Prevention Strategies to Minimize the Infection Risk Associated with Biologic and Targeted Immunomodulators

Figures & data

Table 1 Biologic and Targeted Immunomodulators Classification and Their Impacts on the Immune System

Biologic and Targeted Immunomodulators	Effect on the Immune System	Risk of Infections
TNF inhibitors Infliximab, Adalimumab, Golimumab, Certolizumab, Etanercept	Inactivation of CD4+/CD 8+ T cells; neutropenia	TB, HBV
Co-stimulation modulator Abatacept	Inhibition of APC function; inhibition of T cell stimulation; inhibition of B cell response	Not associated with increased risk of infection
IL-1 targeted agents Anakinra, Canakinumab, Rilonacept	↓ IL-1	TB
CD19 targeted agents Blinatumomab, Inebilizumab	↓ CD19 B Cells; ↓ plasmablasts; hypogammaglobulinemia	Limited data
CD22 targeted agents Epratuzumab, Inotuzumab Ozogamicin, Moxetumomab Pasudotox	Inhibition of B cell proliferation	Not associated with increased risk of infection
CD30 targeted agents Brentuximab Vedotin	Antibody-dependent cellular cytotoxicity; neutropenia	HZ, PCP, CMV, PML
CD38 targeted agents Daratumumab, Isatuximab	Complement-dependent cytotoxicity	VZV (probably)
CD40 targeted agents Dacetuzumab, Lucatumumab	↓B Cells; impairment in T cell function	CMV, PCP Cryptococcus, Cryptosporidium
CD319-targeted agent Elotuzumab	Lymphopenia	VZV
CCR4 targeted agent Mogamulizumab	Lymphopenia	HBV, HZ, CMV
Anti-CD20 monoclonal antibodies Rituximab, Ibritumomab Tiuxetan, Ofatumumab, Ocrelizumab	↓ CD20 B Cells; neutropenia; hypogammaglobulinemia	HBV, HCV, VZV, PML, PCP, Enterovirus
Anti-CD52 monoclonal antibody Alemtuzumab	Inhibition of the action of CD4+ T Cells, B Cells epithelial cells, macrophages, and monocytes	HSV, PCP, TB, VZV, HPV
Component 5 (C5) targeted agent Eculizumab	Complement-mediated cytotoxicity	Neisseria, H. influenzae, S. pneumonia, Aspergillosis
BAFF inhibitor Belimumab	Reduction of B cell population	PML (Rare)
α4-integrin targeted agent Natalizumab	Targeting α4-integrin; inhibition of translocation of leukocytes in BBB	PML
α4-integrin targeted agent Vedolizumab	Targeting α4β7 integrin; inhibition of translocation of leukocytes in the mucosal membrane of the small intestine	Enteric bacterial infections (probably)
IgE targeted agent Omalizumab	Inhibition of the activity of mast cells, basophils, plasma cells, and eosinophils	Helminth infections
IL-5 targeted agent Mepolizumab, Reslizumab	↓ IL-5; inhibition of eosinophil differentiation	Not associated with increased risk of infection
IL-12 and IL-23 targeted agent Ustekinumab	Inhibition of action of NK Cells, Th17, Th1 CD4+ T-cells, ↓ IFNγ	TB, HBV (intracellular pathogens)
IL-17 targeted agents Secukinumab, Ixekizumab, Brodalumab	Inhibition of macrophage stimulation and neutrophil chemotaxis	Mucocutaneous candidiasis
Proteasome inhibitors Bortezomib, Carfilzomib, Ixazomib	Inhibition of the proteasome pathway Inhibition of the activity of T cell	HZ, VZV
BCR-ABL tyrosine kinase inhibitors Imatinib, Dasatinib, Nilotinib, Ponatinib, Bosutinib	Neutropenia; Impairment of B cell response; Reduced CD4+ and CD8+ T cell stimulation	HBV, CMV, EBV
mTOR inhibitors Sirolimus, Everolimus, Temsirolimus	Reduced neutrophil migration; Inhibition of dendritic cell differentiation; Inhibition of T cell stimulation	Bacterial infections TB, HBV, HZ
JAK inhibitors Tofacitinib, Ruxolitinib	Inhibition of differentiation of TH1 and TH17 cells	Bacterial infections, PCP, CMV, HZ, EBV Invasive fungal infections
Sphingosine 1-phosphate receptor modulator Fingolimod	Lymphopenia ↓ CD 4+ and CD8+ T Cells in CSF	HZ, PML, Cryptococcus
IL-6 targeted agents Tocilizumab, Siltuximab	Neutropenia	TB, NTM, HBV, PCP, invasive candidiasis
Agents targeting PD-1/PD-L1 Nivolumab, Pembrolizumab	Increase in activity of T cells	Not associated with increased risk of the infection itself
Agents targeting CTLA-4 Atezolizumab, Ipilimumab, Tremelimumab	Increase in activity of T cells	Not associated with increased risk of the infection itself
Phosphatidylinositol-3-kinase inhibitor Idelalisib	Reduced chemotaxis and cytokine production; neutropenia	PCP, CMV
Bruton Tyrosine kinase inhibitors Ibrutinib, Acalabrutinib	Inhibition of B cell proliferation; hypogammaglobulinemia	Bacterial infections
Monoclonal antibody targeting CD25 Basiliximab	Inhibition of the action of T cells	PCP, CMV

