aspergillus and aspergillosis - escmid: escmid

Aspergillus and aspergillosis: an introduction Malcolm Richardson

Director Mycology Reference Centre

UHSM and University of Manchester

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Aspergillus and aspergillosis

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Aspergillus is in the air

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ASPERGILLOSIS

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A short history of Aspergillus

• First catalogued by P. Michelli in 1729

• First known case of infection: 1815 (jackdaw) • 1842 (human)

• Occupational hazard amongst wig combers • (allergic disease of the lungs).

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Sources of Infection – Soil – Air; spores may be inhaled – Water / storage tanks in hospitals – Food – Compost and decaying vegetation – Fire proofing materials – Bedding, pillows – Ventilation and air conditioning systems – Computer fans

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Members of the family • Genus of around 200 fungi (moulds) worlwide

• Filamentous fungus (opposed to single celled • fungus), reproduction by spores • A. fumigatus, A. flavus, A. niger, A. clavatus

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Where is Aspergillus found?

• Natural habitat: hay and compost.

• Aspergillus spores are easily airborne • (100-200 spores daily). • • Some species withstand heat (Aspergillus • fumigatus), commonly found in compost.

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Pulmonary Aspergillosis

• Allergic Aspergillosis

• Noninvasive Local Colonization

• Invasive Aspergillosis

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Allergic Aspergillosis

• Asthma bronchiale

• Allergic bronchopulmonary aspergillosis ABPA (Types I, III)

• Allergic Aspergillus sinusitis – AAS

• Allergic alveolitis

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ABPA

• Hypersensitivity-reaction

• A. fumigatus

• Bronchial collapse, bronchiectasis

• Lung infiltration by eosinophils

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Noninvasive Local Colonization

• Aspergilloma (cavities)

• Otomycosis

• Onchomycosis

• Eye infection

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Aspergillus sinusitis

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Growth of Aspergillus

1-2 mm per hour

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Invasive Aspergillosis

• Rare, but life-threatening

• Progression speed varies

• Immunocompetency

• Pulmonary vs. disseminated

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EORTC-MSG Standards

• DEFINITE

• positive histology or culture

• PROBABLE

• sputum • antigen

• CT

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Pulmomary aspegillosis

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Aspergilloma

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MORTALITY OF INVASIVE ASPERGILLOSIS IN RELATION TO UNDERLYING DISEASE

Lin, Schranz, Teutsch Clin Infect Dis 2001;32:358

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AID

S

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The Helsinki experience: adults • 1989-1995 • 22 IPA allo BMT • Diagnosis 69-466 (median 131 days post Tx) • 16 (73%) definite or probable • Lung involvement: 90% • CNS: 41% • respiratory symptoms >50% • neurological symptoms 27% • Optimal diagnosis: tissue biopsy • BAL: 8/14 ”suggestive”

Jantunen et al. BMT 2000; 25: 867-871

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The Helsinki experience: children Invasive fungal infections in pediatric bone marrow transplant recipients: single center

experience of 10 years • 148 BMT • 12/73 (16%) infection: allogeneic • 6/75 (8%) infection: autologous • 15/18 died, in 12 IFI as cause of death • 48 suspected infections • allogeneics: severe GVHD major risk factor • steroid dose associated with IFI

Hovi et al. Bone Marrow Transplantation 2000; 26: 999-1004.

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Pathophysiology of aspergillosis

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The life cycle of Aspergillus

Spores Germination

Mass of hyphae (plateau phase)

Hyphal elongation and branching

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Gravity sedimentation

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Aspergillus in tea!

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Air sampling

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Air sampling: >1300 cfu/m3!

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Dust

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Dust collection

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Double door entry: HYKS

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Ceiling tiles: HYKS

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Nosocomial aspergillosis

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Invasive aspergillosis

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DEVELOPMENT OF ASPERGILLOSIS

1 2 3

INHALATION INFECTION COLONIZATION Dissemination

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CAB 0.5mg

CAB 0.8mg

CAB DC

CAB 0.3mg

Day 1 4 7 10

IPA: DISEASE PROGRESSION

2cms/day in vitro

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Aspergillus: Risk of aspergillosis

Risk of aspergillosis

Remission induction

Remission induction

Complete remission

Refractory Refractory

Remission induction Consolidation Allogeneic BM SCT GVHD

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Days after transplant 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170

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Wald et al. J Infect Dis 1997;175:1459

Aspergillus: Time to diagnosis of aspergillosis after BMT

Neutropenia Graft versus host disease

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Assessment of risks following HSCT

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Days Months -7 0 7 14 21 12 6 9 12 -14 6 28 8 10

