Aspergillosis: from diagnosis to prevention

Preface

Contents

Contributors

PART I INTRODUCTION

Introduction

References

Differences and Similarities Amongst Pathogenic Aspergillus Species

1 Introduction

2 Morphology

3 Growth Rate and Thermotolerance

4 Induction of Cytokines and Chemokines

5 Fungal Evasion from the Complement System

6 Metabolic Characteristics

6.1 Enzymes

6.2 Toxins

7 Prevalence

8 Habitat and Distribution

9 Pathology

10 Virulence (Animal Models)

11 Phylogeny, Genetic Diversity and Population Structure

12 Resistance

References

Immunology of Aspergillus and Aspergillosis: The Story So Far

1 Introduction

2 Immunology of Aspergillus: Insights into the Failure of the Immune Response

2.1 Inflammation to Fungi: Friend or Foe?

2.2 Immune Responses to Aspergillus: From Protection to Disease Promotion

2.3 Aspergillosis as an Example of Immune-Related Pathology: Lesson from IRS and CGD

3 Pathogenic Inflammation: The Th17 Pathway

3.1 IL-23/Th17 and the Vicious Circle

4 Dampening Inflammation and Allergy to Aspergillus : Crosstalk Between Treg Subsets

5 Immunity or Tolerance to Aspergillus: The Contribution of the Tryptophan Metabolic Pathway

6 Immunology of Aspergillus: Perspectives on Anti-inflammatory Strategies

6.1 Restraining Pathogenic Th17 Cell Inflammation by Exogenous Kynurenines

6.2 Targeting IDO-Mediated Immune Homeostasis in Fungal Allergy by Steroids

6.3 Exploiting IDO+DC as Fungal Vaccines in Transplantation

7 Concluding Remarks

References

Part IA Aspergillus and the Mycology Laboratory

Identification of Aspergillus at the Species Level

The Importance of Conventional Methods: Microscopy and Culture

1 Introduction

2 Culture Methods

3 Generic Description of Aspergillus Species

3.1 Features of Colonial Morphology Useful for Identification

4 Analysis of Extrolite Production

5 Examination of Microscopic Morphology

5.1 Needle Mounts

5.2 Sellotape Mounts

5.3 Slide Culture

5.4 Preservation of Microscopic Mounts

5.5 Features of Microscopic Morphology Useful for Identification

5.5.1 Conidiophore and Vesicle

5.5.2 Foot Cells

5.5.3 Metulae

5.5.4 Phialides

5.5.5 Spore or Conidium

5.5.6 Cleistothecia

5.5.7 Ascospores

5.5.8 Hülle Cells

5.5.9 Coremia

5.5.10 Sclerotia

6 Descriptions of the Most Clinically Relevant Aspergillus Sections

6.1 Aspergillus Section Fumigati

6.2 Aspergillus Section Flavi

6.3 Aspergillus Section Terrei

6.4 Aspergillus Section Nigri

References

Molecular Methods for Identification of Aspergillus Species

1 Introduction

2 Why Molecular Methods?

2.1 Progression Towards Molecular Methods for Aspergillus Species Identification

2.2 Case Studies

2.2.1 Case study 1: Molecular Methods Reveal Cryptic Species with Decreased In Vitro Susceptibility to Antifungal Drugs

2.2.2 Case study 2: Morphological Characteristics Inconclusive for Species Identification

2.2.3 Case study 3: Lack of Sporulation Hinders Species Identification

2.2.4 Case study 4: Overlapping Morphologies Confound Species Identification

3 Molecular Approaches

4 Summary

5 Disclaimer

References

The Pathology of Aspergillus Infection

1 Introduction

2 Microscopic Morphology

3 Inflammatory Response to Aspergillus

4 Immunological Disorders Due to Aspergillus Infection

5 Bronchocentric Granulomatosis

6 Hypersensitivity Pneumonitis

7 Aspergillus Bronchitis and Chronic Necrotising Aspergillosis

8 Fungal Balls

9 Angioinvasive Aspergillosis

10 Diagnostic Findings

11 Conclusions

References

Galactomannan Testing

1 Introduction

2 Detection of Galactofuranose-Antigens

3 The Introduction of Monoclonal Antibodies

4 Detection of Galf-Containing Molecules by a Sandwich EIA

4.1 General Characteristics of the Sandwich EIA

4.2 Intended Use: Screening Assay or Diagnostic Test?

4.3 Characteristics of the GM EIA

4.3.1 Type and Severity of Immunodeficiency

4.3.2 Timing and Intensity of Sampling

4.3.3 Disease Manifestation of IA

4.3.4 Case Definition of IA

5 Conclusions

References

Beta-D-Glucan Testing

1 Introduction

2 History of BDG Testing in Japan

3 BDG Testing Results for IPA

4 Development of a BDG Assay in the USA

5 False-Positive Results for BDG

6 Preemptive/Presumptive Therapy and Therapeutic Monitoring Using BDG

7 Conclusions

References

Polymerase Chain Reaction (PCR)-Based Tests

1 Principles

1.1 PCR -- An Overview

1.2 Specimen Type

1.3 Extraction Techniques

1.4 PCR Amplification

1.4.1 Oligonucleotide Design

1.4.2 PCR Platform

1.5 Result Interpretation

2 Conventional PCR

3 Real-Time PCR

4 Concluding Remarks

References

Aspergillus Precipitins and Serology

1 Historical Perspective

2 Methods for Detecting Precipitins and IgG Antibodies to Aspergillus

3 IgG Responses to Aspergillus

4 Diagnosis of Allergic Bronchopulmonary Aspergillosis (ABPA) in Cystic Fibrosis (CF)

4.1 Precipitins and IgG to Diagnose ABPA in CF

4.2 Diagnosis of ABPA in CF Using Purified, Recombinant Antigens

5 Diagnosis of ABPA in Asthma Patients

6 Diagnosis of Aspergillosis in Chronic Cavitary Pulmonary Aspergillosis

7 Diagnosis of Fungal Ball

8 Diagnosis of Invasive Aspergillosis in Immunocompromised Patients

9 Diagnosis of Other Forms of Aspergillosis

10 Discussion

References

Specific IgE Testing (RAST)