Abbreviations: APC, antigen-presenting cell; BAFF, B-cell activating factor, CMV, cytomegalovirus; EBV, Epstein-Barr virus; HBV, hepatitis B virus; HCV, hepatitis C virus; H. influenzae, Haemophilus influenzae, HPV, human papillomavirus; HSV, Herpes simplex virus; HZ, herpes zoster; IFNγ, interferon-gamma; IL-1, interleukin-1; IL-5, interleukin-5; NTM, Nontuberculous mycobacteria; PCP, Pneumocystis carinii pneumonia; PML, progressive multifocal leukoencephalopathy; TNF, tumor necrosis factor; TB, tuberculosis; VZV, varicella-zoster virus.

Table 2 Evidence and Recommendations on Screening of Infections in Patients Candidates for Biologic and Targeted Immunomodulatory Therapies

TNF inhibitors	Perform PPD and IGRA; Chest X-ray; smear and culture of the sputum.^Citation13 Check HBs Ag and anti-HBc. Check anti-HBs for immunization status.^Citation13 Screening pap smear abnormalities could be considered.^Citation42
IL-1-targeted agents	Perform PPD and IGRA; Chest X-ray; smear and culture of the sputum.^Citation8
CD19-targeted agents	Check baseline immunoglobulin levels.^Citation10
CD22-targeted agents	Check HBs Ag and anti-HBc; Check anti HBS Ab for immunization status; Check HBV viral load if necessary.^Citation12
CD30-targeted agent	Check HBs Ag and anti-HBc; Check anti HBS Ab for immunization status; Check HBV viral load if necessary.^Citation12
CD-38-targeted agents	Check VZV serology.^Citation12 Check HBs Ag and anti-HBc. Check anti HBS Ab for immunization status. Check HBV viral load if necessary.^Citation12
CD-319-targeted agent	Check VZV serology.^Citation12
CCR4-targeted Agent	Check HBs Ag and anti-HBc. Check anti HBS Ab for immunization status. Check HBV viral load if necessary.^Citation12
Anti-CD20 monoclonal antibodies	Check HBs Ag and anti-HBc. Check anti HBS Ab for immunization status. Check HBV viral load if necessary.^Citation10 Check baseline immunoglobulin levels.^Citation22,Citation83
Anti-CD52 monoclonal antibody	Perform PPD and IGRA; Chest X-ray, smear, and culture of sputum.^Citation10 Check HBs Ag and anti-HBc. Check anti HBS Ab for immunization status. Check HBV viral load if necessary.^Citation10 Check HCV Ab.^Citation10 Check VZV Serology.^Citation10 Yearly screening of HPV is recommended in women.^Citation10
T-Cell Co-stimulation Blocker	Check HBs Ag and anti-HBc. Check anti HBS Ab for immunization status. Check HBV viral load if necessary.^Citation30
Monoclonal antibodies targeting α4-integrin and CD 11a	Brain MRI could be considered.^Citation11 Checking Anti-JCV IgG is recommended.^Citation11
IgE targeted agent	Stool exam; Serologic test for Strongyloides stercoralis is recommended.^Citation8
IL-12 and IL-23-targeted agent	Perform PPD and IGRA; Chest X-ray; smear and culture of sputum.^Citation8 Check HBs Ag and anti-HBc. Check anti HBS Ab for immunization status. Check HBV viral load if necessary.^Citation8
IL-17-targeted agents	Perform PPD and IGRA; Chest X-ray; smear and culture of the sputum.^Citation8
Component 5 (C5)-targeted agents	Real-time PCR for detection of Neisseria gonorrhoeae in highly sexually active patients^Citation8
IL-6-targeted agents	Perform PPD; IGRA; Chest X-ray; smear and culture of sputum.^Citation8 Check HBs Ag and anti-HBc. Check anti HBS Ab for immunization status.^Citation8
Proteasome inhibitors	Check VZV serology.^Citation11
Agents targeting PD-1/PD-L1	Perform PPD and IGRA; Chest X-ray; smear and culture of sputum.^Citation11 Check HBs Ag and anti-HBc. Check anti HBS Ab for immunization status.^Citation11 Check HCV Ab.^Citation11
Monoclonal antibodies against CTLA-4	Perform PPD and IGRA; Chest X-ray; smear and culture of sputum.^Citation11 Check HBs Ag and anti-HBc. Check anti HBS Ab for immunization status.^Citation11 Check HCV Ab.^Citation11
BCR-ABL Tyrosine kinase inhibitors	Check HBs Ag and anti-HBc. Check anti HBS Ab for immunization status. Check HBV viral load if necessary.^Citation9
mTOR Inhibitors	Perform PPD and IGRA; Chest X-ray; smear and culture of sputum.^Citation9 Check HBs Ag and anti-HBc. Check anti HBS Ab for immunization status.^Citation9
JAK inhibitors	Perform PPD and IGRA; Chest X-ray; Smear and culture of sputum.^Citation9 Check HBs Ag and anti-HBc. Check anti HBS Ab for immunization status.^Citation9
Sphingosine 1-phosphate receptor modulator	Check baseline CBC.^Citation11 Check VZV serology.^Citation11
Monoclonal antibody targeting CD25	Perform PPD and IGRA; Chest X-ray or Chest CT scan; smear and culture of sputum.^Citation29 Serologic test for CMV IgG, EBV antibody panel, HSV and VZV IgG, HBsAg, HBcAb, HBsAb, HCV IgG, HIV 1 and 2 antibodies, RPR or TP-PA test for syphilis is recommended according to transplantation protocols.^Citation84

