Viral and Fungal Infections of the Central Nervous System: A Microbiological Perspective

This book covers topics related to viral and fungal infections of the central nervous system (CNS), with a multidisciplinary reach, discussing associated immunology, microbiological aspects, pathologies, timely management, and prevention. The book is structured into five broad sections. The first section provides the reader with valuable insights into the aetiologies and underlying pathophysiological mechanisms of neurological diseases, including host responses. It mentions all bacterial, fungal, parasitic, and viral causes of neuro-infections, along with rarer neuropathogenesis such as prions and mycoplasmas. The chapter also presents detailed epidemiology and prevalence of different CNS infections worldwide. It also reviews various infectious diseases that target the nervous system, such as focal lesions, meningitis, and neurological complications of venous sinus thrombosis. The next two sections delve deep into pathogen-specific diseases of the CNS, namely the viruses and fungi associated with neuro-infections. It mentions detailed excerpts on encephalitic viruses, long-term consequences of neurotropic viruses, mycological neuroinfectious, and even the emerging, less talked of viruses and fungi causing neurological disease. Topics such as principles of vigorous antifungal therapy and surgeries are also discussed in the chapter. The fourth section gives an insight on prospects for efficiently diagnosing and managing viral and fungal CNS infections, to tackle associated morbidities. Features that are often less documented, yet of considerable interest in current times, such as the role of immunosuppression in neurological infections and newer microbiological diagnostic strategies are covered. The last section uniquely provides clinicians with relatable case scenarios. Real case descriptions are included, such as cases of fungal meningitis and other difficult-to-diagnose infections produced by viruses. This book serves as a guide for neurologists, medical microbiologists, and clinical practitioners who deal with patients suspected of neurological infection. Foreword I Foreword II Preface Disclosure Statement Acknowledgments Contents Editors and Contributors Part I: Introduction: An Insight into Central Nervous System (CNS) Infections 1: Etiology and Epidemiology of Central Nervous System Infections 1.1 Introduction 1.2 Epidemiology 1.2.1 Epidemiological Triad 1.3 Viral CNS Infections 1.4 Fungal CNS Infections 1.5 Emerging and Re-emerging Infections 1.6 Bacterial, Mycobacterial, and Parasitic CNS Infections 1.7 Conclusion References 2: Overview of Infective Syndromes of the Central Nervous System and Its Coverings: Decoding Chameleons and Mimics 2.1 Introduction 2.2 Meningitis 2.2.1 The Meninges: Anatomical and Functional Attributes 2.2.2 Routes of CNS Infection 2.2.3 Acute Bacterial Meningitis 2.2.4 Tubercular Meningitis 2.2.5 Chronic Meningitis 2.2.6 Aseptic Meningitis 2.2.7 Meningitis Following Trauma Episodes 2.3 Space-Occupying Lesions and Associated Infections 