1 Introduction

2 Assays for the In Vitro Determination of Specific IgE Antibodies

3 Problems Related to Allergen Extracts and Mould Extracts in Particular

4 Clinical Relevance of Serum IgE

5 Conclusions

References

Molecular Typing of Aspergillus fumigatus Isolates

1 Introduction

2 Practical Procedures

2.1 DNA Isolation

2.2 Multiplex PCR Amplification

2.3 Capillary Electrophoresis

3 Data Analysis and Interpretation

3.1 Stutter Peaks

3.2 Minus-A Peaks

3.3 Spectral Cross-Talk

3.4 Allele Assignment

3.5 Non-integer Alleles

3.6 Double Alleles or Absence of Alleles

4 Concluding Remarks

References

Antifungal Susceptibility Tests of Aspergillus Species

1 Introduction

2 Standardisation of Broth Microdilution Method by the Clinical and Laboratory Standards Institute (CLSI)

2.1 Inoculum Preparation

2.2 Selection of Culture Medium and Incubation Conditions

2.3 Quality Control: The Use of Reference Strains

2.4 Reading Results and Breakpoints for Different Antifungal Drugs

2.4.1 Amphotericin B

2.4.2 Triazoles

2.4.3 Echinocandins

3 Standardisation of Broth Dilution by the European Committee on Antimicrobial Susceptibility Testing (EUCAST)

3.1 Inoculum Preparation

3.2 Selection of Culture Medium and Incubation Conditions

3.3 Quality Control

3.4 Reading Results and Breakpoints for Different Antifungal Drugs

4 Agar-Based Diffusion Susceptibility Testing

4.1 Etest ®

4.2 Antifungal Disk Diffusion Tests Performed According to CLSI Standards

4.3 Disk Diffusion with Antifungal Tablets Manufactured by Rosco Diagnostica (Neo-Sensitabs ® )

5 Commercial Panels for Broth Microdilution Assays with Chromogenic Media

6 Other Methods

6.1 Evaluation of Fungal Biomass Through Metabolic Activity Measurement

6.2 Evaluation of Fungal Biomass Through the Measurement of Oxygen Consumption

6.3 Employment of the Biocell-Tracer 0 System in Susceptibility Tests with Aspergillus spp.

6.4 Employment of the Flow Cytometry System in Susceptibility Tests with Aspergillus spp.

6.5 Real Time PCR

References

Antifungal Therapeutic Drug Monitoring for Invasive Aspergillosis

1 Introduction

2 Itraconazole

2.1 Pharmacology and Pharmacokinetics

2.2 Therapeutic Targets Associated with Success

2.3 Therapeutic Targets Associated with Toxicity

2.4 Measurement of Itraconazole

2.5 Indications for TDM

3 Voriconazole

3.1 Therapeutic Targets Associated with Success

3.2 Therapeutic Targets Associated with Toxicity

3.3 Measurement of Voriconazole

3.4 Indications for TDM

4 Posaconazole

4.1 Pharmacology and Pharmacokinetics

4.2 Measurement of Posaconazole

4.3 Therapeutic Targets Associated with Therapeutic Success

4.4 Therapeutic Targets Associated with Toxicity

4.5 Indications for TDM

5 5-Flucytosine

6 Conclusions

References

Part IB Antifungal Drug Profiles

Azoles

1 Introduction

2 Mechanism of Action

3 Mechanisms of Resistance

4 Aspergillus-Active Azoles

4.1 Itraconazole

4.1.1 Pharmacodynamics

4.1.2 Pharmacokinetics

4.1.3 Dosing

4.1.4 Therapeutic Drug Monitoring

4.1.5 Adverse Effects Profile

4.1.6 Drug Interactions

4.1.7 Clinical Evidence

4.2 Posaconazole

4.2.1 Pharmacodynamics

4.2.2 Pharmacokinetics

4.2.3 Dosing

4.2.4 Therapeutic Drug Monitoring

4.2.5 Adverse Effects Profile

4.2.6 Drug Interactions

4.2.7 Clinical Evidence

4.3 Voriconazole

4.3.1 Pharmacodynamics

4.3.2 Pharmacokinetics

4.3.3 Dosing

4.3.4 Therapeutic Drug Monitoring

4.3.5 Adverse Effects Profile

4.3.6 Drug Interactions

4.3.7 Clinical Evidence

4.4 New and Emerging Azoles

4.4.1 Ravuconazole

4.4.2 Isavuconazole

4.4.3 Albaconazole

5 Conclusion

References

Echinocandins

1 Introduction

2 Pharmacokinetics

3 Pharmacodynamics

4 Serum Factor

5 Paradoxical Effect

6 Drug Resistance

7 Immunogenic Properties

8 Treatment Guidelines

8.1 Empirical Antifungal Therapy

8.2 Primary Therapy of Invasive aspergillosis

8.3 Salvage Therapy of Invasive aspergillosis

8.4 Combination Antifungal Regimens in Clinical Settings

9 Conclusion

References

Polyene Antifungal Agents

1 Introduction

2 Amphotericin B

2.1 Chemical Properties

2.2 Mechanism of Action

2.3 In Vitro Spectrum Against Aspergillus Species

2.4 Mechanisms of Polyene Resistance

2.5 Polyene Antagonism

2.6 Pharmacokinetics

2.7 Pharmacodynamics

2.8 Adverse Effects

3 Lipid Formulations of Amphotericin B

3.1 Chemistry and Pharmacokinetics

3.2 Pharmacology

3.3 Adverse Effects

4 Clinical Evidence Supporting the Use of Amphotericin B for Aspergillosis

5 Non-Intravenous Approaches for Amphotericin B Administration

