Preface
Contents
Part I: Overview of the Epidemiology, Risk and Prevention of Infections
1: Overview of the Risk of Infection Associated with Biologic and Target Therapies
Overview of Targeted and Biological Therapies
Monoclonal Antibodies and Related Agents
Small-Molecule Enzyme Inhibitors
Assessment of the Risk of Infection
References
2: Timeline and Infectious Disease Evaluation of Candidates to New Therapies
Introduction
Timeline of Infectious Complications in Patients on Biologic and Targeted Drugs
Evaluation and Prevention of Infectious Complications in Patients on Biologic and Targeted Treatment
Conclusion
References
3: Safety and Efficacy of Vaccines in Patients on Targeted and Biologic Therapies
Summary Table
Evidence Summary by Medication Class
TNF-Alpha Inhibitors and Abatacept
Hepatitis B (HBV) Vaccine
Pneumococcal Vaccine
Influenza Vaccine
Live Vaccines
IL-1 Inhibitors
IL-6
HBV Vaccine
Pneumococcal Vaccine
Influenza
Tetanus
Live Vaccines
IL-12/23
IL-17
Eculizumab
VEGF Inhibitors (Bevacizumab, Aflibercept)
VEGF-R Inhibitors (Sorafenib, Sunitinib, Axitinib, Pazopanib, Regorafenib, Vandetanib, Cabozantinib, Ramucirumab)
ErbB2/HER2 Inhibitors (Trastuzumab, Pertuzumab)
ErbB Receptor Tyrosine Kinases (Erlotinib, Gefitinib, Afatinib, Osimertinib, Lapatinib, Neratinib)
BCR-ABL Tyrosine Kinase Inhibitors (Imatinib, Dasatinib, Nilotinib, Bosutinib, Ponatinib)
Burton Tyrosine Kinase Inhibitors (Ibrutinib, Acalabrutinib)
PI3K Inhibitors Idelalisib, Buparlisib, Rigosertib, Duvelisib
Janus Kinase Inhibitors (Ruxolitinib, Tofacitinib, Baricitinib)
Pneumococcal Vaccine
Influenza
Tetanus
Live Zoster Vaccine
mTOR Inhibitors (Everolimus, Temsirolimus)
Anti-CD20 (Rituximab, 90Y-Ibritumomab Tiuxetan, Ofatumumab, Ocrelizumab, Veltuzumab, 131I-Tositumomab, Obinutuzumab, Ocaratuzumab, Ublituximab)
Pneumococcal Vaccine
Influenza
Hepatitis B Vaccine
Tetanus
Varicella
Alemtuzumab
Anti CD-38 (Daratumumab, Isatuxumab)
CTLA-4 Inhibitors (Ipilimumab, Tremelimumab)
PD-1 and PD-1 Ligand Inhibitors (Nivolumab, Pembrolizumab, Atezolizumab)
Influenza Vaccine
Recombinant Zoster Vaccine
LFA-3 Inhibitor (Alefacept)
Alpha 4-Integrin and LFA-1 Inhibitors (Natalizumab, Vedolizumab, Efalizumab)
Influenza Vaccine
Other Vaccines
Live Vaccines
Sphingosine 1-Phosphate Receptor Inhibitor (Fingolimod, Siponimod)
Proteosome Inhibitors (Bortezomib, Carfilzomib, Ixazomib)
References
4: Travel and Risk of Infections
Introduction
Infectious Diseases and Risks Factors for Travelers
Modes of Transmission of Infections
Risks Factors for Travelers
Common Infectious Diseases in Travelers
Gastrointestinal Infections
Respiratory Infections
Vector-Borne Infections
Skin Infections
Sexually Transmitted Infections
Other Infections
Fever in Travelers
Health Tourism and Infectious Diseases
Vaccine-Preventable Diseases and Vaccines
Advice for Healthcare Workers to Give Travelers
References
Part II: Specific Agents and Risk of Infections
5: Anti-tumor Necrosis Factor-Alpha Agents
Introduction
Tumor Necrosis Factor-Alpha and the Innate Immune System
Tumor Necrosis Factor-Alpha Inhibitors (TNFI)
Risk of Infection
Mycobacterial Infections
Bacterial and Other Serious Infections
Viral Infections
Hepatitis B
Hepatitis C
Herpes Zoster