Abbreviations: Ab, antibody; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; CMV, cytomegalovirus; EBV, Epstein-Barr virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HBs Ag, hepatitis B surface antigen; HIV, human immunodeficiency viruses; HPV, human papillomavirus; IGRA, interferon-gamma release assay; IL-1, interleukin-1; IL-5, interleukin-5; IL-6, interleukin-6; IL-12, interleukin-12; IL-17, interleukin-17; IL-23, interleukin-23; JAK, Janus kinase; JCV, John Cunningham virus; MRI, Magnetic resonance imaging; mTOR, mammalian target of rapamycin; PCR, Polymerase chain reaction; PD1, programmed death 1; PD-L 1Programmed death-ligand 1; PPD, purified protein derivative; PML, progressive multifocal leukoencephalopathy ; RPR, rapid plasma reagin; TNF, tumor necrosis factor; TP-PA, Treponema pallidum particle agglutination; VZV, varicella-zoster virus.

Table 3 Evidence and Recommendations on the Prevention and Management of Infections in Patients Candidates for Biologic and Targeted Immunomodulatory Therapies

TNF Inhibitors	Treatment with TNF inhibitors should be started at least one month after initiation of the anti-TB regimen (isoniazid, rifampin, or the combination of isoniazid and rifampin). TNF inhibitors should be discontinued if active tuberculosis occurs.^Citation13
	Tenofovir or Entecavir is recommended for infected HBs Ag-positive patients at least two weeks before the initiation of TNF inhibitors. Antiviral agents should be continued for at least six months after the withdrawal of TNF inhibitors.^Citation13,Citation85 Antiviral prophylaxis is not recommended in HBs-Ag negative and anti-HBc-positive patients treated with TNF inhibitors.^Citation13 Tenofovir or Entecavir is recommended in the case of HBV reactivation. TNF inhibitors are not recommended in the acute phase of hepatitis B, chronic untreated hepatitis B, and HBV infected patients with Child-Pugh B and C.^Citation86
	Some experts consider PCP prophylaxis for patients with rheumatologic diseases under TNF inhibitors who have underlying pulmonary diseases or receiving ≥ 15 mg/day prednisolone for more than four weeks.^Citation39
IL-1-targeted agents	In the case of latent tuberculosis, treatment with isoniazid for nine months, rifampin for four months, or the combination of isoniazid and rifampin for three months is recommended.^Citation8
	Some experts consider PCP prophylaxis for patients with rheumatologic diseases under IL-1 targeted agents who have underlying pulmonary diseases or receiving ≥ 15 mg/day prednisolone for more than four weeks.^Citation39
CD22-targeted agents	Antiviral treatment is recommended in HBS-Ag positive patients who are candidates for CD-22 targeted agents.^Citation12 Monitoring of HBV viral load is recommended in HBS-Ag negative and anti-HBc-positive patients.^Citation12
CD30-targeted agent	Both HBs Ag positive and HBs Ag negative anti-HBc positive patients should receive antiviral prophylaxis before the administration of brentuximab vedotin.^Citation12
	HSV prophylaxis is recommended in patients on brentuximab vedotin.^Citation12
	PCP prophylaxis is recommended in patients on brentuximab vedotin.^Citation12
	Secondary CMV prophylaxis is recommended in patients with a history of CMV disease who are candidates for brentuximab vedotin rechallenge.^Citation12
CD38-targeted agents	Antiviral treatment could be considered in HBS-Ag positive patients who are candidates for CD-38 targeted agents.^Citation12 Monitoring of HBV viral load is recommended in HBS-Ag negative and HBV-Ab positive patients.^Citation12
	HSV prophylaxis is recommended in VZV seropositive patients at least one week before the administration of daratumumab and continued for 12 weeks after discontinuation^Citation12
	PCP prophylaxis is recommended in patients receiving concomitant glucocorticoids, and CD-38 targeted agents.^Citation12
CD40-targeted agents	PCP prophylaxis should be considered in patients on CD-40 targeted agents.^Citation12
	Regular monitoring of CMV PCR and signs, as well as symptoms of CMV disease, are recommended in patients on CD-40 targeted agents.^Citation12
CD319-targeted agents	HSV prophylaxis is recommended in VZV seropositive patients.^Citation12
	PCP prophylaxis is recommended in patients receiving concomitant glucocorticoids and elotuzumab.^Citation12
CCR4-targeted agent	PCP prophylaxis is recommended in patients on mogamulizumab.^Citation12
	HSV prophylaxis is recommended in patients on mogamulizumab.^Citation12
	Tenofovir or entecavir is recommended in HBs Ag positive patients who are candidates for treatment with mogamulizumab.^Citation12 HBV viral load should be monitored in HBs Ag-negative/anti-HBc-positive patients who are candidates for treatment with mogamulizumab. Prophylaxis with lamivudine could be considered in HBs Ag negative and anti-HBc-positive patients.^Citation12
Anti-CD20 monoclonal antibodies	HBs Ag-positive patients should receive antiviral prophylaxis (preferably tenofovir or entecavir) before the administration of anti-CD20 monoclonal antibodies. HBs Ag-negative/anti-HBc-positive patients should receive antiviral prophylaxis (could be lamivudine) before administration of anti-CD20 monoclonal antibodies. Antiviral agents should be continued for at least 12–18 months after the completion of anti-CD20 monoclonal antibody treatment and if viral load remains undetectable.^Citation10,Citation14 HBV viral load should be monitored for 12 months after discontinuation of antiviral prophylaxis.^Citation10 Anti-CD20 monoclonal antibodies should be discontinued if reactivation of hepatitis B occurs.