6 Conclusions

References

5-Flucytosine

1 Introduction

2 Pharmacology

2.1 Mode of Action

2.2 Pharmacokinetics

2.3 Toxicity

3 Susceptibility

4 In Vivo Activity

5 Activity in Combination

6 Conclusions

References

Terbinafine

1 Mechanism of Action, Spectrum of Activity and Clinical Uses of Terbinafine

2 Profile of Activity In Vitro Against Aspergillus Species

3 Clinical Use of Terbinafine in Aspergillosis

4 Combination Therapy with Terbinafine

References

PART II INVASIVE PULMONARY ASPERGILLOSIS

Epidemiology of Invasive Pulmonary Aspergillosis

1 Introduction

2 Organism Factors

2.1 Aspergillus Species

2.2 Sources of Aspergillus Species

2.2.1 Air and Ventilation Systems

2.2.2 Water

2.2.3 Other Sources of Aspergillus

3 Host Factors

3.1 Patients with Haematological Malignancies

3.2 Haematopoietic Stem Cell Transplantation

4 Impact of Prophylaxis on the Epidemiology of Aspergillosis

References

Pathogenesis of Invasive Pulmonary Aspergillosis

1 Introduction

2 The Study of Aspergillus Virulence

3 Aspergillus Species and Pathogenicity

4 Interaction of Inhaled Aspergillus Conidia with the Respiratory Epithelium

4.1 RodA

4.2 Asp f2

4.3 Sialic Acids

5 Innate Immunity Against Aspergillus : Detection and Evasion

6 Angioinvasion

6.1 Gliotoxin

6.2 Fumagillin

6.3 Actibind

6.4 Cytochalasin E

7 Melanin

7.1 Quenching of Reactive Oxigen Intermediates (ROI)

7.2 Interference with Intracellular Trafficking of Phagocytised Conidia

7.3 beta -Glucan Masking

8 Non-melanin Antioxidants

9 Thermotolerance

9.1 CgrA

9.2 thtA

10 Proteinases

11 Calcineurin

12 Siderophores

13 Secondary Metabolites

13.1 Ribonucleotoxins

13.2 Gliotoxin (GT)

13.2.1 LaeA

13.2.2 GliZ

14 Host-Specific Characteristics of Aspergillus Pathogenesis

15 Summary

References

Clinical Manifestations of Invasive Pulmonary Aspergillosis

1 Introduction

2 Clinical Characteristics of IPA

3 Radiographic Manifestations

4 Influence of the State of the Host Immunity on Clinical and Radiographic Findings

5 Differential Diagnosis

References

Diagnosis

Diagnosing Aspergillosis: The Role of Invasive Diagnostic*15ptInterventions

1 Introduction

2 Biopsies

2.1 Percutaneous Transthoracic Lung Biopsies

2.2 Bronchoscopic Lung Biopsies

2.3 Open Lung Biopsies

3 Bronchoscopy

4 Spectrum of Aspergillus Species

5 Specimen Procedures

5.1 Microscopic Examination

5.2 Culture Techniques

5.3 Serology Assays

5.4 PCR Assays

References

Optimising the Use of Non-invasive Tests: From Blood*15ptto Radiology

1 Introduction

2 IPA in Severely Neutropenic Patients

2.1 Clinical Manifestations

2.2 Radiology

2.3 Serology and Antigen Detection

2.3.1 Galactomannan

2.3.2 -Glucan

2.3.3 Polymerase Chain Reaction (PCR)

3 IPA in Non-Neutropenic Allogeneic HSCT Recipients

3.1 Clinical Manifestations

3.2 Radiology

3.3 Serology and Antigen Detection

4 IPA in Other Settings

4.1 IPA in Solid Organ Transplant Recipients

4.1.1 Lung Transplantation

4.1.2 Other Organ Transplants

4.2 IPA in Intensive Care Unit Patients

5 Conclusions

References

Defining Invasive Aspergillosis: What the Revised*15ptEORTC/MSG Definitions Have in Store

1 Introduction

2 Revising the Definitions

3 From Infection to Disease

4 Expansion of Host Factors

5 No More Major and Minor Clinical Features

6 Indirect Mycological Tests

7 Improvements

8 Known Issues

References

Treatment of Invasive Pulmonary Aspergillosis

1 Antifungal Treatment: Drugs of Choice and Alternatives

2 Combination Antifungal Therapy

3 Surgical Treatment

4 Immune Modulation

5 Summary

References

Antifungal Prophylaxis in Haematology

1 Introduction

2 Clinical Evidence

3 Conclusion

4 Future Perspectives

References

Part IIA Particularities in Special Populations

Invasive Aspergillosis in Paediatric Patients

1 Introduction

2 Populations at Risk and General Epidemiology

3 Special Epidemiology and Presentation

3.1 Neonates

3.2 Children with Primary Immunodeficiencies

3.3 Children with Acquired Immunodeficiencies

3.3.1 Iatrogenic Immunosuppression

3.3.2 Cancer

3.3.3 Allogeneic Haematopoietic Stem Cell Transplantation (HSCT)

3.3.4 Solid Organ Transplantation (SOT)

3.3.5 HIV Infection

3.3.6 Children with Severe Acute Illnesses or Trauma

3.3.7 Children with Chronic Airway Diseases

4 Diagnostic Considerations

5 Options for Treatment

6 Approaches to Prevention

6.1 Primary Prophylaxis

6.2 Secondary Prophylaxis

7 Conclusions

References

Invasive Aspergillosis in the Intensive Care Unit: Beyond the Typical Haematological Patient

