Aspergillosis: from diagnosis to prevention (eBook)

Preface 6
Contents 8
Contributors 14
PART I INTRODUCTION 21
Introduction 22
References 24
Differences and Similarities Amongst Pathogenic Aspergillus Species 25
1 Introduction 26
2 Morphology 27
3 Growth Rate and Thermotolerance 32
4 Induction of Cytokines and Chemokines 33
5 Fungal Evasion from the Complement System 33
6 Metabolic Characteristics 34
6.1 Enzymes 34
6.2 Toxins 36
7 Prevalence 37
8 Habitat and Distribution 38
9 Pathology 38
10 Virulence (Animal Models) 40
11 Phylogeny, Genetic Diversity and Population Structure 42
12 Resistance 44
References 45
Immunology of Aspergillus and Aspergillosis: The Story So Far 51
1 Introduction 52
2 Immunology of Aspergillus: Insights into the Failure of the Immune Response 53
2.1 Inflammation to Fungi: Friend or Foe? 53
2.2 Immune Responses to Aspergillus: From Protection to Disease Promotion 53
2.3 Aspergillosis as an Example of Immune-Related Pathology: Lesson from IRS and CGD 56
3 Pathogenic Inflammation: The Th17 Pathway 57
3.1 IL-23/Th17 and the Vicious Circle 58
4 Dampening Inflammation and Allergy to Aspergillus : Crosstalk Between Treg Subsets 60
5 Immunity or Tolerance to Aspergillus: The Contribution of the Tryptophan Metabolic Pathway 61
6 Immunology of Aspergillus: Perspectives on Anti-inflammatory Strategies 63
6.1 Restraining Pathogenic Th17 Cell Inflammation by Exogenous Kynurenines 63
6.2 Targeting IDO-Mediated Immune Homeostasis in Fungal Allergy by Steroids 64
6.3 Exploiting IDO+DC as Fungal Vaccines in Transplantation 65
7 Concluding Remarks 65
References 66
Part IA Aspergillus and the Mycology Laboratory 71
Identification of Aspergillus at the Species Level 72
The Importance of Conventional Methods: Microscopy and Culture 72
1 Introduction 73
2 Culture Methods 74
3 Generic Description of Aspergillus Species 74
3.1 Features of Colonial Morphology Useful for Identification 75
4 Analysis of Extrolite Production 75
5 Examination of Microscopic Morphology 76
5.1 Needle Mounts 76
5.2 Sellotape Mounts 76
5.3 Slide Culture 77
5.4 Preservation of Microscopic Mounts 77
5.5 Features of Microscopic Morphology Useful for Identification 77
5.5.1 Conidiophore and Vesicle 78
5.5.2 Foot Cells 79
5.5.3 Metulae 79
5.5.4 Phialides 80
5.5.5 Spore or Conidium 80
5.5.6 Cleistothecia 81
5.5.7 Ascospores 81
5.5.8 Hülle Cells 84
5.5.9 Coremia 84
5.5.10 Sclerotia 84
6 Descriptions of the Most Clinically Relevant Aspergillus Sections 84
6.1 Aspergillus Section Fumigati 84
6.2 Aspergillus Section Flavi 87
6.3 Aspergillus Section Terrei 88
6.4 Aspergillus Section Nigri 88
References 89
Molecular Methods for Identification of Aspergillus Species 91
1 Introduction 91
2 Why Molecular Methods? 92
2.1 Progression Towards Molecular Methods for Aspergillus Species Identification 92
2.2 Case Studies 93
2.2.1 Case study 1: Molecular Methods Reveal Cryptic Species with Decreased In Vitro Susceptibility to Antifungal Drugs 93
2.2.2 Case study 2: Morphological Characteristics Inconclusive for Species Identification 94
2.2.3 Case study 3: Lack of Sporulation Hinders Species Identification 94
2.2.4 Case study 4: Overlapping Morphologies Confound Species Identification 95
3 Molecular Approaches 96
4 Summary 98
5 Disclaimer 98
References 99
The Pathology of Aspergillus Infection 102
1 Introduction 103
2 Microscopic Morphology 103
3 Inflammatory Response to Aspergillus 106
4 Immunological Disorders Due to Aspergillus Infection 107
5 Bronchocentric Granulomatosis 108
6 Hypersensitivity Pneumonitis 108
7 Aspergillus Bronchitis and Chronic Necrotising Aspergillosis 110
8 Fungal Balls 110
9 Angioinvasive Aspergillosis 112
10 Diagnostic Findings 115
11 Conclusions 118
References 119
Galactomannan Testing 120
1 Introduction 120
2 Detection of Galactofuranose-Antigens 122
3 The Introduction of Monoclonal Antibodies 123
4 Detection of Galf-Containing Molecules by a Sandwich EIA 123
4.1 General Characteristics of the Sandwich EIA 124
4.2 Intended Use: Screening Assay or Diagnostic Test? 125
4.3 Characteristics of the GM EIA 125
4.3.1 Type and Severity of Immunodeficiency 125
4.3.2 Timing and Intensity of Sampling 127
4.3.3 Disease Manifestation of IA 128
4.3.4 Case Definition of IA 128