	ECIL and ESCMID guidelines recommend PCP prophylaxis in patients receiving anti-CD20 monoclonal antibodies and corticosteroids equivalent to ≥ 20 mg prednisolone for more than four weeks.^Citation10,Citation26 ECIL and NCCN guidelines recommend PCP prophylaxis in CLL patients treated with Rituximab/Ofatumumab/Obinutuzumab, and purine analogs/high dose methylprednisolone; Fludarabine-Cyclophosphamide-Rituximab (FCR) and Pentostatin-Cyclophosphamide-Rituximab (PCR) regimens for ≥ six months after completion of treatment.^Citation14,Citation26 Some experts consider PCP prophylaxis for granulomatosis polyangiitis patients on rituximab and patients with rheumatologic diseases who have underlying pulmonary diseases.^Citation39 PCP prophylaxis is optional for patients undergoing R-CHOP 14 regimen.^Citation26
	The third international consensus on CMV prophylaxis in solid organ transplant weakly recommends CMV prophylaxis in donor/recipient seropositive patients who are candidates for rituximab therapy during treatment of solid organ transplant rejection or desensitization protocol for up to 6 months.^Citation15
	Antiviral prophylaxis against HSV and VZV is recommended in CLL patients during therapy with Rituximab/Ofatumumab/Obinutuzumab, and fludarabine/high dose methylprednisolone; Fludarabine-Rituximab (FR), Fludarabine-Cyclophosphamide-Rituximab (FCR) and Pentostatin-Cyclophosphamide-Rituximab (PCR) for 6–12 months after discontinuation of the chemotherapy regimen.^Citation87
Anti-CD52 monoclonal antibody	In the case of latent tuberculosis patients undergoing alemtuzumab therapy, concomitant treatment with isoniazid for nine months, rifampin for four months, or the combination of isoniazid and rifampin for three months is recommended.^Citation10
	In the case of latent tuberculosis, tenofovir or entecavir is recommended in all HBs Ag positive patients who are candidates for treatment with alemtuzumab. Antiviral agents should be continued for at least 6–12 months after the last dose of alemtuzumab.^Citation10 HBV viral load should be monitored in HBs Ag-negative and anti-HBc positive patients who are candidates for treatment with alemtuzumab. Prophylaxis with lamivudine could be considered in HBs Ag negative and Anti HBc-positive patients.^Citation10
	PCP prophylaxis is recommended in patients treated with alemtuzumab for hematologic malignancies and indications other than multiple sclerosis for at least 2–6 months and should be continued until CD4^+ ≥ 200 cells/μL.^Citation26 PCP infection associated with alemtuzumab used in multiple sclerosis is extremely rare, and prophylaxis is not routinely recommended.^Citation64 If alemtuzumab is administered for solid organ transplantation induction, the American Society of Transplant recommends PCP prophylaxis for at least 6–12 months after induction. Life long duration of PCP prophylaxis may be considered for lung and small bowel transplant or patients with chronic CMV infection or prior history of PCP infection.^Citation17 If alemtuzumab is administered for conditioning of allogeneic hematopoietic stem cell transplantation, PCP prophylaxis is recommended for at least six months.^Citation14
	CMV prophylaxis should be considered in hematologic malignancies with the initiation of each cycle of alemtuzumab therapy and continued for at least two months until CD4^+≥200 cells/μL.^Citation14 If alemtuzumab is administered for solid organ transplantation induction, the third international consensus on CMV in solid organ transplant recommends CMV prophylaxis for six months in CMV IgG Donor+/Recipients± for kidney transplants, 3–6 months for liver, heart, pancreas recipients and 6–12 months for lung recipients.^Citation15 CMV prophylaxis is not currently required in multiple sclerosis patients; CMV DNAemia testing is recommended in the presence of signs and symptoms of mononucleosis. Some experts recommend weekly monitoring of CMV-DNAemia for the first month after initiating alemtuzumab.^Citation64
	If alemtuzumab is administered for induction of allogeneic hematopoietic stem cell transplantation, VZV prophylaxis is recommended for one year.^Citation14 HSV prophylaxis should be considered in hematologic malignancies and other off-label indications with the initiation of each cycle of alemtuzumab therapy and continued for at least two months until CD4^+≥200 cells/μL.^Citation10,Citation14 HSV prophylaxis should be considered in multiple sclerosis patients with the initiation of each cycle of alemtuzumab therapy and continued for at least two months until CD4^+≥200 cells/μL.^Citation14,Citation64 If alemtuzumab is administered for solid organ transplantation induction immunosuppressive therapy, HSV/VZV prophylaxis is recommended in CMV IgG Donor-/Recipient- (low-risk CMV) transplants.^Citation15
	Listeria- and toxoplasma-free diet should be recommended in patients under alemtuzumab therapy.^Citation10
T-Cell Co-stimulation Blocker	Antiviral treatment is recommended in HBs Ag- positive patients who are candidates for abatacept therapy.^Citation30 Monitoring of HBV viral load is recommended in HBsAg-negative and anti-HBc- positive patients.^Citation30
	Some experts consider PCP prophylaxis for patients with rheumatologic diseases under abatacept who have underlying pulmonary diseases or receiving ≥ 15 mg/day prednisolone for more than four weeks.^Citation39
Agent targeting B-cell activating factor	Some experts consider PCP prophylaxis for patients with rheumatologic diseases under abatacept who have underlying pulmonary diseases or receiving ≥ 15 mg/day prednisolone for more than four weeks.^Citation39
IgE-targeted agent	In the case of parasitic infections, patients should be treated with a specific antiparasitic agent prior to omalizumab administration.^Citation8
IL-5-targeted agents	Some experts recommend PCP prophylaxis in Eosinophilic Granulomatosis with Polyangiitis (EGPA) patients on IL-5 targeted agents.^Citation39
IL-12 and IL-23-targeted agent	In the case of latent tuberculosis, treatment with isoniazid for nine months, rifampin for four months, or the combination of isoniazid and rifampin for three months could be considered.^Citation8
	Antiviral treatment is recommended in HBS-Ag positive patients who are candidates for ustekinumab therapy.^Citation8 Monitoring of HBV viral load is recommended in HBS-Ag negative and HBV-Ab positive patients.^Citation8