1 Is Invasive Aspergillosis (IA) a Problem in the ICU?

2 Who is at Risk for Developing IA in the ICU?

3 Do Patients Acquire IA in the ICU?

4 Disease Manifestations in the ICU

5 Are the Available Diagnostic Tools Applicable to Patients in the ICU?

6 Antifungals for the Treatment of IA in the ICU

7 Future Directions

References

Aspergillosis in Surgical Patients

1 Introduction

2 Post-Operative Aspergillus Endocarditis, Aortitis and Vascular Prosthetic Infections

2.1 Illustrative Case (1)

2.1.1 Key Messages for This Case

2.2 Literature Review on Aspergillus Endocarditis Following Heart Surgery

3 Aspergillosis Following Neurosurgery

3.1 Illustrative Case (2)

3.1.1 Key Messages for This Case

3.2 Illustrative Case (3)

3.2.1 Key Messages for This Case

3.3 Literature Review on Aspergillosis After Neurosurgery

4 Aspergillus Wound Infections and Mediastinitis

5 Aspergillosis Following Ophthalmological Surgeries

6 Aspergillosis and Surgical Dental Procedures

7 Other (Rare) Clinical Presentations

8 Diagnosis

9 Treatment

10 Prevention

11 Conclusions

References

Invasive Aspergillosis in Chronic Granulomatous Disease

1 Clinical Manifestations, Genetics, and Diagnosis of Chronic Granulomatous Disease

2 NADPH Oxidase

3 Invasive Aspergillosis in CGD

4 Therapy for Invasive Aspergillosis

5 Prophylaxis Against Fungal Infections

6 Interferon-gamma

7 Granulocyte Transfusions

8 Haematological Stem Cell Transplantation

9 Gene Therapy

10 Chronic Granulomatous Disease: A Disorder of Tryptophan Metabolism

11 Conclusions

References

Aspergillosis in Drug Addicts

1 Introduction

2 Invasive Pulmonary Aspergillosis and Other Forms of Aspergillosis in Cannabis/Marijuana Smokers

3 Invasive Pulmonary Aspergillosis in Intravenous Drug Users

4 Other Forms of Aspergillosis in Intravenous Drug Users

4.1 Aspergillus Endophthalmitis

4.2 Aspergillus Endocarditis

4.3 Aspergillus Osteomyelitis

4.4 Central Nervous System Aspergillosis

4.5 Renal Aspergillosis

5 Conclusions

References

Invasive Aspergillosis and HIV Infection

1 Introduction, incidence and epidemiology

2 Clinical Manifestations

3 Diagnosis

4 Therapy

References

Invasive Pulmonary Aspergillosis in Solid Organ Transplant Recipients

1 Epidemiology and Risk Factors

2 Clinical Presentation

2.1 Lung Transplant Recipients

2.2 Liver Transplant Recipients

2.3 Heart Transplant Recipients

2.4 Kidney Transplant Recipients

3 Diagnosis of Invasive Aspergillosis in Solid Organ Transplant Recipients

4 Therapy of Invasive Aspergillosis in Solid Organ Transplant Recipients

5 Prophylaxis of Invasive Aspergillosis in Solid Organ Transplant Recipients

6 Conclusions

References

PART III CHRONIC CAVITARY PULMONARY ASPERGILLOSIS

Chronic Cavitary Pulmonary Aspergillosis and Fungal Balls

1 Introduction

2 Aetiology

3 Epidemiology

4 Pathogenesis

5 Clinical Manifestations and Natural History

6 Fungal Ball and AIDS

7 Diagnosis

7.1 Proposed Diagnostic Criteria

7.2 Radiological Findings

7.3 Sputum Examination

7.4 Aspergillus Precipitins

8 Treatment

8.1 Role of Surgery

8.2 Antifungal Therapy

8.2.1 Itraconazole

8.2.2 Voriconazole

8.2.3 Intravenous Antifungal Therapy

8.2.4 Intra-Cavitary Use of Antifungal Drugs

8.3 Bronchial Artery Embolisation and Haemoptysis Control

8.4 Other Measures

8.5 Monitoring Therapy

9 Prevention

10 Comments About Our Study

10.1 Fungal Ball Due to Aspergillus niger

10.2 Fungal Ball Due to Scedosporium apiospermum (Pseudallescheria boydii)

10.3 Actinomycotic Intra-Cavitary Lung Lesions

References

Pathogenesis of Chronic Cavitary Pulmonary Aspergillosis: The Importance of the Host Immune System

1 Introduction

2 Innate Defence Mechanisms Against CCPA

3 The Importance of Collectins

3.1 Mannose Binding Lectin (MBL)

3.2 Lung Surfactant Proteins

3.3 Pentraxin 3

4 Cytokine and Cellular Immunity Against CCPA

5 Toll-Like Receptors

6 Concluding Remarks

References

Current Surgical Strategies for Chronic Cavitary Pulmonary Aspergillosis

1 Introduction

2 Surgical Outcomes and Options

3 Localisation of Cavernostomy

4 Open-Window Thoracostomy

5 Preoperative Preparation

6 Surgical Techniques

6.1 Preparation of Muscle Flap

6.2 Muscle Flap

6.3 How to Insert the Muscle Graft

6.4 Cover Plan

6.5 Cutaneous Plan and Drainage

7 Conclusions

References

PART IV ALLERGIC PULMONARY SYNDROMES ASSOCIATED WITH ASPERGILLOSIS

Overview of Aspergillus Allergens

1 Introduction

2 The World of Fungal Allergens

3 The Allergen Repertoire of Aspergillus fumigatus

4 Diagnostic Value of Recombinant A. fumigatus Allergens

5 Cross- and Autoreactivity

6 Structural Aspects of Fungal Allergens

7 Therapy of Fungal Allergy

8 Conclusions

References

Allergic bronchopulmonary aspergillosis (ABPA)