5 Conclusions 131
References 132
Beta-D-Glucan Testing 140
1 Introduction 140
2 History of BDG Testing in Japan 141
3 BDG Testing Results for IPA 142
4 Development of a BDG Assay in the USA 144
5 False-Positive Results for BDG 144
6 Preemptive/Presumptive Therapy and Therapeutic Monitoring Using BDG 144
7 Conclusions 145
References 146
Polymerase Chain Reaction (PCR)-Based Tests 149
1 Principles 150
1.1 PCR -- An Overview 150
1.2 Specimen Type 151
1.3 Extraction Techniques 153
1.4 PCR Amplification 157
1.4.1 Oligonucleotide Design 157
1.4.2 PCR Platform 158
1.5 Result Interpretation 158
2 Conventional PCR 160
3 Real-Time PCR 163
4 Concluding Remarks 165
References 165
Aspergillus Precipitins and Serology 172
1 Historical Perspective 173
2 Methods for Detecting Precipitins and IgG Antibodies to Aspergillus 173
3 IgG Responses to Aspergillus 175
4 Diagnosis of Allergic Bronchopulmonary Aspergillosis (ABPA) in Cystic Fibrosis (CF) 176
4.1 Precipitins and IgG to Diagnose ABPA in CF 176
4.2 Diagnosis of ABPA in CF Using Purified, Recombinant Antigens 177
5 Diagnosis of ABPA in Asthma Patients 177
6 Diagnosis of Aspergillosis in Chronic Cavitary Pulmonary Aspergillosis 178
7 Diagnosis of Fungal Ball 178
8 Diagnosis of Invasive Aspergillosis in Immunocompromised Patients 179
9 Diagnosis of Other Forms of Aspergillosis 179
10 Discussion 180
References 180
Specific IgE Testing (RAST) 183
1 Introduction 183
2 Assays for the In Vitro Determination of Specific IgE Antibodies 184
3 Problems Related to Allergen Extracts and Mould Extracts in Particular 185
4 Clinical Relevance of Serum IgE 186
5 Conclusions 187
References 187
Molecular Typing of Aspergillus fumigatus Isolates 189
1 Introduction 190
2 Practical Procedures 192
2.1 DNA Isolation 192
2.2 Multiplex PCR Amplification 193
2.3 Capillary Electrophoresis 194
3 Data Analysis and Interpretation 194
3.1 Stutter Peaks 195
3.2 Minus-A Peaks 195
3.3 Spectral Cross-Talk 196
3.4 Allele Assignment 197
3.5 Non-integer Alleles 199
3.6 Double Alleles or Absence of Alleles 201
4 Concluding Remarks 201
References 202
Antifungal Susceptibility Tests of Aspergillus Species 204
1 Introduction 205
2 Standardisation of Broth Microdilution Method by the Clinical and Laboratory Standards Institute (CLSI) 206
2.1 Inoculum Preparation 206
2.2 Selection of Culture Medium and Incubation Conditions 207
2.3 Quality Control: The Use of Reference Strains 208
2.4 Reading Results and Breakpoints for Different Antifungal Drugs 209
2.4.1 Amphotericin B 209
2.4.2 Triazoles 210
2.4.3 Echinocandins 210
3 Standardisation of Broth Dilution by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) 210
3.1 Inoculum Preparation 211
3.2 Selection of Culture Medium and Incubation Conditions 212
3.3 Quality Control 213
3.4 Reading Results and Breakpoints for Different Antifungal Drugs 213
4 Agar-Based Diffusion Susceptibility Testing 214
4.1 Etest ® 215
4.2 Antifungal Disk Diffusion Tests Performed According to CLSI Standards 216
4.3 Disk Diffusion with Antifungal Tablets Manufactured by Rosco Diagnostica (Neo-Sensitabs ® ) 217
5 Commercial Panels for Broth Microdilution Assays with Chromogenic Media 218
6 Other Methods 219
6.1 Evaluation of Fungal Biomass Through Metabolic Activity Measurement 219
6.2 Evaluation of Fungal Biomass Through the Measurement of Oxygen Consumption 220
6.3 Employment of the Biocell-Tracer 0 System in Susceptibility Tests with Aspergillus spp. 220
6.4 Employment of the Flow Cytometry System in Susceptibility Tests with Aspergillus spp. 221
6.5 Real Time PCR 221
References 222
Antifungal Therapeutic Drug Monitoring for Invasive Aspergillosis 227
1 Introduction 228
2 Itraconazole 228
2.1 Pharmacology and Pharmacokinetics 228
2.2 Therapeutic Targets Associated with Success 229
2.3 Therapeutic Targets Associated with Toxicity 230
2.4 Measurement of Itraconazole 230
2.5 Indications for TDM 230
3 Voriconazole 231
3.1 Therapeutic Targets Associated with Success 231
3.2 Therapeutic Targets Associated with Toxicity 232
3.3 Measurement of Voriconazole 232
3.4 Indications for TDM 232
4 Posaconazole 233
4.1 Pharmacology and Pharmacokinetics 233
4.2 Measurement of Posaconazole 234
4.3 Therapeutic Targets Associated with Therapeutic Success 234