2.4 Healthcare-Associated Infections of the CNS 2.5 Viral Encephalitis and Encephalopathies 2.6 Mycotic Neuro-Invasions 2.6.1 Blood-Brain-Barrier Interactions in Fungal Invasion 2.6.2 Rhino-Cerebellar Syndromes 2.6.3 Disseminated Syndromes 2.7 Infections of the Brainstem, Cerebellum, and Spine 2.7.1 Epidural Abscess of the Spine 2.7.2 Neurodegenerative Disorders with Possible Infective Linkages 2.7.3 Peripheral Nerve Involvement in CNS Infections 2.7.4 Transverse Myelitis, etc. 2.8 Tropical Neuro-Infections 2.8.1 Brain Injury Caused by Neuro-Parasites 2.8.2 Cerebral Malaria 2.8.3 Emerging and Re-emerging Tropical CNS Infections 2.9 Post-infection Neurological Complications References 3: Clinical Presentation and Diagnosis of CNS Infections Through a Systematic Approach 3.1 Introduction 3.2 Clinical Presentation 3.2.1 Meningitis 3.2.2 Encephalitis 3.2.3 Brain Abscess 3.3 Physical Examination 3.3.1 Fever 3.3.2 Classical Maneuvers 3.3.3 Neurological Examination 3.3.4 Ancillary signs 3.4 Diagnostics 3.4.1 Initial Laboratory Tests 3.4.2 Lumbar puncture 3.4.3 Neuroimaging 3.4.4 Cerebrospinal Fluid (CSF) Analysis 3.5 Summary References 4: Immune Responses in Infections of the Central Nervous System 4.1 Immune Responses in the Cerebrospinal Fluid 4.2 T-Cell-Mediated Immune-Regulation 4.3 Cellular and Humoral Immune Responses Against Different Pathogens 4.4 Neurotropism 4.5 Immunosuppressive Effects of Pathogens 4.6 Infection-Induced Autoimmune Responses References Part II: Viral Pathogens: Pathogenesis, Pathology, Diagnosis and Treatment 5: Herpesvirus Infections of the Central Nervous System 5.1 Herpesviruses in Central Nervous System Infections 5.1.1 Introduction 5.1.2 General Features for Herpetic CNS Infections 5.1.3 Diagnosis of Herpetic Encephalitis 5.1.4 Treatment of Herpetic Infections of CNS 5.1.4.1 Initial Management 5.1.4.2 Empirical Treatment of Encephalitis 5.2 Emphasis on Individual HHV Types Causing Infections of the CNS 5.2.1 HHV-1 Also Known as Herpes Simplex Virus Type-1 (HSV-1) 5.2.1.1 Introduction 5.2.1.2 Pathogenesis 5.2.1.3 Clinical Features 5.2.1.4 Laboratory Diagnosis of HSV-1 Encephalitis 5.2.2 Treatment 5.2.3 Human Herpes Virus (HHV)-2 Also Known as Herpes Simplex Virus Type-2 5.2.3.1 Introduction 5.2.3.2 Pathogenesis 5.2.3.3 Clinical Features 5.2.3.4 Diagnosis 5.2.3.5 Treatment 5.2.4 Human Herpes Virus (HHV)-3 Varicella Zoster Virus 5.2.4.1 Introduction 5.2.4.2 Clinical Features 5.2.4.3 Diagnosis 5.2.4.4 Treatment 5.2.5 Human Herpes Virus (HHV)-4 Also Known as Epstein-Barr Virus (EBV) 5.2.5.1 Introduction 5.2.5.2 Pathogenesis 5.2.5.3 Clinical Features 5.2.5.4 Diagnosis and Treatment 5.2.6 Human Herpes Virus (HHV)-5 Also Known as Human Cytomegalovirus (HCMV) 5.2.6.1 Introduction 5.2.6.2 Pathogenesis and Clinical Features 5.2.6.3 Diagnosis and Treatment 5.2.7 Human Herpes Virus (HHV)-6 Also Known as HHV-6 5.2.7.1 Introduction 5.2.7.2 Pathogenesis and Clinical Features 5.2.7.3 Diagnosis 5.2.7.4 Treatment 5.2.8 Human Herpes Virus (HHV)-7 Also Known as HHV-7 5.2.8.1 Introduction 5.2.8.2 Pathogenesis 5.2.8.3 Clinical Features 5.2.8.4 