Weeks Transplant

ENGRAFTMENT PRE-TRANSPLANT

EARLY POST-ENGRAFTMENT

LATE POST-ENGRAFTMENT

treatment

Disease likelihood

Prophylaxis

remote

High risk Host factors

Empirical

possible

Persistent fever Mucositis

Pre-emptive

Probable disease

Clinical features

Mycological evidence features

Specific

proven

Tissue evidence

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Risk periods for mycosis following HSCT

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Days Months -7 0 7 14 21 12 6 9 12 -14 6 28 8 10

Weeks Transplant

ENGRAFTMENT PRE-TRANSPLANT

EARLY POST-ENGRAFTMENT

LATE POST-ENGRAFTMENT

Stem cells acute GvHD low IgG

neutropenia corticosteroids

chronic GvHD

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Aspergillus: Risk factors for aspergillosis after BMT – building

works


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Risk factors for aspergillosis after BMT – season


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Winter Spring Summer Autumn

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Risk factors for aspergillosis after BMT – building works


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The application of a quantitative risk assessment paradigm to the acquisition

of nosocomial infection caused by Aspergillus species

•hazard identification •exposure assessment •dose-response relationship •risk characterisation •risk management •communication

Wilkinson 1998; HIS Electronic News Bulletin

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Acceptable levels

• HEPA filtered air: 0 • Open ward:? • General hospital areas: ? • Outdoor air: highly variable/seasonal

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Bioaerosols in the hospital environment

• What are bioaerosols? • Can bioaerosols cause health problems • What are the sources of bioaerosols in

hospital? • What measures can be taken to control

bioaerosols in the hospital? • How can I control the cause of

bioaerosols?

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Building materials Ceiling tiles, insulation, Aspergillus. painted surfaces, wallpaper Cladosporium Carpet Alternaria Stachybotrys Dust Alternaria Cladosporium Penicillium

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Sources of Aspergillus spp.

• Environment • Food

– long list! – Sharing of salt and pepper pots – autoclave pepper

• standing water • ice-making machines • fomites

– carpets/furniture/fabrics/soft toys

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Fungal contamination of food distributed to neutropenic patients

Food Contaminated Fungi samples (%) Tea 100 A. fum, A. flavus Pepper 100 A. fum, A. niger

Freeze-dried soup 20 A. fum, A. niger Apricot 66 A. fum, A. flavus Kiwi 50 A. fum Banana 25 A. fum Grapefruit juice 15 A. fum

Bouakline et al. JCM 2000; 38: 4272-4273.

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Kitchens as a source of A. niger infection

• 3 cases of cutaneous infection: BMT unit • A. niger isolated:

– surfaces – side vent of ice-maker – tea caddy

• No isolates from bedroom • I patient infected with environmental strain

Loudon et al., JHI 1996

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Aspergillosis due to carpet contamination

• 13 cases of IA: July 1991 - March 1992 • construction • fire in adjacent building • open window • carpet tiles: Aspergillus spp. • shampoo cleaning replaced by water extraction:

dramatic reduction in cases of IA • Carpet tiles: ?source or ?marker of airborne

spores Gerson et al., Infect Contr Hosp Epidemiol 1994

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Water as a source of filamentous fungi in a childhood bone marrow

transplantation unit • 168 filtered water samples • 20 water-related surfaces: swabbed • Moulds recovered from all water samples

– Aspergillus fumigatus • 60% taps • 75% main water supply

• Water-related surfaces: 25% positive for moulds (only 2 samples positive for A. fumigatus)

Warris et al. JHI 2001; 47: 143-148.

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Aspergillus species aerosols in hospitals: showering as a potential

mode of exposure • Conidia can be isolated from hospital

water supplies • gradient of aerosolized concentrations

may exist between bathrooms and bedrooms in individual units

• ?higher airborne spore concentrations when water is running

Anaissie et al., CID 2001; 33: 1546-1548.

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Aspergillus spp. aerosols in hospitals: showering as a potential mode of exposure

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Refinements of environmental assessment during an outbreak investigation of IA in a

leukemia and BMT unit

• study stresses: – adequate pressure differentials between

corridors and patient rooms – double-door entry into patient rooms – large-volume (1, 200 L) sampling

superior Chloe et al. Infect Control Hosp Epidemiol 2000; 21: 18-23.

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Assessment

• Structural survey • Air • Surfaces • Dust • Water analysis • Fabrics • Carpets • Relative humidity

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Dust!