4.4 Therapeutic Targets Associated with Toxicity 234
4.5 Indications for TDM 234
5 5-Flucytosine 234
6 Conclusions 235
References 235
Part IB Antifungal Drug Profiles 239
Azoles 240
1 Introduction 240
2 Mechanism of Action 241
3 Mechanisms of Resistance 242
4 Aspergillus-Active Azoles 242
4.1 Itraconazole 243
4.1.1 Pharmacodynamics 243
4.1.2 Pharmacokinetics 243
4.1.3 Dosing 244
4.1.4 Therapeutic Drug Monitoring 245
4.1.5 Adverse Effects Profile 245
4.1.6 Drug Interactions 246
4.1.7 Clinical Evidence 247
4.2 Posaconazole 248
4.2.1 Pharmacodynamics 248
4.2.2 Pharmacokinetics 248
4.2.3 Dosing 249
4.2.4 Therapeutic Drug Monitoring 249
4.2.5 Adverse Effects Profile 250
4.2.6 Drug Interactions 250
4.2.7 Clinical Evidence 250
4.3 Voriconazole 254
4.3.1 Pharmacodynamics 254
4.3.2 Pharmacokinetics 254
4.3.3 Dosing 255
4.3.4 Therapeutic Drug Monitoring 255
4.3.5 Adverse Effects Profile 255
4.3.6 Drug Interactions 256
4.3.7 Clinical Evidence 257
4.4 New and Emerging Azoles 257
4.4.1 Ravuconazole 257
4.4.2 Isavuconazole 260
4.4.3 Albaconazole 261
5 Conclusion 262
References 263
Echinocandins 272
1 Introduction 273
2 Pharmacokinetics 274
3 Pharmacodynamics 276
4 Serum Factor 277
5 Paradoxical Effect 278
6 Drug Resistance 278
7 Immunogenic Properties 279
8 Treatment Guidelines 280
8.1 Empirical Antifungal Therapy 280
8.2 Primary Therapy of Invasive aspergillosis 281
8.3 Salvage Therapy of Invasive aspergillosis 281
8.4 Combination Antifungal Regimens in Clinical Settings 281
9 Conclusion 282
References 282
Polyene Antifungal Agents 289
1 Introduction 290
2 Amphotericin B 290
2.1 Chemical Properties 291
2.2 Mechanism of Action 292
2.3 In Vitro Spectrum Against Aspergillus Species 292
2.4 Mechanisms of Polyene Resistance 294
2.5 Polyene Antagonism 294
2.6 Pharmacokinetics 295
2.7 Pharmacodynamics 297
2.8 Adverse Effects 299
3 Lipid Formulations of Amphotericin B 301
3.1 Chemistry and Pharmacokinetics 302
3.2 Pharmacology 303
3.3 Adverse Effects 304
4 Clinical Evidence Supporting the Use of Amphotericin B for Aspergillosis 304
5 Non-Intravenous Approaches for Amphotericin B Administration 304
6 Conclusions 307
References 307
5-Flucytosine 314
1 Introduction 314
2 Pharmacology 315
2.1 Mode of Action 315
2.2 Pharmacokinetics 316
2.3 Toxicity 316
3 Susceptibility 316
4 In Vivo Activity 317
5 Activity in Combination 318
6 Conclusions 320
References 320
Terbinafine 323
1 Mechanism of Action, Spectrum of Activity and Clinical Uses of Terbinafine 323
2 Profile of Activity In Vitro Against Aspergillus Species 324
3 Clinical Use of Terbinafine in Aspergillosis 325
4 Combination Therapy with Terbinafine 327
References 328
PART II INVASIVE PULMONARY ASPERGILLOSIS 332
Epidemiology of Invasive Pulmonary Aspergillosis 333
1 Introduction 334
2 Organism Factors 335
2.1 Aspergillus Species 336
2.2 Sources of Aspergillus Species 337
2.2.1 Air and Ventilation Systems 337
2.2.2 Water 338
2.2.3 Other Sources of Aspergillus 338
3 Host Factors 339
3.1 Patients with Haematological Malignancies 339
3.2 Haematopoietic Stem Cell Transplantation 339
4 Impact of Prophylaxis on the Epidemiology of Aspergillosis 341
References 343
Pathogenesis of Invasive Pulmonary Aspergillosis 349
1 Introduction 350
2 The Study of Aspergillus Virulence 350
3 Aspergillus Species and Pathogenicity 353
4 Interaction of Inhaled Aspergillus Conidia with the Respiratory Epithelium 353
4.1 RodA 357
4.2 Asp f2 357
4.3 Sialic Acids 358
5 Innate Immunity Against Aspergillus : Detection and Evasion 358
6 Angioinvasion 361
6.1 Gliotoxin 362
6.2 Fumagillin 362
6.3 Actibind 363
6.4 Cytochalasin E 363
7 Melanin 363
7.1 Quenching of Reactive Oxigen Intermediates (ROI) 364
7.2 Interference with Intracellular Trafficking of Phagocytised Conidia 364
7.3 beta -Glucan Masking 364
8 Non-melanin Antioxidants 364
9 Thermotolerance 365
9.1 CgrA 365
9.2 thtA 366
10 Proteinases 366
11 Calcineurin 366
12 Siderophores 367
13 Secondary Metabolites 367
13.1 Ribonucleotoxins 368
13.2 Gliotoxin (GT) 368
13.2.1 LaeA 369
13.2.2 GliZ 370
14 Host-Specific Characteristics of Aspergillus Pathogenesis 370
15 Summary 372
References 373
Clinical Manifestations of Invasive Pulmonary Aspergillosis 384
1 Introduction 385