	Some experts consider PCP prophylaxis in rheumatologic disease patients on ustekinumab who have underlying pulmonary diseases or receiving ≥ 15 mg/day prednisolone for more than four weeks.^Citation39
IL-17-targeted agents	In the case of latent tuberculosis, treatment with isoniazid for nine months, rifampin for four months, or the combination of isoniazid and rifampin for three months could be considered.^Citation8
	Some experts consider PCP prophylaxis in rheumatologic disease patients on secukinumab who have underlying pulmonary diseases or receiving ≥ 15 mg/day prednisolone for more than four weeks.^Citation39
Component 5 (C5)-targeted agents	Ciprofloxacin 500 mg Bid or penicillin V 250 mg Bid orally should be administered for at least four weeks after completion of vaccination preferably until antibody titer reaches protective.^Citation8
	The third international consensus on CMV in solid organ transplant weakly recommends CMV prophylaxis in donor/recipient seropositive patients who are candidates for eculizumab therapy during and up to 6 months after treatment of solid organ transplant rejection.^Citation15
IL-6-targeted agents	In the case of latent tuberculosis, treatment with isoniazid for nine months, rifampin for four months, or the combination of isoniazid and rifampin for three months could be considered.^Citation8
	Antiviral treatment is recommended in HBsAg positive patients who are candidates for IL-6 targeted agents.^Citation8 Monitoring of HBV viral load is recommended in HBs Ag-negative/anti-HBc positive patients.^Citation8
	Some experts recommend consideration of PCP prophylaxis in rheumatologic disease patients on tocilizumab who have underlying pulmonary diseases or receiving ≥ 15 mg/day prednisolone for more than four weeks.^Citation39
Proteasome inhibitors	HSV/VZV prophylaxis is recommended in VZV seropositive patients at least four weeks after discontinuation of therapy.^Citation11
	PCP prophylaxis could be considered in multiple myeloma patients treated with high dose corticosteroids.^Citation11
	The third international consensus on CMV prophylaxis in solid organ transplant weakly recommends CMV prophylaxis in donor/recipient seropositive patients who are candidates for bortezomib therapy during treatment of solid organ transplant rejection or desensitization protocol and up to 6 months later.^Citation15
Agents targeting PD-1/PD-L1 and agents targeting CTLA-4	Autoimmune manifestations of PD-1/PD-L1 targeted and CTLA-4 blockade agents may require treatment with corticosteroids or TNF inhibitors. ECIL and ESCMID experts recommend PCP prophylaxis in patients treated with corticosteroids equivalent to ≥ 20 mg prednisolone for more than four weeks.^Citation11,Citation88 The Society for Immunotherapy of Cancer recommends PCP prophylaxis in patients treated with corticosteroids equivalent to ≥ 30 mg prednisolone for more than three weeks.^Citation88
	In the case of latent tuberculosis, treatment with isoniazid or rifampin is recommended in patients treated with anti-PD-1/CTLA-4 blocking agents and TNF inhibitors. Antiviral prophylaxis against hepatitis B is recommended if necessary in patients treated with anti-PD-1 and TNF inhibitors.^Citation11
	Antiviral prophylaxis against hepatitis B is recommended if necessary in patients treated with anti-PD-1/CTLA-4 blocking agents and TNF inhibitors.^Citation11
BCR-ABL Tyrosine kinase inhibitors	Antiviral agent against hepatitis B is recommended for HBV infected HBs Ag-positive before administration of BCR-ABL tyrosine kinase inhibitors.^Citation9 HBV viral load should be monitored in HBs Ag-negative/anti-HBc-positive patients who are candidates for treatment with BCR-ABL tyrosine kinase inhibitors.^Citation9
mTOR inhibitors	In the case of latent tuberculosis, treatment with isoniazid for nine months, rifampin for four months, or the combination of isoniazid and rifampin for three months could be considered.^Citation9
	Antiviral agents could be considered in chronic HBV–infected patients.^Citation9
JAK inhibitors	In the case of latent tuberculosis, treatment with isoniazid for nine months, rifampin for four months, or the combination of isoniazid and rifampin for three months should be considered.^Citation9
	Antiviral prophylaxis is recommended in HBS-Ag positive patients.^Citation9 Monitoring of viral load is recommended in HBsAg-negative/anti-HBc-positive patients.^Citation9
	PCP prophylaxis could be considered in patients receiving a high dose of JAK inhibitors, and concomitant corticosteroid therapy, and lymphopenic patients.^Citation9
Sphingosine 1-phosphate receptor modulator	Acyclovir/Valacyclovir prophylaxis could be considered for patients treated with corticosteroid pulse beyond 3–5 days and fingolimod.^Citation63
Bruton Tyrosine kinase inhibitors	PCP prophylaxis is recommended in CLL patients treated with ibrutinib in the presence of additional risk factors, including concomitant fludarabine or high dose corticosteroid therapy.^Citation9,Citation87
Phosphatidylinositol-3-kinase inhibitors	PCP prophylaxis is recommended in CLL patients who are candidates for idelalisib therapy up to 2–6 months after discontinuation.^Citation9
Monoclonal antibody targeting CD25	In the case of latent tuberculosis, treatment with isoniazid for nine months is recommended. The recipients who have received an organ from donors with latent tuberculosis should be considered for treatment with isoniazid for nine months.^Citation29 Recipients with active tuberculosis should be treated prior to transplantation.^Citation29 PCP prophylaxis is recommended in transplant recipients who have received basiliximab induction for at least 6–12 months.^Citation89 CMV prophylaxis/preemptive therapy is recommended in Donor+/Recipient- liver and all kidney transplant recipients for 3–6 months, respectively.^Citation15