Epidemiology of Allergic Bronchopulmonary Aspergillosis

1 Introduction

2 Environmental Factors Influencing the Occurrence of ABPA

3 Genetic Factors Influencing the Epidemiology of ABPA

4 Prevalence of Aspergillus Hypersensitivity in Patients with Asthma

5 Prevalence of ABPA in Patients with Asthma

6 Prevalence of ABPA in Cystic Fibrosis

7 Occurrence of ABPA Without Asthma

8 Occurrence of ABPA in Other Situations

9 Coexistence of ABPA and Fungal Balls

10 ABPA-Like Syndrome with Other Fungi (Allergic Bronchopulmonary Mycosis)

11 Conclusions

References

ABPA as an Occupational Disease

1 Introduction

2 ABPA Related to Cane Sugar Mills

3 ABPA Related to Small Workshops of Soybean Products

4 Treatment and Prevention

References

Pathogenesis of ABPA

1 Introduction

2 Aspergillus Fumigatus , Pathogen and Allergen

3 Clinical and Pathologic Features of ABPA

4 Dysfunction of Cystic Fibrosis Transmembrane Regulator, the Airway Epithelium and ABPA

5 The Innate Immune Response and the Development of ABPA: The Role of Collectins

6 The Innate Immune Response and the Development of ABPA: The Role of Phagocytic Cells

7 The Adaptive Immune Response and the Development of ABPA

8 Conclusions

References

Clinical Manifestations and Natural History of*15ptAllergic Bronchopulmonary Aspergillosis

1 Introduction

2 Clinical Features of ABPA

3 History

4 Physical Examination

5 Laboratory Findings

5.1 Skin Tests

5.2 Immunological Studies

6 Radiological Investigations

7 Pulmonary Function Tests

8 Natural History

9 Conclusions

References

How to Diagnose Allergic Bronchopulmonary Aspergillosis

1 Introduction

2 Proposed Diagnostic Criteria

3 ABPA in Association with Other Aspergillus -Related Diseases

3.1 Allergic Aspergillus sinusitis

3.2 Fungal Balls

4 ABPA and Cystic Fibrosis

5 Familial Occurrence of ABPA

6 ABPA Without Asthma

7 ABPA and Other Lung Disorders

8 Allergic Bronchopulmonary Mycosis

9 Radiological Findings

9.1 Plain Chest Roentgenography

9.1.1 Transient Changes

9.1.2 Permanent Changes

9.2 Demonstration of Central Bronchiectasis

9.3 Other Computed Tomography Appearances

10 Sputum Examination

11 Blood Tests

11.1 Eosinophilia

11.2 Precipitating Antibodies Against A. Fumigatus

11.3 Serum IgE

11.3.1 Specific IgE/IgG to A. Fumigatus

11.4 Recombinant Aspergillus fumigatus Allergens

11.4.1 Diagnosing ABPA in CF Using Recombinant Allergens

12 Skin Testing

12.1 Skin Testing with Recombinant Allergens in Cystic Fibrosis

References

The Treatment of ABPA

1 General Principles of Treatment of Allergic Bronchopulmonary Aspergillosis

2 Steroid Therapy

3 Antifungal Therapy

4 Other Adjunctive Anti-asthma Therapies for ABPA Exacerbations

5 Monitoring Therapy

6 Differentiating an Exacerbation of Cystic Fibrosis (CF) from ABPA in Patients with Both Diseases

7 Potential Therapies

References

Severe Asthma with Fungal Sensitisation (SAFS)