2 Clinical Characteristics of IPA 385
3 Radiographic Manifestations 387
4 Influence of the State of the Host Immunity on Clinical and Radiographic Findings 389
5 Differential Diagnosis 390
References 391
Diagnosis 393
Diagnosing Aspergillosis: The Role of Invasive Diagnostic*15ptInterventions 393
1 Introduction 394
2 Biopsies 395
2.1 Percutaneous Transthoracic Lung Biopsies 395
2.2 Bronchoscopic Lung Biopsies 396
2.3 Open Lung Biopsies 396
3 Bronchoscopy 397
4 Spectrum of Aspergillus Species 397
5 Specimen Procedures 397
5.1 Microscopic Examination 399
5.2 Culture Techniques 400
5.3 Serology Assays 400
5.4 PCR Assays 401
References 402
Optimising the Use of Non-invasive Tests: From Blood*15ptto Radiology 408
1 Introduction 409
2 IPA in Severely Neutropenic Patients 410
2.1 Clinical Manifestations 410
2.2 Radiology 411
2.3 Serology and Antigen Detection 413
2.3.1 Galactomannan 413
2.3.2 -Glucan 414
2.3.3 Polymerase Chain Reaction (PCR) 414
3 IPA in Non-Neutropenic Allogeneic HSCT Recipients 414
3.1 Clinical Manifestations 415
3.2 Radiology 415
3.3 Serology and Antigen Detection 415
4 IPA in Other Settings 416
4.1 IPA in Solid Organ Transplant Recipients 416
4.1.1 Lung Transplantation 416
4.1.2 Other Organ Transplants 417
4.2 IPA in Intensive Care Unit Patients 417
5 Conclusions 418
References 419
Defining Invasive Aspergillosis: What the Revised*15ptEORTC/MSG Definitions Have in Store 424
1 Introduction 425
2 Revising the Definitions 425
3 From Infection to Disease 426
4 Expansion of Host Factors 426
5 No More Major and Minor Clinical Features 426
6 Indirect Mycological Tests 429
7 Improvements 429
8 Known Issues 430
References 433
Treatment of Invasive Pulmonary Aspergillosis 437
1 Antifungal Treatment: Drugs of Choice and Alternatives 438
2 Combination Antifungal Therapy 441
3 Surgical Treatment 442
4 Immune Modulation 442
5 Summary 444
References 445
Antifungal Prophylaxis in Haematology 449
1 Introduction 450
2 Clinical Evidence 450
3 Conclusion 454
4 Future Perspectives 454
References 455
Part IIA Particularities in Special Populations 458
Invasive Aspergillosis in Paediatric Patients 459
1 Introduction 460
2 Populations at Risk and General Epidemiology 460
3 Special Epidemiology and Presentation 461
3.1 Neonates 462
3.2 Children with Primary Immunodeficiencies 463
3.3 Children with Acquired Immunodeficiencies 464
3.3.1 Iatrogenic Immunosuppression 464
3.3.2 Cancer 464
3.3.3 Allogeneic Haematopoietic Stem Cell Transplantation (HSCT) 465
3.3.4 Solid Organ Transplantation (SOT) 466
3.3.5 HIV Infection 467
3.3.6 Children with Severe Acute Illnesses or Trauma 467
3.3.7 Children with Chronic Airway Diseases 467
4 Diagnostic Considerations 467
5 Options for Treatment 469
6 Approaches to Prevention 472
6.1 Primary Prophylaxis 472
6.2 Secondary Prophylaxis 474
7 Conclusions 474
References 474
Invasive Aspergillosis in the Intensive Care Unit: Beyond the Typical Haematological Patient 482
1 Is Invasive Aspergillosis (IA) a Problem in the ICU? 483
2 Who is at Risk for Developing IA in the ICU? 486
3 Do Patients Acquire IA in the ICU? 487
4 Disease Manifestations in the ICU 488
5 Are the Available Diagnostic Tools Applicable to Patients in the ICU? 489
6 Antifungals for the Treatment of IA in the ICU 496
7 Future Directions 496
References 497
Aspergillosis in Surgical Patients 501
1 Introduction 502
2 Post-Operative Aspergillus Endocarditis, Aortitis and Vascular Prosthetic Infections 502
2.1 Illustrative Case (1) 502
2.1.1 Key Messages for This Case 504
2.2 Literature Review on Aspergillus Endocarditis Following Heart Surgery 504
3 Aspergillosis Following Neurosurgery 505
3.1 Illustrative Case (2) 505
3.1.1 Key Messages for This Case 506
3.2 Illustrative Case (3) 506
3.2.1 Key Messages for This Case 508
3.3 Literature Review on Aspergillosis After Neurosurgery 508
4 Aspergillus Wound Infections and Mediastinitis 508
5 Aspergillosis Following Ophthalmological Surgeries 509
6 Aspergillosis and Surgical Dental Procedures 509
7 Other (Rare) Clinical Presentations 509
8 Diagnosis 511
9 Treatment 511
10 Prevention 511
11 Conclusions 513
References 513
Invasive Aspergillosis in Chronic Granulomatous Disease 522
1 Clinical Manifestations, Genetics, and Diagnosis of Chronic Granulomatous Disease 523