Abbreviations: CLL, chronic lymphocytic leukemia; CMV, cytomegalovirus; ECIL, European conference on infections in leukemia; ESCMID, European Society of Clinical Microbiology and Infectious Diseases; IgE, Immunoglobulin E; IgG, Immunoglobulin G; IL-1, interleukin-1; IL-5, interleukin-5; IL-6, interleukin-6; IL-12, interleukin-12; IL-17, interleukin-17; IL-23, interleukin-23; HBs Ag, hepatitis B surface antigen; HBV, hepatitis B virus; HSV, Herpes simplex virus; JAK, Janus kinase; mTOR, mammalian target of rapamycin; NCCN, National Comprehensive Cancer Network, PCP, Pneumocystis carinii pneumonia; PCR, Polymerase chain reaction; PD1, programmed death 1; PD-L1, Programmed death-ligand 1; R-CHOP, rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride (doxorubicin hydrochloride), vincristine; TNF, tumor necrosis factor; VZV, varicella-zoster virus.

Table 4 Evidence and Recommendations on Monitoring of Patients on Biologic and Targeted Immunomodulatory Therapies

CD19-targeted agents	Risk of neutropenia: CBC monitoring is recommended^Citation10 If neurologic or cognitive impairment occurred, MRI should be considered, and CSF for JC virus DNA PCR should be tested.^Citation10 Monitoring for signs and symptoms of catheter-related infections should be considered in patients receiving blinatumomab.^Citation10
CD30-targeted agents	Risk of neutropenia: CBC monitoring is recommended.^Citation12 If neurologic or cognitive impairment occurred, MRI should be considered and CSF for JC virus DNA PCR should be tested.^Citation12 Regular monitoring of CMV PCR and signs and symptoms of CMV disease is recommended in patients on brentuximab vedotin.^Citation12
CD38-targeted agents	Risk of neutropenia: CBC monitoring is recommended.^Citation12
CD40-targeted agents	Risk of neutropenia: CBC monitoring is recommended.^Citation12
CD319-targeted agents	Risk of lymphopenia: CBC monitoring is recommended.^Citation12
CCR4-targeted agents	Monitoring of lymphocyte count is recommended.^Citation12 Regular monitoring of CMV PCR and signs and symptoms of CMV disease is recommended in patients on mogamulizumab.^Citation12
Anti-CD20 monoclonal antibodies	If neurologic or cognitive impairment occurs, MRI should be considered, and CSF for JC virus DNA PCR should be tested. Monitor immunoglobulin levels during treatment with anti-CD20 monoclonal antibodies.^Citation22,Citation90 Immunoglobulin levels are best to be monitored every 6–12 months and at least up to 1 year after discontinuation of rituximab. Long term monitoring of IgG levels in patients with bronchiectasis or those treated with immunosuppressive agents is reasonable.^Citation22 Immunoglobulin replacement therapy with 0.4g/kg/month (SC or IV) could be considered in case of persistent infections associated with low IgG level; in patients with low IgG level and concomitant comorbidities (neutropenia, bronchiectasis) or concomitant use of immunosuppressive agents, including corticosteroids.^Citation22 Late-onset neutropenia episodes are mostly mild and do not predispose patients to infections as much as hypogammaglobulinemia.^Citation91,Citation92 The optimal approach in patients with a history of late-onset neutropenia is unclear; however, re-treatment with rituximab has been safe in most cases.^Citation92 The role of GCSF in anti-CD20 associated neutropenia is not clearly defined; the decision should be made on a case-by-case basis.^Citation91 Limited data have demonstrated the occurrence of late-onset neutropenia with other anti-CD20 therapies including obinutuzumab, ofatumumab, and ocrelizumab.^Citation93
T-Cell Co-stimulation blocker	Brain MRI and CSF analysis for JCV PCR should be obtained if neurologic impairment (visual disturbance, progressive paresis, cognitive impairment) occurs.^Citation42