1 Introduction

2 Association of Fungal Sensitisation and Severe Asthma

3 Fungi as Allergens

4 Protease-Induced Airway Inflammation

5 Volatile Organic Compounds (VOCs)

6 Survivor Effect

7 Allergic Bronchopulmonary Aspergillosis s (ABPA): A Historical Perspective

8 Severe Asthma with Fungal Sensitisation (SAFS)

9 Diagnosis of SAFS

9.1 Severe Asthma

9.2 Fungal Sensitisation

9.3 Distinction Between SAFS and ABPA

9.4 Imaging

10 Treatment of SAFS

10.1 Antifungal Azoles -- The Fast Study

10.2 Anti-IgE Therapy

11 Summary

References

PART V ASPERGILLUS SINUSITIS

Aspergillus Sinusitis

1 Introduction

2 Incidence

3 Immunology and Host-Pathogen Interactions in Fungal Sinus Disease

4 Fungal Ball (Aspergilloma)

4.1 Introduction

4.2 Diagnostic Criteria

4.3 Pathophysiology and Natural Course

4.4 Radiologic Features

4.5 Treatment

5 Allergic Aspergillus Sinusitis

5.1 Epidemiology

5.2 Clinical Features

5.3 Diagnostic Criteria

5.4 Pathophysiology and Natural Course

5.5 Radiologic Features

5.6 Treatment

5.6.1 Surgical Treatment

5.6.2 Medical Treatment

5.7 Follow-Up

6 Chronic Invasive Fungal Sinusitis

6.1 Diagnosis

6.2 Diagnostic Criteria

6.3 Pathophysiology and Natural Course

6.4 Radiologic Features

6.5 Treatment

6.5.1 Surgical Treatment

6.5.2 Medical Therapy

6.6 Follow-Up

7 Acute Invasive Fungal Sinusitis

7.1 Introduction

7.2 Diagnostic Criteria

7.3 Pathophysiology and Natural Course

7.4 Natural Course

7.5 Radiologic Features

7.6 Treatment

7.6.1 Medical Therapy

7.6.2 Surgical Treatment

7.7 Follow-Up

8 Summary

References

PART VI OVERLAP SYNDROMES

Aspergillus Overlap Syndromes

1 Introduction

2 Fungal Balls and Allergic Bronchopulmonary Aspergillosis (ABPA)

3 ABPA and Invasive Aspergillosis

4 Allergic Aspergillus Sinusitis Overlap Syndromes

5 Overlap Between Aspergillosis and Other Respiratory Diseases

5.1 Hypersensitivity Pneumonitis

5.2 Mucoid Impaction of the Bronchus (MIB)

5.3 Bronchocentric Granulomatosis (BG)

6 Conclusions

References

PART VII OTHER PRESENTATIONS OF ASPERGILLOSIS

Cerebral Aspergillus Infections and Meningitis

1 Introduction

2 Clinical Characteristics and Diagnostic Approach

3 Aspects of Central Nervous System Pharmacokinetics

4 Treatment Strategies

5 Future Developments

References

Osteoarticular and Epidural Infections

1 Osteoarticular Aspergillosis

1.1 Clinical Presentation

1.2 Diagnosis

1.3 Treatment

1.4 Surgical Management

2 Epidural Infections due to Aspergillus

2.1 Clinical Presentation

2.2 Diagnosis

2.3 Treatment

References

Aspergillosis of the Digestive Tract

1 Introduction

2 Aspergillosis of the Digestive Tract

2.1 Primary Digestive Aspergillosis

2.1.1 Oral Cavity

2.1.2 Upper Digestive Tract

2.1.3 Lower Digestive Tract

3 Conclusion

References

Cardiac Aspergillosis

1 Introduction

2 Aetiology and Epidemiology

3 Risk Factors

4 Outcomes

5 Pathogenesis

6 Clinical Presentation

6.1 Native Valve Endocarditis

6.2 Prosthetic Valve Endocarditis