Diagnosis and Treatment 5.2.9 Human Herpes Virus 8 (HHV-8) Also Known as Kaposi Sarcoma-Associated Herpes Virus (KSHV) 5.2.9.1 Introduction 5.2.9.2 Pathogenesis and Clinical Features 5.2.9.3 Diagnosis and Treatment References 6: Enterovirus-Associated Meningoencephalitis and Enteroviruses in Patients with Acute Encephalitis 6.1 Pathogens 6.1.1 Overview of Enteroviruses 6.1.2 Viral Structure 6.1.3 Epidemiological Profile 6.2 Etiopathogenesis 6.2.1 Routes of Central Nervous System Invasion 6.2.1.1 Through the Bloodstream 6.2.1.2 Through the Peripheral Circulating Immune Cells (Trojan Horse Route) 6.2.1.3 Through Nerves in the Periphery Via Retrograde Axonal Transport and Trans-Synaptic Propagation 6.2.2 Cell Receptors for Virus Entry 6.2.3 Tropism 6.2.4 Enteroviruses and Autophagy 6.2.5 Persistent Infection 6.3 Diagnosis 6.3.1 Presenting Features 6.3.2 Differential Diagnosis 6.3.3 Laboratory Diagnostics 6.3.3.1 Cerebrospinal Fluid (CSF) Biochemistry 6.3.3.2 Electron Microscopy 6.3.3.3 Immunohistochemistry 6.3.3.4 Molecular Methods 6.3.3.5 Serology 6.3.3.6 Viral Culture 6.3.4 Imaging 6.4 Management and Treatment 6.4.1 General 6.4.2 Antivirals 6.4.3 Newer Agents 6.4.4 Complications/Prognosis 6.4.5 Prevention References 7: Encephalitic Arboviruses 7.1 Introduction 7.2 Diagnostic Criteria of Encephalitis (Refer to Table 7.1) 7.2.1 Viral Encephalitis Pathogenesis 7.3 Arbovirus Causing Encephalitis (Refer to Table 7.2) 7.3.1 Japanese Encephalitis Virus 7.3.1.1 WHO Recommended Case Definition for Japanese Encephalitis (JE) (WHO n.d.-a) 7.3.1.1.1 Clinical Case Definition 7.3.1.1.2 Case Classification 7.3.2 Chikungunya Virus 7.3.3 Dengue Virus 7.3.4 Zika Virus 7.4 Clinical Manifestation of Arboviral Encephalitis 7.5 Diagnosis 7.5.1 Case Classification 7.5.1.1 Probable 7.5.1.2 Confirmed 7.5.1.3 Laboratory Criteria for Diagnosis of Arboviral encephalitis (Venkatesan and Geocadin 2014): 7.6 Treatment 7.7 Preventive strategies (Olliaro et al. 2018) References 8: Neurological Illnesses Involved in Human Immunodeficiency Virus and Human T cell Lymphotropic Virus Infections 8.1 Brain 8.1.1 HAND (HIV-Associated Neurocognitive Disorders) 8.1.2 Opportunistic Infections 8.1.2.1 Tuberculous Meningitis 8.1.2.2 CNS Toxoplasma Infection 8.1.2.3 CNS Fungal Infections 8.1.2.3.1 Cryptococcal Meningitis (CM) 8.1.2.4 Opportunistic Viral Infections 8.1.2.4.1 Cytomegalovirus 8.1.2.4.2 Herpes Zoster Virus 8.1.2.4.3 PML (Progressive Multifocal Leukoencephalopathy) 8.1.2.5 Primary CNS Lymphoma (PCNSL) 8.2 Spinal Cord 8.2.1 Diseases Affecting Spinal Cord in Early Stages of HIV 8.2.2 Spinal Cord Involvement in Late and Uncontrolled HIV Stages 8.3 Peripheral Nerves References 9: Neurological Complications of Measles and Mumps 9.1 Measles and Its Neurological Complications 9.1.1 Introduction 9.1.2 Virology 9.1.3 Pathogenesis 9.1.3.1 Neuropathophysiology 9.1.4 Clinical Manifestations 9.1.4.1 Classic Measles 9.1.4.2 Modified Measles 9.1.4.3 Atypical Measles 9.1.5 Diagnosis 9.1.6 Management 9.1.7 Neurological Complications 9.1.7.1 Primary Measles Encephalitis 9.1.7.1.1 Epidemiology 9.1.7.1.2 