• Fungal aerosols can vary widely between different locations and over short time periods

• Indoor dust – deposited over long periods of time – will reflect long-term exposure history – easy and cheap to collect

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Concentrations of airborne Aspergillus compared to the incidence of invasive

aspergillosis: lack of correlation • 54-week air sampling period • A. fumigatus and A. flavus: mean 1.83 cfu m-3 • Individual samples: maximum: 11.6 cfu m-3 • No correlation with season or ward • 6 cases of IPA during sampling period • No association with fluctuations in air count Conclusion: “the available data do not

provide a firm link between hospital exposure and an increased incidence of aspergillosis”

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Objectives of air sampling 1

• Correlation of outbreaks with hospital construction/demolition

• identification of potential sources of nosocomial aspergillosis

• prediction of contamination from outside sources

• identification of defects/breakdown in ventilation/filtration systems

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Objectives of air sampling 2

• Monitoring of cleaning procedures • Efficacy of HEPA filters in LAF rooms • Monitoring of procedures to contain

hospital building work from hospital wards/single-bedded units

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A deadly dust may be in the wind during renovations

Hospital infection control

• Deaths – despite aggressive control measures • ??Community-acquired aspergillosis • Put guidelines in the contract • one death should prompt inquiry • water may be source of Aspergillus • Conduct regular walk-throughs

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Late onset of IA in BMT patients at a university hospital

• 93 allogeneic and 149 autologous pts • 20 month period • 0% IA autologous • 15.1% allogeneic: overall incidence 5.8% • Median time to occurrence: 92 days • No de novo cases prior to engraftment • Survival 100 days from diagnosis 29% • Conclusions

– shift towards late occurrence – outpatient environment surveillance

Grow et al., BMT 2002; 29: 15-19

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Is IA community-acquired?

• 70% of cases community-acquired (Patterson et al.)

• hospital environmental control measures will not influence community-acquired cases

• control/preventative measures – surveillance of home environments – prophylaxis

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Invasive mold infections in allogeneic BMT recipients

• 94 adult patients • 15 cases invasive mould infections:

– A. fumigatus 7/15 (47%) – Aspergillus species 5/15

• Median time to onset: 102 days (18-470) “Although these data suggest community rather then nosocomial

acquition because of the late timing of clinically evident disease, the source of these pathogens remains speculative because

detailed epidemiological surveys were not conducted during the study period”

Baddley et al. CID 2001; 32: 1319-1324.

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Nosocomially vs. community-acquired IA

Nosocomial • Due to break in, or

contamination of hospital water system

• Due to break in HEPA filtration system

• Due to construction or demolition work in the hospital

Community-acquired • Due to occupational

activities • Due to leisure activities • Due to exposure to

Aspergillus spores (minimum effective dose not known)

Praz-Christinaz et al. Transplant Infect Dis 2007; 9: 175-181

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Diagnosis • Consider it!

• Direct examination (sputum, BAL, tissue)

• Histology

• Antigen, Antibody

• Radiologic findings

• Galactomannan from cell wall • ELISA, sens and spec >90%

• PCR for fungal DNA

• various targets, sens ~ 100%, spec ~ 70%

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Diagnosis of systemic fungal infection

Infectious Disease Physician

Clinician Microbiologist

Pharmaceutical Industry

Pathologist

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Prevention is better than cure

• avoidance of exposure • prospective surveillance: standard protocol • prophylaxis • patient screening: nasal swabs/BAL

– Galactomannan ELISA – PCR

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Non-culture approaches to fungal diagnosis

Cell wall components

Cytoplasmic antigens

Metabolites

Genomic DNA sequences

Candida Aspergillus Detection

Mannans 1,3-β-D-glucans chitin

Enolase HSP-90

arabinitol

C-14 lanosterol demethylase Chitin synthase Actin Aspartate proteinase Ribosomal RNA genes

Galactomannan 1,3-β-D-glucans chitin

D-mannitol

C-14-lanosterol demethylase Alkaline protease Mitochondrial DNA HSP-90 Ribosomal RNA genes

LA ELISA RIA Amebocyte lysate assay Spectrophotometry

PCR

GLC Mass spectroscopy

ELISA Immunoblot

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Aspergillus, friend of mankind

• A. oryzae and A. sojae (soy sauce and miso)

• A. niger (citric acid)

• A. nidulans (genetic model)

• Washing powder, hard cheese, flavourings

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Prevention is better than cure Avoid exposure in the hospital and in the

home

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Surveillance strategy

•understand the ecology of Aspergillus

•avoid exposure

•risk assessment: hospitals and homes

•prospective air and dust sampling

•personal air samplers

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aspergillus and aspergillosis - escmid: escmid

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