Agent targeting B-cell activating factor (BAFF, BLyS)	Brain MRI and CSF analysis for JCV PCR should be obtained if neurologic impairment (visual disturbance, progressive paresis, cognitive impairment) occurs.^Citation42
Monoclonal antibody targeting α4-integrin and CD 11a	After the completion of the first year of therapy, JCV PCR should be tested every three months in JCV-seronegative patients treated with natalizumab.^Citation11 JCV PCR should be tested every six months in JCV-seropositive patients with IgG antibody index ≤ 1.5.^Citation11 The risks versus benefits of therapy should be considered in JCV seropositive patients with IgG antibody index ≥ 1.5 and JCV seropositive patients who have received natalizumab for more than 48 weeks.^Citation11 For the early diagnosis of PML, the high sensitive assay should be utilized to detect JCV DNA. Negative CSF JCV PCR does not exclude PML even in repeated lumbar punctures.^Citation44 Monitoring of signs and symptoms of PML (ataxia, dysarthria, motor weakness, and cognitive impairment) should be considered for at least six months after discontinuation of natalizumab.^Citation11 Brain MRI and CSF analysis for JCV PCR should be obtained if neurologic impairment (visual disturbance, progressive paresis, cognitive impairment) occurs. Natalizumab should be discontinued if PML develops.^Citation11 No cases of PML have been observed with vedolizumab in the clinical trials so far.^Citation42
Component 5 (C5) targeted agent	Patients treated with eculizumab should be monitored for signs and symptoms of meningococcal disease (headache, nausea, vomiting, fever, rash, confusion, flu-like symptoms, photophobia, arthralgia, tenosynovitis).^Citation8
BCR-ABL tyrosine kinase Inhibitors	Weekly CMV PCR could be considered for HSCT patients on dasatinib.^Citation9
JAK inhibitors	Lymphocyte and neutrophil count should be monitored while treatment with tofacitinib; discontinue tofacitinib if lymphocyte count< 500 cells/mm^3 or ANC < 500 cells/mm^3.^Citation94   Neutrophil count should be monitored while treatment with ruxolitinib. Interrupt treatment with ruxolitinib if ANC < 500 cells/mm^3.^Citation95  Monitor for signs and symptoms of HSV infections. In case of mild Herpes Zoster infection in inflammatory bowel disease patients, some experts recommend holding tofacitinib until resolution of infection; in disseminated Herpes Zoster infections, alternative therapies could be considered.^Citation96
Sphingosine 1-phosphate receptor modulator	CBC should be monitored during therapy. Fingolimod should be interrupted in patients with absolute lymphocyte count < 0.2*10^9 /l.^Citation97 Cases of cryptococcal meningitis and PML have been reported in patients receiving fingolimod. Monitor for signs and symptoms (ataxia, dysarthria, motor weakness, cognitive impairment, headache, photosensitivity, and personality changes).^Citation11 Screening for pap smear abnormalities could be considered during treatment with fingolimod.^Citation97
Bruton Tyrosine kinase inhibitors	If neurologic or cognitive impairment occurs during treatment with ibrutinib, MRI should be considered and CSF for JC virus DNA PCR should be tested.^Citation9
Phosphatidylinositol-3-kinase inhibitors	Monitoring for CMV PCR is recommended in seropositive patients on idelalisib. If signs and symptoms of CMV disease (leukopenia, thrombocytopenia, colitis, pneumonitis, nausea, vomiting, diarrhea, or abdominal pain) occurred during treatment with an idelalisib, check for CMV PCR. Idelalisib should be discontinued in case of severe diarrhea, significant elevations in hepatic enzymes, or pneumonitis.^Citation9