Clinical Presentation 9.1.7.1.3 Diagnosis 9.1.7.1.4 Treatment 9.1.7.1.5 Prognosis 9.1.7.1.6 Neuropathophysiology and Neuropathology 9.1.7.2 Postinfectious Encephalomyelitis 9.1.7.2.1 Epidemiology 9.1.7.2.2 Clinical Presentation 9.1.7.2.3 Diagnosis 9.1.7.2.4 Treatment 9.1.7.2.5 Prognosis 9.1.7.2.6 Neuropathophysiology and Neuropathology 9.1.7.2.7 Postvaccination Encephalomyelitis 9.1.7.3 Subacute Sclerosing Panencephalitis (SSPE) 9.1.7.3.1 Epidemiology 9.1.7.3.2 Clinical Presentation 9.1.7.3.3 Diagnosis 9.1.7.3.4 Treatment 9.1.7.3.5 Prognosis 9.1.7.3.6 Neuropathophysiology and Neuropathology 9.1.7.3.7 Immunization and SSPE 9.1.7.4 Measles Inclusion Body Encephalitis 9.1.7.4.1 Epidemiology 9.1.7.4.2 Clinical Presentation 9.1.7.4.3 Diagnosis 9.1.7.4.4 Treatment 9.1.7.4.5 Prognosis 9.1.7.4.6 Neuropathophysiology and Neuropathology 9.1.7.5 Hearing Loss 9.2 Mumps and Its Neurological Complications 9.2.1 Introduction 9.2.2 Virology 9.2.3 Pathogenesis 9.2.4 Clinical Manifestations 9.2.5 Diagnosis 9.2.6 Management and Treatment 9.2.7 Neurological Complications 9.2.7.1 Meningitis 9.2.8 Encephalitis 9.2.8.1 Hearing Loss References 10: Rabies Encephalitis: A Disease Characterized By Complex Neuropathogenic Pathways and Diagnostic Difficulties 10.1 Introduction 10.2 Rabies Virus Structure 10.3 Epidemiology 10.4 Transmission 10.5 Pathogenesis (Fig. 10.2) 10.6 Immune Evasion 10.7 Clinical Presentation 10.8 Diagnosis 10.8.1 Sample Collection 10.8.1.1 Saliva 10.8.1.2 Cornea 10.8.1.3 Skin Biopsy 10.8.1.4 CSF 10.8.2 Laboratory Testing 10.8.2.1 Negri Bodies 10.8.2.2 DFAT 10.8.2.3 DRIT 10.8.2.4 RADT 10.8.2.5 NAAT 10.8.2.6 ELISA 10.8.2.7 RFFIT 10.8.2.8 RTCIT 10.8.2.9 MIT/BT 10.9 Differential Diagnosis 10.10 Management and Prevention 10.10.1 Wound Toilet 10.10.2 Passive Immunization 10.10.2.1 Equine Rabies Immunoglobulin (ERIG) 10.10.2.2 Human Rabies Immunoglobulins (HRIG) 10.10.2.3 Dose of Rabies Immunoglobulins (RIG) 10.10.3 Active Immunization References 11: Miscellaneous CNS Viral Infections: Underappreciated Causes of Neurologic Disease 11.1 Overview and List of Miscellaneous Viral CNS Infections 11.2 Parechovirus A 11.3 Rubella Virus 11.4 Hepatitis C Virus and Hepatitis E Virus: Associated Neurological Disorders 11.5 John Cunningham Virus 11.5.1 Viral Structure 11.5.2 Epidemiological Profile 11.5.3 Aetiopathogenesis 11.5.4 Diagnosis 11.5.5 Management, Treatment, and Prevention 11.6 Lymphocytic Choriomeningitis Virus 11.6.1 Viral Structure 11.6.2 Aetiopathogenesis 11.6.3 Diagnosis 11.6.4 Management, Treatment, and Prevention 11.7 Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) 11.8 Prion-Related CNS Disorders 11.8.1 Structure 11.8.2 Epidemiological Profile 11.8.3 Aetiopathogenesis 11.8.4 Diagnosis 11.8.5 Management, Treatment, and Prevention References Part III: Fungal Pathogens: Pathogenesis, Pathology, Diagnosis and Treatment 12: Neuro-Infections Caused By Candida Species 12.1 Pathogen 12.2 Pathogenesis 12.3 Pathology, Risk Factors, and Clinical Manifestations of Neuro-Candidiasis 12.4 Diagnosis 12.4.1 CSF Analysis 12.4.2 Neuroimaging 12.5 Treatment 12.5.1 