2 NADPH Oxidase 524
3 Invasive Aspergillosis in CGD 525
4 Therapy for Invasive Aspergillosis 528
5 Prophylaxis Against Fungal Infections 528
6 Interferon-gamma 529
7 Granulocyte Transfusions 529
8 Haematological Stem Cell Transplantation 530
9 Gene Therapy 530
10 Chronic Granulomatous Disease: A Disorder of Tryptophan Metabolism 531
11 Conclusions 532
References 533
Aspergillosis in Drug Addicts 539
1 Introduction 540
2 Invasive Pulmonary Aspergillosis and Other Forms of Aspergillosis in Cannabis/Marijuana Smokers 540
3 Invasive Pulmonary Aspergillosis in Intravenous Drug Users 541
4 Other Forms of Aspergillosis in Intravenous Drug Users 543
4.1 Aspergillus Endophthalmitis 543
4.2 Aspergillus Endocarditis 543
4.3 Aspergillus Osteomyelitis 550
4.4 Central Nervous System Aspergillosis 550
4.5 Renal Aspergillosis 550
5 Conclusions 550
References 551
Invasive Aspergillosis and HIV Infection 553
1 Introduction, incidence and epidemiology 553
2 Clinical Manifestations 555
3 Diagnosis 557
4 Therapy 558
References 559
Invasive Pulmonary Aspergillosis in Solid Organ Transplant Recipients 561
1 Epidemiology and Risk Factors 562
2 Clinical Presentation 563
2.1 Lung Transplant Recipients 563
2.2 Liver Transplant Recipients 565
2.3 Heart Transplant Recipients 565
2.4 Kidney Transplant Recipients 566
3 Diagnosis of Invasive Aspergillosis in Solid Organ Transplant Recipients 566
4 Therapy of Invasive Aspergillosis in Solid Organ Transplant Recipients 567
5 Prophylaxis of Invasive Aspergillosis in Solid Organ Transplant Recipients 568
6 Conclusions 570
References 570
PART III CHRONIC CAVITARY PULMONARY ASPERGILLOSIS 576
Chronic Cavitary Pulmonary Aspergillosis and Fungal Balls 577
1 Introduction 578
2 Aetiology 579
3 Epidemiology 579
4 Pathogenesis 580
5 Clinical Manifestations and Natural History 581
6 Fungal Ball and AIDS 583
7 Diagnosis 584
7.1 Proposed Diagnostic Criteria 585
7.2 Radiological Findings 585
7.3 Sputum Examination 589
7.4 Aspergillus Precipitins 589
8 Treatment 590
8.1 Role of Surgery 591
8.2 Antifungal Therapy 591
8.2.1 Itraconazole 591
8.2.2 Voriconazole 592
8.2.3 Intravenous Antifungal Therapy 593
8.2.4 Intra-Cavitary Use of Antifungal Drugs 593
8.3 Bronchial Artery Embolisation and Haemoptysis Control 594
8.4 Other Measures 594
8.5 Monitoring Therapy 594
9 Prevention 594
10 Comments About Our Study 595
10.1 Fungal Ball Due to Aspergillus niger 595
10.2 Fungal Ball Due to Scedosporium apiospermum (Pseudallescheria boydii) 601
10.3 Actinomycotic Intra-Cavitary Lung Lesions 606
References 607
Pathogenesis of Chronic Cavitary Pulmonary Aspergillosis: The Importance of the Host Immune System 613
1 Introduction 614
2 Innate Defence Mechanisms Against CCPA 616
3 The Importance of Collectins 617
3.1 Mannose Binding Lectin (MBL) 618
3.2 Lung Surfactant Proteins 619
3.3 Pentraxin 3 621
4 Cytokine and Cellular Immunity Against CCPA 622
5 Toll-Like Receptors 627
6 Concluding Remarks 630
References 632
Current Surgical Strategies for Chronic Cavitary Pulmonary Aspergillosis 635
1 Introduction 636
2 Surgical Outcomes and Options 637
3 Localisation of Cavernostomy 638
4 Open-Window Thoracostomy 638
5 Preoperative Preparation 639
6 Surgical Techniques 639
6.1 Preparation of Muscle Flap 640
6.2 Muscle Flap 640
6.3 How to Insert the Muscle Graft 640
6.4 Cover Plan 641
6.5 Cutaneous Plan and Drainage 641
7 Conclusions 641
References 642
PART IV ALLERGIC PULMONARY SYNDROMES ASSOCIATED WITH ASPERGILLOSIS 644
Overview of Aspergillus Allergens 645
1 Introduction 646
2 The World of Fungal Allergens 648
3 The Allergen Repertoire of Aspergillus fumigatus 648
4 Diagnostic Value of Recombinant A. fumigatus Allergens 651
5 Cross- and Autoreactivity 652
6 Structural Aspects of Fungal Allergens 653
7 Therapy of Fungal Allergy 653
8 Conclusions 654
References 655
Allergic bronchopulmonary aspergillosis (ABPA) 660
Epidemiology of Allergic Bronchopulmonary Aspergillosis 660
1 Introduction 661
2 Environmental Factors Influencing the Occurrence of ABPA 662
3 Genetic Factors Influencing the Epidemiology of ABPA 663
4 Prevalence of Aspergillus Hypersensitivity in Patients with Asthma 663
5 Prevalence of ABPA in Patients with Asthma 665