6.3 Myocarditis and Mural Endocarditis

6.4 Pericarditis

7 Diagnosis

7.1 Imaging

7.2 Microbiology

7.3 Histopathology

7.4 Antigen Detection

8 Treatment

8.1 Endocarditis

8.2 Myocardial and Pericardial Aspergillosis

9 Conclusion

References

Aspergillus Thyroiditis

1 Introduction

2 Aspergillosis and the Thyroid

3 Conclusion

References

Aspergillus Endophthalmitis

1 Introduction

2 Frequency of Occurrence of Aspergillus Endophthalmitis

3 Aetiological Agents of Aspergillus Endophthalmitis

4 Risk Factors

4.1 Risk Factors for Exogenous Aspergillus Endophthalmitis

4.2 Risk Factors for Endogenous Aspergillus Endophthalmitis

5 Clinical Features of Aspergillus Endophthalmitis

5.1 Symptoms of Aspergillus Endophthalmitis

5.2 Signs of Aspergillus Endophthalmitis

6 Diagnosis of Aspergillus Endophthalmitis

6.1 Imaging Studies

6.2 Microbiological Investigations

6.2.1 Collection of Samples

6.2.2 Direct Microscopic Examination and Culture

6.2.3 Microbiological Investigations in Aspergillus Endophthalmitis

6.3 Molecular Methods for Diagnosis of Aspergillus Endophthalmitis

7 Histopathological Studies on Aspergillus Endophthalmitis

8 Treatment of Aspergillus Endophthalmitis

8.1 General Principles of Treatment of Fungal Endophthalmitis

8.1.1 Vitrectomy

8.1.2 Antifungal Agents

8.2 General Principles of Treatment of Exogenous Fungal Endophthalmitis

8.2.1 Recommended Measures for Post-Operative Fungal Endophthalmitis

8.2.2 Recommended Measures for Fungal Endophthalmitis Developing from Fungal Keratitis

8.3 Treatment of Aspergillus Endophthalmitis

8.3.1 Treatment of Endogenous Aspergillus Endophthalmitis

8.3.2 Treatment of Exogenous (Post-Operative) Aspergillus Endophthalmitis

8.3.3 Treatment of Exogenous (Post-traumatic) Aspergillus Endophthalmitis

References

Urinary Tract Infections Caused by Aspergillus Species

1 Introduction

2 Pathogenesis

3 Pathological Features

4 Clinical Manifestations

5 Diagnosis

6 Management

7 Outcome

8 Prostatic Aspergillosis

References

Superficial infections

Cutaneous and Wound Aspergillosis

1 Introduction

2 History

3 Classification of the Disease

4 Epidemiology

4.1 Neonates

4.2 Systemic Steroid Therapy

4.3 Other Immunosuppressive Agents

4.4 Cancers Including Haematological Malignancies

4.5 HSCT Recipients

4.6 Solid Organ Transplant Recipients

4.7 HIV Infection

4.8 Burn Victims

4.9 Placement of Hickman Catheters

4.10 Maceration of Skin

4.11 Construction Work in Hospitals

4.12 Improper Cleaning of Air Conditioning Ducts, Contaminated Ventilating Systems

4.13 Post-Surgical Wound Infections

4.14 Other Recognised Risk Factors

5 The Fungi

6 Pathogenesis

7 Pathology

8 Clinical Features

8.1 Contiguous Spread of Deep Aspergillus Infection

8.2 Onychomycosis

9 Laboratory Diagnosis

10 Differential Diagnosis

11 Management

11.1 Surgery

11.2 Systemic Antifungal Agents

11.3 Topical Therapy

11.4 Onychomycosis

References

Onychomycosis Due to Aspergillus Species

1 Introduction