Duration References 13: Cryptococcosis of the Central Nervous System 13.1 Introduction 13.2 Cryptococcus 13.3 Epidemiology 13.4 Pathogenicity 13.4.1 The Described Ways Through Which the Organism Crosses the BBB 13.4.1.1 The `Trojan Horse ́ Mechanism 13.4.1.2 Paracellular Passage 13.4.1.3 Transcellular Passage 13.4.2 Virulence 13.4.2.1 Capsule 13.4.2.2 Melanin 13.4.2.3 Thermotolerance 13.4.3 Reason for Neurotropism 13.5 Clinical Manifestations 13.5.1 Meningitis/Meningoencephalitis 13.5.2 Cryptococcoma 13.5.3 CNS Cryptococcosis and HIV Seronegative 13.6 Laboratory Diagnosis of Cryptococcal Meningitis 13.6.1 CSF Composition 13.6.2 Microscopic Examination 13.6.2.1 India Ink Stain 13.6.2.2 Other Staining Methods 13.6.2.3 The Histopathological Analysis 13.6.3 Antigen Detection 13.6.3.1 Cryptococcal Antigen (CrAg) 13.6.3.2 Latex Agglutination Test (LAT) 13.6.3.3 Lateral Flow Assay (LFA) 13.6.3.4 Screening of Blood for Cryptococcal Antigen 13.6.3.5 Screening of Urine Sample 13.6.4 Culture 13.6.5 MALDI-TOF MS 13.6.6 Other Tests 13.7 Treatment of Cryptococcal Meningitis 13.7.1 WHO Recommendation 13.7.1.1 Induction Therapy 13.7.1.2 Alternative Induction Regimens 13.7.1.3 Consolidation Therapy (2018 Recommendation) 13.7.1.4 Maintenance (2018 Recommendation) 13.7.2 Managing Raised Intracranial Pressure 13.7.3 Monitoring Treatment Response 13.7.4 Persistent or Recurrent Symptoms 13.7.5 Managing Relapse 13.7.6 Species-Based Treatment 13.7.7 Treatment in Pregnant Women with Cryptococcosis 13.7.8 IRIS 13.7.9 Antifungals 13.7.9.1 Polyenes 13.7.9.2 Flucytosine 13.7.9.3 Fluconazole 13.8 Outcome 13.9 Repurposing Old Drugs 13.9.1 Fenbendazole 13.9.2 Macrolides 13.9.3 Antimalarial Drug Mefloquine 13.9.4 Sertraline and Tamoxifen 13.10 Drug Combination Therapy 13.11 Drugs in Pipeline 13.11.1 Monoclonal Antibody 18B7 13.11.2 Benzyl thioureas (BTUs) 13.11.3 Other Drugs 13.12 Vaccines 13.13 Prevention Strategies: WHO Recommendations References 14: Mold Infections of the Central Nervous System 14.1 Introduction 14.2 Etiologic Agents 14.3 Burden of CNS Fungal Infections 14.4 Epidemiology 14.4.1 CNS Aspergillosis 14.4.2 Rhino-Orbito-Cerebral Mucormycosis 14.4.3 CNS Fusariosis 14.5 Pathogenesis 14.6 Pathogenesis by Specific Fungi 14.6.1 Aspergillus species 14.6.2 Mucorales 14.6.3 Fusarium species 14.6.4 Scedosporium species 14.6.5 Cladophialophora bantiana 14.6.6 Verruconis gallopava 14.7 Clinical Presentation 14.7.1 CNS Aspergillosis 14.7.2 Rhino-Orbito-Cerebral Mucormycosis 14.7.3 CNS Fusariosis 14.8 Diagnosis 14.8.1 CNS Aspergillosis 14.8.2 Rhino-Orbito-Cerebral Mucormycosis 14.8.3 CNS Fusariosis 14.8.4 Other Mold Infections 14.9 Management 14.9.1 Antifungal Therapy 14.9.2 Surgery 14.9.3 Adjunctive Therapies 14.9.4 Supportive Care 14.9.5 Monitoring 14.10 Conclusion References 15: Role of Dimorphic Fungi in CNS Infections 15.1 Dimorphic Fungal Infection 15.1.1 Dimorphic Fungi Involving the CNS 15.2 Histoplasmosis 15.2.1 Pathogenesis 15.2.2 Clinical Presentation 15.2.3 Diagnosis 15.2.4 Treatment and Subsequent Diagnostic Testing 15.3 Blastomycosis 15.3.1 Epidemiology 15.3.2 