6 Prevalence of ABPA in Cystic Fibrosis 666
7 Occurrence of ABPA Without Asthma 667
8 Occurrence of ABPA in Other Situations 667
9 Coexistence of ABPA and Fungal Balls 669
10 ABPA-Like Syndrome with Other Fungi (Allergic Bronchopulmonary Mycosis) 669
11 Conclusions 669
References 670
ABPA as an Occupational Disease 678
1 Introduction 678
2 ABPA Related to Cane Sugar Mills 679
3 ABPA Related to Small Workshops of Soybean Products 679
4 Treatment and Prevention 681
References 682
Pathogenesis of ABPA 683
1 Introduction 684
2 Aspergillus Fumigatus , Pathogen and Allergen 684
3 Clinical and Pathologic Features of ABPA 685
4 Dysfunction of Cystic Fibrosis Transmembrane Regulator, the Airway Epithelium and ABPA 686
5 The Innate Immune Response and the Development of ABPA: The Role of Collectins 687
6 The Innate Immune Response and the Development of ABPA: The Role of Phagocytic Cells 688
7 The Adaptive Immune Response and the Development of ABPA 689
8 Conclusions 690
References 692
Clinical Manifestations and Natural History of*15ptAllergic Bronchopulmonary Aspergillosis 695
1 Introduction 696
2 Clinical Features of ABPA 697
3 History 697
4 Physical Examination 698
5 Laboratory Findings 698
5.1 Skin Tests 698
5.2 Immunological Studies 699
6 Radiological Investigations 700
7 Pulmonary Function Tests 701
8 Natural History 702
9 Conclusions 707
References 707
How to Diagnose Allergic Bronchopulmonary Aspergillosis 713
1 Introduction 714
2 Proposed Diagnostic Criteria 715
3 ABPA in Association with Other Aspergillus -Related Diseases 716
3.1 Allergic Aspergillus sinusitis 716
3.2 Fungal Balls 716
4 ABPA and Cystic Fibrosis 717
5 Familial Occurrence of ABPA 717
6 ABPA Without Asthma 717
7 ABPA and Other Lung Disorders 719
8 Allergic Bronchopulmonary Mycosis 719
9 Radiological Findings 719
9.1 Plain Chest Roentgenography 720
9.1.1 Transient Changes 720
9.1.2 Permanent Changes 723
9.2 Demonstration of Central Bronchiectasis 724
9.3 Other Computed Tomography Appearances 725
10 Sputum Examination 726
11 Blood Tests 726
11.1 Eosinophilia 727
11.2 Precipitating Antibodies Against A. Fumigatus 727
11.3 Serum IgE 727
11.3.1 Specific IgE/IgG to A. Fumigatus 727
11.4 Recombinant Aspergillus fumigatus Allergens 728
11.4.1 Diagnosing ABPA in CF Using Recombinant Allergens 728
12 Skin Testing 729
12.1 Skin Testing with Recombinant Allergens in Cystic Fibrosis 729
References 730
The Treatment of ABPA 734
1 General Principles of Treatment of Allergic Bronchopulmonary Aspergillosis 735
2 Steroid Therapy 735
3 Antifungal Therapy 737
4 Other Adjunctive Anti-asthma Therapies for ABPA Exacerbations 739
5 Monitoring Therapy 740
6 Differentiating an Exacerbation of Cystic Fibrosis (CF) from ABPA in Patients with Both Diseases 741
7 Potential Therapies 743
References 744
Severe Asthma with Fungal Sensitisation (SAFS) 747
1 Introduction 748
2 Association of Fungal Sensitisation and Severe Asthma 748
3 Fungi as Allergens 749
4 Protease-Induced Airway Inflammation 750
5 Volatile Organic Compounds (VOCs) 750
6 Survivor Effect 751
7 Allergic Bronchopulmonary Aspergillosis s (ABPA): A Historical Perspective 751
8 Severe Asthma with Fungal Sensitisation (SAFS) 752
9 Diagnosis of SAFS 753
9.1 Severe Asthma 754
9.2 Fungal Sensitisation 754
9.3 Distinction Between SAFS and ABPA 754
9.4 Imaging 755
10 Treatment of SAFS 755
10.1 Antifungal Azoles -- The Fast Study 755
10.2 Anti-IgE Therapy 756
11 Summary 757
References 757
PART V ASPERGILLUS SINUSITIS 762
Aspergillus Sinusitis 763
1 Introduction 764
2 Incidence 766
3 Immunology and Host-Pathogen Interactions in Fungal Sinus Disease 768
4 Fungal Ball (Aspergilloma) 769
4.1 Introduction 769
4.2 Diagnostic Criteria 770
4.3 Pathophysiology and Natural Course 771
4.4 Radiologic Features 771
4.5 Treatment 772
5 Allergic Aspergillus Sinusitis 772
5.1 Epidemiology 772
5.2 Clinical Features 773
5.3 Diagnostic Criteria 774
5.4 Pathophysiology and Natural Course 776
5.5 Radiologic Features 777
5.6 Treatment 778
5.6.1 Surgical Treatment 778
5.6.2 Medical Treatment 779
5.7 Follow-Up 782
6 Chronic Invasive Fungal Sinusitis 782
6.1 Diagnosis 782
6.2 Diagnostic Criteria 783
6.3 Pathophysiology and Natural Course 783
6.4 Radiologic Features 784
6.5 Treatment 785
