidemiology

• Increasing number of susceptible hosts: transplant type

• Center to center differences, patient selection

• Greater laboratory expertise in detection & identification of fungi

• Use of new transplant modalities for hematopietic stem cell transplantation

• Changing surgical techniques: evolution in organ transplant practices

• Use of corticosteroid-sparing regimens and overall conservative approach to immunosuppression

• Use of novel immunosuppressive agents

• Antimicrobial prophylactic practices

• Underlying Diseases

• Poor diagnostic tools

Singh 2001; Denning 2005, Kontoyiannis 2005, Lass-Flörl 2005


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Principal changes in the epidemiology of invasive fungal infection

J.J. Cast΄on-Osorio et al. / International Journal of Antimicrobial Agents 32 Suppl. 2 (2008) S103–S109


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And the Epidemiology is changing Candida and Aspergillus species are the leading causes of

IFI in patients with hematological malignancies

Candida Data from 311 hospitals from 1989 to 1999 have demonstrated that:

– Bloodstream infections caused by C albicans have significantly decreased (P < .001)1

– Bloodstream infection caused by C glabrata have significantly increased (P = .05)1

– Data from TRANSNET reported that C. glabrata accounts for 32% of infections whereas C. albicans accounts for only 22% of infections2

increased prophylactic use of azoles and widespread use of antifungal agents for febrile neutropenia

prolonged echinocandin treatment

1. Trick WE et al. Clin Infect Dis. 2002;35:627-630.

2. Pappas PG. Focus on Fungal Infections 2007.


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Invasive Aspergillosis occurs in 20% of Allogeneic HSCT, 10% of AML, 5% of ALL and 2% of Autologous HSCT

- Increase in 2006 : 40 cases per 1000 transplants

- Improvement of survival rates from 2001 to 2006

Zygomycetes: Data from the US Transplant-Associated Infection Surveillance Network (TRANSNET) have demonstrated that:

- Incidence of zygomycosis per thousand HCTs has increased from

1.7 in 2001 to 6.2 in 20041

- By early 2006, approximately 24% of all invasive mould infections

in the transplant population were caused by the Zygomycetes2

Prolonged use of voriconazole (prophylaxis or treatment)?

Fusarium and Scedosporium species: important etiologic agents 3

1. Park BJ et al. ICAAC 2007

2. Pappas PG. Focus on Fungal Infections 2007. 3. Upton A , Mark KA 2006.

And the Epidemiology is changing


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Changing Epidemiology of Invasive Mycoses Summary

• Invasive mycoses remain a major cause of morbidity and mortality in high risk patients

• Aspergillus, Candida and Cryptococcus are major etiologic agents.

• The epidemiology of Candida infections is changing so that the proportion of infections caused by C. albicans is decreasing while non-albicans species are becoming more common.

• Incidence and clinical presentation of invasive mycoses differ in transplantation groups and in other immunosuppressed hosts.

• Other opportunistic moulds (Mucorales) may also be important pathogens in haematologic and diabetic patients.

• Any fungi isolated from immunocompromised patients should be considered as pathogens.


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Remember:

• ‘Until we can show that the apparent size of the mycoses problem is deceptively small,

• ‘that in reality the mycoses are common diseases, and that the toll they take in misery and mortality is high,

• ‘we cannot expect to obtain the support we need for research and development’

Libero Ajello 1970


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Zygomyco.net: an ECMM/ISHAM registry


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Changing epidemiology of invasive fungal infections