Pathogenesis 15.3.3 Clinical Features 15.3.4 Diagnosis 15.3.5 Treatment 15.4 Coccidioidomycosis 15.4.1 Clinical Features 15.4.2 Diagnosis 15.4.3 Treatment 15.5 Paracoccidioidomycosis 15.6 Talaromyces Marneffei 15.7 Sporotrichosis References 16: Melanized Fungi in CNS Infections 16.1 Introduction 16.2 Melanized Fungi 16.3 Melanized CNS Fungal Infections 16.4 Pathophysiology 16.5 Clinical Manifestations 16.6 Diagnosis 16.7 Medical Management 16.8 Surgical Management References 17: Miscellaneous CNS Fungal Infections 17.1 Introduction 17.2 Penicillium 17.2.1 P. commune 17.2.2 P. chrysogenum 17.2.2.1 Growth Characteristics and Identification 17.2.2.2 Treatment 17.3 Scedosporium 17.3.1 Growth Characteristics and Identification 17.3.2 Treatment 17.4 Trichosporon 17.4.1 Pathogenesis 17.4.2 Growth Characteristics and Identification 17.4.3 CNS Infections of Trichosporon spp. 17.4.4 Treatment 17.5 Fusarium 17.5.1 Growth Characteristics and Identification 17.5.2 Pathogenesis 17.5.3 CNS Infections of Fusarium spp. 17.5.4 Treatment References Part IV: Future Insights into Central Nervous System Infections 18: Advanced Microbiological Diagnostic Techniques in Viral Infections of the Central Nervous System 18.1 Introduction 18.2 Diagnostic Approaches in Virology 18.3 Serving Purposes of Diagnostic Virology 18.4 Advanced Diagnostic Techniques 18.4.1 Advanced Nucleic Acid Amplification Methods 18.4.1.1 Multiplex PCR Assays 18.4.1.1.1 Filmarray ME Panel 18.4.1.1.2 MeningoFinder 2Smart 18.4.1.1.3 Fast Track Meningitis Kits 18.4.1.1.4 Allplex Meningitis-V1 andV2 Assays 18.4.1.1.5 Viral CNS Flow Chip 18.4.1.2 PCR-Electrospray Ionization Mass Spectrometry(PCR/ESI-MS) 18.4.1.3 Helicase-Dependent Amplification 18.4.1.4 Loop-Mediated Isothermal Amplification 18.4.2 Advanced Nucleic Acid Sequencing Methods 18.4.2.1 Target Amplicon Sequencing 18.4.2.2 Whole Genome Sequencing (WGS) 18.4.2.3 Metagenomic Sequencing 18.4.2.3.1 Shotgun Sequencing Method 18.4.2.3.2 Limitations of Metagenomics 18.4.2.4 In Situ Sequencing (ISS) 18.4.2.4.1 Characteristics of the ISS References 19: Advanced Microbiological Diagnostic Techniques in Fungal Infections of the Central Nervous System 19.1 Introduction 19.1.1 Clinical Picture of Fungal CNS Infections 19.1.2 Etiological Agents Associated with Fungal Infections of the CNS 19.1.3 Immunological States Predisposing to Various Fungal Infections of the CNS 19.1.3.1 Treatment-Induced Immunosuppression 19.1.3.2 Immunodeficiency Syndromes 19.1.4 Clinical Syndromes 19.2 Diagnostic Modalities 19.2.1 Microbiological Techniques for Isolating Fungi (Hage et al. 2019; Lockhart et al. 2021; Vainionpää and Leinikki 2008) 19.3 Microscopic Examination 19.3.1 KOH 19.3.2 Calcofluor with KOH 19.3.3 Gram ́s Stain 19.3.4 India Ink 19.3.5 Periodic Acid Schiff 19.3.6 Gomori ́s Methenamine Silver Stain: Grocott ́s Modification 19.3.7 Fluorescent Antibody Staining 19.3.8 Histopathology 19.3.9 Immunohistochemistry 19.3.10 Laser Microdissection 19.4 Fungal Culture 19.4.1 Culture Methods 19.5 Non-culture Methods 19.5.1 Histology and Special Stains 19.5.2 Nucleic Acid Detection/Biomarkers 