6.5.1 Surgical Treatment 785
6.5.2 Medical Therapy 786
6.6 Follow-Up 787
7 Acute Invasive Fungal Sinusitis 787
7.1 Introduction 787
7.2 Diagnostic Criteria 788
7.3 Pathophysiology and Natural Course 788
7.4 Natural Course 789
7.5 Radiologic Features 790
7.6 Treatment 790
7.6.1 Medical Therapy 791
7.6.2 Surgical Treatment 792
7.7 Follow-Up 793
8 Summary 793
References 794
PART VI OVERLAP SYNDROMES 799
Aspergillus Overlap Syndromes 800
1 Introduction 801
2 Fungal Balls and Allergic Bronchopulmonary Aspergillosis (ABPA) 802
3 ABPA and Invasive Aspergillosis 805
4 Allergic Aspergillus Sinusitis Overlap Syndromes 808
5 Overlap Between Aspergillosis and Other Respiratory Diseases 809
5.1 Hypersensitivity Pneumonitis 810
5.2 Mucoid Impaction of the Bronchus (MIB) 811
5.3 Bronchocentric Granulomatosis (BG) 811
6 Conclusions 811
References 813
PART VII OTHER PRESENTATIONS OF ASPERGILLOSIS 815
Cerebral Aspergillus Infections and Meningitis 816
1 Introduction 817
2 Clinical Characteristics and Diagnostic Approach 818
3 Aspects of Central Nervous System Pharmacokinetics 820
4 Treatment Strategies 824
5 Future Developments 826
References 827
Osteoarticular and Epidural Infections 834
1 Osteoarticular Aspergillosis 835
1.1 Clinical Presentation 836
1.2 Diagnosis 837
1.3 Treatment 839
1.4 Surgical Management 840
2 Epidural Infections due to Aspergillus 840
2.1 Clinical Presentation 840
2.2 Diagnosis 841
2.3 Treatment 841
References 842
Aspergillosis of the Digestive Tract 844
1 Introduction 844
2 Aspergillosis of the Digestive Tract 845
2.1 Primary Digestive Aspergillosis 846
2.1.1 Oral Cavity 851
2.1.2 Upper Digestive Tract 851
2.1.3 Lower Digestive Tract 855
3 Conclusion 861
References 861
Cardiac Aspergillosis 869
1 Introduction 870
2 Aetiology and Epidemiology 870
3 Risk Factors 871
4 Outcomes 872
5 Pathogenesis 872
6 Clinical Presentation 873
6.1 Native Valve Endocarditis 873
6.2 Prosthetic Valve Endocarditis 873
6.3 Myocarditis and Mural Endocarditis 874
6.4 Pericarditis 875
7 Diagnosis 875
7.1 Imaging 876
7.2 Microbiology 876
7.3 Histopathology 877
7.4 Antigen Detection 877
8 Treatment 878
8.1 Endocarditis 878
8.2 Myocardial and Pericardial Aspergillosis 879
9 Conclusion 880
References 880
Aspergillus Thyroiditis 884
1 Introduction 884
2 Aspergillosis and the Thyroid 885
3 Conclusion 888
References 888
Aspergillus Endophthalmitis 891
1 Introduction 892
2 Frequency of Occurrence of Aspergillus Endophthalmitis 892
3 Aetiological Agents of Aspergillus Endophthalmitis 893
4 Risk Factors 893
4.1 Risk Factors for Exogenous Aspergillus Endophthalmitis 893
4.2 Risk Factors for Endogenous Aspergillus Endophthalmitis 893
5 Clinical Features of Aspergillus Endophthalmitis 894
5.1 Symptoms of Aspergillus Endophthalmitis 894
5.2 Signs of Aspergillus Endophthalmitis 895
6 Diagnosis of Aspergillus Endophthalmitis 895
6.1 Imaging Studies 896
6.2 Microbiological Investigations 896
6.2.1 Collection of Samples 896
6.2.2 Direct Microscopic Examination and Culture 896
6.2.3 Microbiological Investigations in Aspergillus Endophthalmitis 896
6.3 Molecular Methods for Diagnosis of Aspergillus Endophthalmitis 897
7 Histopathological Studies on Aspergillus Endophthalmitis 897
8 Treatment of Aspergillus Endophthalmitis 898
8.1 General Principles of Treatment of Fungal Endophthalmitis 898
8.1.1 Vitrectomy 898
8.1.2 Antifungal Agents 898
8.2 General Principles of Treatment of Exogenous Fungal Endophthalmitis 899
8.2.1 Recommended Measures for Post-Operative Fungal Endophthalmitis 899
8.2.2 Recommended Measures for Fungal Endophthalmitis Developing from Fungal Keratitis 900
8.3 Treatment of Aspergillus Endophthalmitis 900
8.3.1 Treatment of Endogenous Aspergillus Endophthalmitis 900
8.3.2 Treatment of Exogenous (Post-Operative) Aspergillus Endophthalmitis 902
8.3.3 Treatment of Exogenous (Post-traumatic) Aspergillus Endophthalmitis 903
References 904
Urinary Tract Infections Caused by Aspergillus Species 908
1 Introduction 909
2 Pathogenesis 909
3 Pathological Features 910
4 Clinical Manifestations 910
5 Diagnosis 911
6 Management 911
7 Outcome 912
8 Prostatic Aspergillosis 912
References 913
Superficial infections 915
Cutaneous and Wound Aspergillosis 915
1 Introduction 916
2 History 917