Fungal Infections
Pneumocystis Pneumonia
Conclusion
References
6: CD22, CD30, CD33, CD38, CD40, SLAMF-7 and CCR4
CD22-Targeted Agents: Epratuzumab, Inotuzumab Ozogamicin, Moxetumomab Pasudotox
CD22 Antigen
Mechanism of Action and Current Indications of Anti-CD22 Monoclonal Antibodies
Clinical Evidence
Risk of Infections and Its Management
CD30-Targeted Agents: Brentuximab Vedotin
CD30 Antigen
Mechanism of Action and Current Indications for CD30 Monoclonal Antibodies
Clinical Evidence
Risk of Infections and Its Management
CD33-Targeted Agents: Gemtuzumab Ozogamicin, Vadastuximab Talirine
CD33 Antigen
Mechanism of Action and Current Indications of Anti-CD33 Monoclonal Antibodies
Clinical Evidence
Risk of Infection and Its Management
CD38-Targeted Agents: Daratumumab, Isatuximab
CD38 Antigens
Mechanism of Action and Current Indications of Anti-CD38 Monoclonal Antibodies
Clinical Evidence
Risk of Infection and Its Management
CD40 Targeted Agents: Selicrelumab, Dacetuzumab, Lucatumumab
CD40 Antigen
Mechanism of Action, Approved Indications and Off-Labels Use of CD40 Monoclonal Antibodies
Clinical Evidence
Risk of Infections and Its Management
CD319 (SLAMF7) Agents: Elotuzumab
SLAMF7 (Previous CD139) Antigen
Mechanism of Action, Approved Indications, and Off-Label Use of Anti-CD139 Monoclonal Antibodies
Clinical Evidence
Risk of Infections and Its Management
CCR-4-Targeted Agents: Mogamulizumab
Chemokine Receptor 4, CCR-4
Mechanism of Action, Approved Indications, and Off-Label Use of CCR-4 Monoclonal Antibodies
Clinical Evidence
Risk of Infection and Its Management
References
7: CD19, CD20 and CD52
Introduction
Anti-CD20 Agents
Available Agents and Their Main Indications
Mechanism of Action and the Pathogenesis of Increased Risk of Infectious Complications
The Rates of Infectious Complications in Patients Treated with Anti-CD20
HBV Reactivation in Patients Treated with Anti-CD20 Agents
Other Infectious Complications
Hypogammaglobulinaemia and the Risk of Infections
HGG and the Risk of Infections
Hypogammaglobulinaemia (HGG) Management
Neutropenia and the Risk of Infections
CD19-Targeting Agents
Available Agents
Mechanism of Action and the Risk of Infectious Complications
CD52-Targeting Agents
Available Agents
Mechanism of Action and the Risk of Infectious Complications
Vaccination in Patients Receiving Anti-CD20, Anti-CD19 and Anti-CD52 Agents
References
8: Cell-Surface Receptors: EGFR- and VEGFR-Targeted Agents
Introduction
Agents Targeting EGFR
mAbs Against EGFR
Mechanism of Action
Approved Indications
Expected Impact on Susceptibility to Infection
Available Clinical Data
Conclusions and Suggested Prevention Strategies
EGFR-Targeted TKIs
Mechanism of Action
Approved Indications
Expected Impact on Infection Risk
Available Clinical Data
Conclusions and Suggested Prevention Strategies
Agents Targeting VEGF/VEGF Receptor (VEGFR)
Intravenous Agents Targeting VEGF/VEGFR
Mechanism of Action
Approved Indications
Expected Impact on Susceptibility to Infection
Available Clinical Data
Conclusions and Suggested Prevention Strategies
TKIs Targeting VEGFR
Mechanism of Action, Approved Indications, and Off-Label Use
Expected Impact on Susceptibility to Infection
Available Clinical Data