19.6 Serology 19.6.1 Detection of Fungal Antibodies 19.6.2 Complement Fixation 19.6.3 Immunodiffusion 19.6.4 Detection of Fungal Antigens 19.6.5 1,3-beta-d-Glucan Assay 19.6.6 Fully Automatic Chemiluminescence Immunoassay System 19.6.7 Galactomannan 19.6.8 Lateral Flow Assay 19.6.9 Latex Agglutination 19.6.10 Enzyme Immunoassay 19.6.11 Mannan Detection 19.6.12 Enolase 19.6.13 Secreted Aspartyl Proteinase 19.7 Tests for Detection of Metabolites 19.7.1 d-Arabinitol 19.7.2 Mannitol in Aspergillus and Cryptococcus Infections 19.8 Tests for Detection of CMI 19.8.1 Skin Testing 19.9 Matrix-Assisted Laser Desorption/Ionization-Time of Flight Mass Spectrometry (MALDI-TOF MS) 19.9.1 Commercially Available Are as Follows 19.10 Molecular Diagnostics 19.10.1 Multiplex PCR 19.10.2 Panfungal PCR Assays 19.10.3 Syndromic Testing 19.10.4 Multiplex Tandem PCR (MT-PCR) 19.10.5 PCR-ELISA 19.10.6 Fluorescent In Situ Hybridization (FISH) 19.10.7 Microarray 19.10.8 DNA Array Hybridization 19.10.9 Electrophoretic Karyotyping (EK) 19.10.10 Multilocus Enzyme Electrophoresis (MLEE) 19.10.11 Light Cycler Septi Fast (LC-SF) 19.10.12 Multianalyte Profiling (xMAP) System 19.10.13 Loop Mediated Isothermal Amplification 19.10.14 Nanotechnology Approaches 19.11 Genome-Based Fungal Identification and Characterization 19.11.1 Direct Clinical Specimen-Based Precision Diagnosis of IFDs Using DNA Metabarcoding 19.12 Future Prospects in Diagnosis of Fungal Infection 19.12.1 Artificial Intelligence Methods 19.13 Conclusion References+ 20: Association of Viral and Fungal Infections of the CNS During Immunosuppression 20.1 Introduction 20.2 Viral Infections in Immunocompromised Individuals 20.2.1 Pathogenesis 20.2.2 Common Viruses Associated with CNS Infection 20.2.2.1 Herpesviridae 20.2.2.1.1 Herpes Simplex Viruses (HSV) 20.2.2.1.2 Varicella-Zoster Virus (VZV) 20.2.2.1.3 Cytomegalovirus (CMV) 20.2.2.1.4 Epstein-Barr Virus (EBV) 20.2.2.1.5 HHV-6 20.2.2.2 Adenoviridae 20.2.2.3 Papovaviridae 20.2.2.3.1 John Cunningham Virus (JCV) 20.2.3 Laboratory Diagnosis of Viral CNS Infections 20.2.3.1 Abnormalities Detected in the CSF Following Viral Infections in the Immunocompromised 20.2.3.2 Virus Isolation 20.2.3.3 Antigen Detection 20.2.3.3.1 In Situ Hybridization 20.2.3.4 Serology: Antibodies in CSF or Serum 20.2.3.5 PCR 20.2.3.6 MRI 20.2.3.7 Angiography 20.2.4 Treatment 20.2.4.1 HSV 20.2.4.2 VZV 20.2.4.3 CMV 20.2.4.4 EBV 20.2.4.5 HHV 6 20.2.4.6 Adenoviruses 20.3 Fungal Infections in the Immunocompromised Host 20.3.1 Mechanisms of CNS Fungal Invasion in the Immunocompromised Host 20.3.2 Candida 20.3.3 Cryptococcus 20.3.4 Aspergillus 20.3.5 Mucorales (Zygomycetes) 20.3.6 Histoplasma 20.3.7 Miscellaneous Fungi Causing Infection in the Immunocompromised Individual 20.3.8 Common CNS Manifestations of Fungal Infections Are as Follows 20.3.9 Common Clinical Features 20.3.10 Laboratory Diagnosis of Fungal CNS Infections 20.3.10.1 Imaging 20.3.10.2 CSF Examination 20.3.10.3 Antigen Detection 20.3.10.4 PCR 20.3.10.5 Other Rapid Automated Diagnostic Tests 20.3.10.6 Culture 20.3.11 Treatment References