3 Classification of the Disease 917
4 Epidemiology 918
4.1 Neonates 919
4.2 Systemic Steroid Therapy 919
4.3 Other Immunosuppressive Agents 920
4.4 Cancers Including Haematological Malignancies 920
4.5 HSCT Recipients 920
4.6 Solid Organ Transplant Recipients 920
4.7 HIV Infection 920
4.8 Burn Victims 921
4.9 Placement of Hickman Catheters 921
4.10 Maceration of Skin 921
4.11 Construction Work in Hospitals 922
4.12 Improper Cleaning of Air Conditioning Ducts, Contaminated Ventilating Systems 922
4.13 Post-Surgical Wound Infections 922
4.14 Other Recognised Risk Factors 922
5 The Fungi 922
6 Pathogenesis 923
7 Pathology 924
8 Clinical Features 926
8.1 Contiguous Spread of Deep Aspergillus Infection 928
8.2 Onychomycosis 928
9 Laboratory Diagnosis 929
10 Differential Diagnosis 929
11 Management 930
11.1 Surgery 930
11.2 Systemic Antifungal Agents 931
11.3 Topical Therapy 931
11.4 Onychomycosis 932
References 932
Onychomycosis Due to Aspergillus Species 936
1 Introduction 937
2 Clinical Forms 938
3 Mycological Diagnosis 939
4 Special Characteristics of Onychomycosis Due to Aspergillus Species 941
5 Treatment 942
References 944
Aspergillus Keratitis 947
1 Introduction to Fungal Keratitis and Aspergillus Keratitis 948
2 Aetiological Agents of Aspergillus Keratitis 949
3 Risk Factors for Aspergillus Keratitis 949
4 Diagnosis of Aspergillus Keratitis 951
4.1 History and Clinical Features 951
4.2 Non-invasive Methods of Diagnosis 952
4.3 Microbiological Diagnosis of Aspergillus Keratitis 952
4.3.1 Sampling 952
4.3.2 Direct Microscopic Examination 953
4.3.3 Culture 953
4.4 Histopathological Diagnosis of Aspergillus Keratitis 954
4.5 Polymerase Chain Reaction (PCR) in Diagnosis of Aspergillus Keratitis 955
4.6 Antifungal Susceptibility Testing 956
5 Pathogenesis of Aspergillus Keratitis 956
5.1 Putative Agent Factors in the Pathogenesis of Aspergillus Keratitis 957
5.1.1 Adherence to Corneal Tissue and Invasiveness by Aspergillus 957
5.1.2 Toxigenicity of Ocular Aspergillus Isolates 957
5.2 Putative Host (Corneal Tissue) Factors in the Pathogenesis of Aspergillus Keratitis 958
5.2.1 Matrix Metalloproteinases and Polymorphonuclear Leucocytes 958
5.2.2 TLR and Corneal Immune Responses to A. fumigatus 958
5.2.3 The Plasminogen Activator-Plasmin System in Pathogenesis 959
5.3 Molecular Pathogenesis of Aspergillus Keratitis 959
6 Management of Aspergillus Keratitis 959
6.1 Medical Therapy of Aspergillus Keratitis 959
6.1.1 Non-specific Measures in the Medical Therapy of Aspergillus Keratitis 960
6.1.2 Specific Compounds in the Medical Therapy of Aspergillus Keratitis 960
6.2 Surgery in the Management of Aspergillus Keratitis 964
6.2.1 Debridement in Aspergillus Keratitis 964
6.2.2 Lamellar Keratectomy/Keratoplasty in Aspergillus Keratitis 964
6.2.3 Conjunctival Flap in Aspergillus Keratitis 965
6.2.4 Amniotic Membrane Transplantation in Aspergillus Keratitis 965
6.2.5 Therapeutic Penetrating Keratoplasty 965
6.2.6 Anterior Chamber Tap 966
References 966
Aspergillus Otitis 973
1 Introduction 974
2 Epidemiology 974
3 Aetiology and Pathogenesis 974
4 Clinical Aspects 975
5 Laboratory Diagnosis 976
6 Treatment and Prophylaxis 977
References 978
How to Diagnose Allergic Bronchopulmonary Aspergillosis 982
1 Introduction 983
2 Proposed Diagnostic Criteria 984
3 ABPA in Association with Other Aspergillus -Related Diseases 985
3.1 Allergic Aspergillus Sinusitis 985
3.2 Fungal Balls 985
4 ABPA and Cystic Fibrosis 986
5 Familial Occurrence of ABPA 986
6 ABPA Without Asthma 986
7 ABPA and Other Lung Disorders 988
8 Allergic Bronchopulmonary Mycosis 988
9 Radiological Findings 988
9.1 Plain Chest Roentgenography 989
9.1.1 Transient Changes 989
9.1.2 Permanent Changes 992
9.2 Demonstration of Central Bronchiectasis 993
9.3 Other Computed Tomography Appearances 994
10 Sputum Examination 995
11 Blood Tests 995
11.1 Eosinophilia 996
11.2 Precipitating Antibodies Against A. fumigatus 996
11.3 Serum IgE 996
11.3.1 Specific IgE/IgG to A. fumigatus 996
11.4 Recombinant Aspergillus fumigatus Allergens 997
11.4.1 Diagnosing ABPA in CF Using Recombinant Allergens 997
12 Skin Testing 998
12.1 Skin Testing with Recombinant Allergens in Cystic Fibrosis 998
References 999
Index 1004