Conclusions and Suggested Prevention Strategies
References
9: Interleukin-1 Targeted Agents
Introduction
Available IL-1-Targeting Agents
Infectious Complications of Interleukin-1 (IL-1)-Targeted Agents
Anakinra
Canakinumab
Rilonacept
Gevokizumab
Tuberculosis
Opportunistic Infections
Conclusions
References
10: Interleukin-6 Targeted Agents
Introduction
Mechanism of Action and Expected Impact on Infection Risk
Available Clinical Data
Conclusions and Suggested Prevention Strategies
References
11: Interleukin-12 and -23 Targeted Agents
Introduction: The Role of IL-12 and IL-23 in Immunity and Disease
IL-12 and IL-23 as Therapeutic Targets
Overall and Serious Infections
IL-12-Targeted Agents
IL-23-Targeted Agents
Tuberculosis
Other Opportunistic Infections
Viral Hepatitis
Hepatitis B Virus
Hepatitis C Virus
Recommendations for Infection Risk Management
References
12: Sphingosine-1 Phosphate Receptor Modulators
Biologic/Immune-Targeted Agent
Mechanism of Action
Current Indications for the Use
The Described Risk of Infections
References
13: Immune Checkpoint Inhibitors
Introduction to Immune Checkpoint Blockade
CTLA-4 Immune Checkpoint
PD-1/PD-L1 Immune Checkpoint
Brief History of Immune Checkpoint Inhibitors
Mechanism of Action of Immune Checkpoint Inhibitors
Indications
CTLA-4 Inhibitors: Ipilimumab (Yervoy®)
Tremelimumab
PD-1 Inhibitors: Pembrolizumab (Keytruda®)
Nivolumab (Opdivo®)
Cemiplimab (Libtayo®)
PD-L1 Inhibitors: Atezolizumab (Tecentriq®)
Avelumab (Bavencio®)
Durvalumab (Imfinzi®)
Checkpoint Inhibitors and Infections
Mechanisms Predisposing to Infection
Risk of Infection
Current Guidelines
Using Checkpoint Inhibitors to Treat Infections
Sepsis
HIV
JC Virus
Hepatitis B
Invasive Fungal Infections
COVID-19
Mouse Models of Infection
Summary
References
14: α4-Integrin (and Other Leukocyte Integrin)-Targeting Agents
Introduction
Integrins Overview
Integrins: A Complex Structure with Unique Biology
Leukocyte Integrins
Integrins as Therapeutic Targets
Leukocyte-Integrin-Targeting Agents
Monoclonal Antibodies: Mechanism of Action
Other Therapeutic Agents
Approved Indications of Integrin-Targeting Agents
Natalizumab
Vedolizumab
Infectious Complications of Integrin-Targeting Agents
Natalizumab
Vedolizumab
Efalizumab
Prevention Strategies in MS Patients Receiving Natalizumab
PML Risk Stratification
JCV Serostatus and MRI
Previous Immunosuppression
Duration of Natalizumab Treatment
Additional Biomarkers for Risk Stratification
Additional Preventive Strategies
Conclusions
References
15: Tyrosine-Kinase Inhibitors
Introduction
The Tyrosine Kinase Inhibitor Family
BCR-ABL Inhibitors
Mechanism of Action (MOA) and Indications
Risk of Infection
Prevention of Infection
Janus-Associated Kinases (JAK) Inhibitors
MOA and Indication
Risk of Infection
Prevention of Infection
Bruton’s Tyrosine Kinase (BTK) Inhibitors
MOA and Indication
Risk of Infection
Prevention of Infection
Phosphatidylinositol 3-Kinase (PI3K) Inhibitors
MOA and Indication
Risk of Infection
Prevention of Infection
Anaplastic Lymphoma Kinase (ALK) Inhibitors
MOA and Indication
Risk of Infection
Prevention of Infection
Spleen (Syk) TKI
MOA and Indication
Risk of Infection
Prevention of Infection
Conclusion
References
16: Bcl-2, JAK and mTOR Inhibitors