2 Clinical Forms

3 Mycological Diagnosis

4 Special Characteristics of Onychomycosis Due to Aspergillus Species

5 Treatment

References

Aspergillus Keratitis

1 Introduction to Fungal Keratitis and Aspergillus Keratitis

2 Aetiological Agents of Aspergillus Keratitis

3 Risk Factors for Aspergillus Keratitis

4 Diagnosis of Aspergillus Keratitis

4.1 History and Clinical Features

4.2 Non-invasive Methods of Diagnosis

4.3 Microbiological Diagnosis of Aspergillus Keratitis

4.3.1 Sampling

4.3.2 Direct Microscopic Examination

4.3.3 Culture

4.4 Histopathological Diagnosis of Aspergillus Keratitis

4.5 Polymerase Chain Reaction (PCR) in Diagnosis of Aspergillus Keratitis

4.6 Antifungal Susceptibility Testing

5 Pathogenesis of Aspergillus Keratitis

5.1 Putative Agent Factors in the Pathogenesis of Aspergillus Keratitis

5.1.1 Adherence to Corneal Tissue and Invasiveness by Aspergillus

5.1.2 Toxigenicity of Ocular Aspergillus Isolates

5.2 Putative Host (Corneal Tissue) Factors in the Pathogenesis of Aspergillus Keratitis

5.2.1 Matrix Metalloproteinases and Polymorphonuclear Leucocytes

5.2.2 TLR and Corneal Immune Responses to A. fumigatus

5.2.3 The Plasminogen Activator-Plasmin System in Pathogenesis

5.3 Molecular Pathogenesis of Aspergillus Keratitis

6 Management of Aspergillus Keratitis

6.1 Medical Therapy of Aspergillus Keratitis

6.1.1 Non-specific Measures in the Medical Therapy of Aspergillus Keratitis

6.1.2 Specific Compounds in the Medical Therapy of Aspergillus Keratitis

6.2 Surgery in the Management of Aspergillus Keratitis

6.2.1 Debridement in Aspergillus Keratitis

6.2.2 Lamellar Keratectomy/Keratoplasty in Aspergillus Keratitis

6.2.3 Conjunctival Flap in Aspergillus Keratitis

6.2.4 Amniotic Membrane Transplantation in Aspergillus Keratitis

6.2.5 Therapeutic Penetrating Keratoplasty

6.2.6 Anterior Chamber Tap

References

Aspergillus Otitis

1 Introduction

2 Epidemiology

3 Aetiology and Pathogenesis

4 Clinical Aspects

5 Laboratory Diagnosis

6 Treatment and Prophylaxis

References

How to Diagnose Allergic Bronchopulmonary Aspergillosis

1 Introduction

2 Proposed Diagnostic Criteria

3 ABPA in Association with Other Aspergillus -Related Diseases

3.1 Allergic Aspergillus Sinusitis

3.2 Fungal Balls

4 ABPA and Cystic Fibrosis

5 Familial Occurrence of ABPA

6 ABPA Without Asthma

7 ABPA and Other Lung Disorders

8 Allergic Bronchopulmonary Mycosis

9 Radiological Findings

9.1 Plain Chest Roentgenography

9.1.1 Transient Changes

9.1.2 Permanent Changes

9.2 Demonstration of Central Bronchiectasis

9.3 Other Computed Tomography Appearances

10 Sputum Examination

11 Blood Tests

11.1 Eosinophilia

11.2 Precipitating Antibodies Against A. fumigatus

11.3 Serum IgE

11.3.1 Specific IgE/IgG to A. fumigatus

11.4 Recombinant Aspergillus fumigatus Allergens

11.4.1 Diagnosing ABPA in CF Using Recombinant Allergens

12 Skin Testing

12.1 Skin Testing with Recombinant Allergens in Cystic Fibrosis

References

Index