mTOR Inhibitors
JAK Inhibitors
BCL-2 Inhibitors
References
17: Infection Associated with the Use of CAR T Cells
Introduction
Mechanism of Action of CAR T-Cell Therapy
Main Toxicities Following CAR T-Cell Therapy
CRS and ICANS
Cytopenia
Hypogammaglobulinemia
Incidence of Infection
Risk Factors for Infections
Main Types of Infection
Bacterial Infection
Viral Infections
Fungal Infections
Latent Infections and Screening Strategies
Prophylactic Regimens in Patients Receiving CAR T-Cell Therapy
Vaccination
Conclusions
References
Part III: Clinical Conditions Associated with the Use of Biologic and Targeted Therapies
18: Pulmonary Infiltrates
Introduction
Infectious Pulmonary Complications
Bacterial Infections
Mycobacterial Infections
Respiratory Viruses
Fungal
Noninfectious Pulmonary Complications
Interstitial Lung Disease
Pleural Disease
Pulmonary Nodules
Drug-Induced Pulmonary Toxicity
Practical Evaluation of Pulmonary Infiltrates
Clinical History
Investigations
Blood Investigations
Urine Investigations
Respiratory Investigations
Imaging
Prevention
References
19: Tuberculosis
Introduction
TNF-α Inhibitors
Screening and Therapy of LTBI
Non-anti-TNF Biologics and Other Targeted Immunomodulators
IL-1 Inhibitors
IL-6 Inhibitors
IL-12/23 Inhibitors
IL-17 Inhibitors
T-Cell Co-stimulation Inhibitors
B-Lymphocyte Depletion Therapy
JAK Kinase Inhibitors
References
20: Cytomegalovirus and Other Herpesviruses
Introduction
Cytomegalovirus and Immune Control of Infection
Immune Control of Infection
Biologic Drugs and Risk of Herpes Infection
Tumor Necrosis Factor Alpha (TNF-α) Inhibitor Drugs: Adalimumab, Certolizumab, Etanercept, Golimumab, and Infliximab
Drugs Targeting Specific B-Cell Receptors
Anti-CD20: Obinutuzumab, Ocrelizumab, Ofatumumab, Rituximab, and Y-Ibritumomab Tiuxetan
Anti-CD30: Brentuximab Vedotin
Anti-CD38: Daratumumab
Phosphatidylinositol 3-Kinase (PI3K) Inhibitors: Idelalisib, Buparlisib, Rigosertib, and Duvelisib
Drugs Targeting T-Cell Activation
IgG Against Cytotoxic T-Lymphocyte-Associated Protein 4: Blockade of CD28-CD80/86 Interaction by Abatacept and Belatacept
Direct T-Cell Inhibitors
Anti-CD52 Drugs: Alemtuzumab
Interleukin-4, Interleukin-5, and Interleukin-6 Inhibitors
Interleukin-4 Inhibitors: Dupilumab
Interleukin-5 Inhibitors: Benralizumab, Mepolizumab, and Reslizumab
Interleukin-6 Inhibitors: Tocilizumab, Sarilumab, and Siltuximab
Checkpoint Inhibitors
Agents Targeting Cytotoxic T-Lymphocyte-Associated Protein 4 (Ipilimumab and Tremelimumab) and Programmed Cell Death Protein-1 and Ligand-1 (Nivolumab, Pembrolizumab, and Atezolizumab)
Tyrosine Kinase Inhibitors Used in Hematologic Malignancies
BCR-ABL Tyrosine Kinase Inhibitor: Bosutinib, Dasatinib, Imatinib, Nilotinib, and Ponatinib
Janus Kinase Inhibitors
Ruxolitinib, Tofacitinib, and Baricitinib
mTOR Inhibitors
Everolimus, Sirolimus, and Temsirolimus
Other Biologic Drugs Associated with the Risk of Herpesvirus Infections
Sphingosine 1-Phosphate Receptor Modulator: Fingolimod
Proteasome Inhibitors: Bortezomib, Carfilzomib, and Ixazomib
CCR4 Inhibitors: Mogamulizumab
Antiviral Prophylaxis Against Herpesvirus Infection
Prophylaxis Against Herpes Simplex Virus and Varicella-Zoster Virus
Cytomegalovirus
References
21: Invasive Fungal Disease
Introduction
Invasive Candidiasis
Clinical Presentation of Invasive Candidiasis
Biologics and Targeted Therapies Associated with Increased Risk of Invasive Candidiasis
TNF-α Inhibitors (E.G. Infliximab, Etanercept, Adalimumab, Certolizumab, Golimumab)
Anti-IL-17 Agents (Secukinumab, Ixekizumab, Brodalumab)
Other Agents with Reported Associations with Invasive Candidiasis
Impact of Biologics and Targeted Therapies on Investigation, Treatment and Prophylaxis of Invasive Candidiasis
Cryptococcosis
Clinical Presentation of Cryptococcosis
Biologics and Targeted Therapies Associated with Increased Risk of Cryptococcosis
TNF-α Inhibitors
Ibrutinib and Other Tyrosine Kinase Inhibitors
Other Biologic and Targeted Therapies with Reported Associations with Cryptococcosis
Impact of Biologics and Targeted Therapies on Investigation, Treatment and Prophylaxis of Cryptococcosis
Invasive Mould Disease
Clinical Presentation of Invasive Mould Disease
Biologics and Targeted Therapies Associated with Increased Risk of Invasive Mould Disease
BTK Inhibitors
Other Agents with Reported Associations with Invasive Mould Disease
Impact of Biologics and Targeted Therapies on Investigation, Treatment and Prophylaxis of Invasive Mould Disease
Pneumocystis jirovecii Pneumonia
Clinical Presentation of Pneumocystis jirovecii Pneumonia
Biologics and Targeted Therapies Associated with Increased Risk of Pneumocystis jirovecii Pneumonia
Anti-CD52 Therapy
PI3K Inhibitors
TNF-α Inhibitors
BTK Inhibitors
Other Agents with Reported Associations with PJP
Impact of Biologics and Targeted Therapies on Investigation, Treatment and Prophylaxis of Pneumocystis jirovecii Pneumonia
Other Invasive Fungal Diseases Including Endemic Mycoses
Clinical Presentation of Endemic Mycoses
Biologics and Targeted Therapies Associated with Increased Risk of Endemic Mycoses
TNF-α Inhibitors (Infliximab, Etanercept, Adalimumab, Golimumab, Certolizumab)
Other Agents with Reported Associations with Endemic Mycoses
Impact of Biologics and Targeted Therapies on Investigation, Treatment and Prophylaxis of Endemic Mycoses
Conclusion
References
22: Progressive Multifocal Leukoencephalopathy
Introduction
PML Related with α4-Integrin-Targeted Agents
Underlying Mechanisms of Natalizumab-Related PML
Epidemiology and Risk Factors for Natalizumab-Related PML
Clinical Features and Management
Preventive Algorithms
PML Related to Monoclonal Antibodies Against Lymphoma and Leukemia Surface Antigens
Anti-CD20 Monoclonal Antibodies
Antibodies Against Lymphoma and Leukemia Cell Surface Antigens
Alemtuzumab
Brentuximab
Drugs Targeted to Intracellular Signaling Pathways
References
23: Hepatitis Viruses
Introduction
Hepatitis B
Hepatitis C
B-Cell-Depleting Antibodies
Anti-TNF-α
Anti-IL-1R Antagonists
Anti-IL-6/Anti-IL-6R
Anti-IL-12/23
Anti-IL-17
Integrin Inhibitors
JAK/STAT
CTLA-4 Fusion Proteins
CTLA-4 Inhibitors
PD-1/PD-L1 Inhibitors
Anti-CD52
Anti-CCR4
Summary
References
24: Immune-Targeted Therapies for COVID-19
Introduction
Immunomodulatory Agents for the Treatment of COVID-19
Interleukin-6 Antagonists
Tocilizumab
Siltuximab
JAK/STAT Pathway Inhibitor
Ruxolitinib
Baricitinib
Il-1 Antagonist
Anakinra
References
Index