Abbreviations: ANC, absolute neutrophil count; BAFF, B-cell activating factor; BLyS, B Lymphocyte Stimulator; CBC, complete blood cells; CSF, cerebrospinal fluid; CMV, cytomegalvirus; GCSF, Granulocyte-colony stimulating factor; HSCT, Hematopoietic stem cell transplantation; MRI, magnetic resonance imaging; JCV, John Cunningham virus; PCR, polymerase chain reaction; PML, progressive multifocal leukoencephalopathy.

Table 5 Evidence and Recommendations on Immunization of Patients on Biologic and Targeted Immunomodulatory Therapies

TNF inhibitors	Immunization with inactivated vaccines during therapy with TNF inhibitors is recommended.^Citation98 Non-immunized patients who were at risk should ideally complete the HBV vaccine series ≥ two weeks prior to the initiation of TNF inhibitors.^Citation16 The EMA label of TNF inhibitors recommends that infants born from mothers on TNF inhibitors receive live vaccines after ≥ five months of last adalimumab injection,^Citation99 ≥ four months of last etanercept injection,^Citation100 ≥ six months of last golimumab injection,^Citation101 ≥ five months after certolizumab injection^Citation102 and ≥ six months after birth in infliximab treated mothers;^Citation66 however, vaccine response to Haemophilus influenzae in infants born from mothers on biologic therapies including infliximab, adalimumab, certolizumab pegol, and golimumab is not impaired. The Canadian Dermatology Association strongly recommends routine immunization schedule for infants exposed to biologic agents during pregnancy and lactation.^Citation103 EULAR recommends that live attenuated vaccines should be avoided during the first six months of life in newborns exposed to TNF inhibitors after 22 weeks of gestation.^Citation98
IL-1-targeted agents	In patients receiving IL-1 targeted agents, vaccination against Pneumococcus and Haemophilus influenzae type B should be considered. Infants born from mothers on canakinumab could receive live vaccines after ≥ 16 weeks of the last injection.^Citation68 If a live vaccine is required; patients on rilonacept could be vaccinated ≥ six weeks of the last dose and ≥ six weeks before the next dose.^Citation104
CD19-targeted agents	The recommendations on vaccination with anti-CD20 therapies could be extrapolated to anti-CD19 targeted agents such as blinatumomab.^Citation28 Live vaccines for infants born from mothers on CD19 targeted agents should be postponed until B cell recovery.^Citation105
Anti-CD20 monoclonal antibodies	Tetanus immunoglobulin should be administered in patients with contaminated wounds who have received anti-CD20 monoclonal antibodies in the past six months.^Citation98,Citation106 Live attenuated vaccines should not be received within six months of anti-CD20 monoclonal antibody administration.^Citation10 For optimal immunization in patients on rituximab, vaccination should be deferred to at least 5–6 months after the last dose and at least one month before the next dose.^Citation98,Citation103 If the time window is not possible inactivated vaccines could be administered considering suboptimal response.^Citation98 Administration of second booster dose of inactivated influenza vaccine is associated with superior immunity response.^Citation28 Non-immunized patients who are candidates for R-CHOP therapy should complete HBV vaccines ≥ 4 weeks prior to the initiation of rituximab.^Citation14 Patients should ideally complete the required vaccines ≥ six weeks prior to the initiation of ocrelizumab. Live vaccines are not recommended until B cell depletion in patients treated with ocrelizumab (may take up to 72 weeks).^Citation106,Citation107 Case reports have demonstrated that immunization of infants born from mothers on rituximab therapy up to the third trimester was not attenuated.^Citation103 The Canadian Dermatology Association strongly recommends routine immunization schedule vaccines for infants exposed to rituximab during pregnancy and lactation;^Citation103,Citation108 however, EULAR recommends that Live-attenuated vaccines should be avoided during the first six months of life in newborns exposed to biologic agents in the second half of pregnancy.^Citation98 The EMA label of ocrelizumab, obinutuzumab, and ofatumumab recommends that administration of live vaccines in neonates born from mothers receiving these agents during pregnancy should be postponed until B cell repletion.^Citation106,Citation109, ^Citation110
Anti-CD52 monoclonal antibodies	Live vaccines should be avoided up to at least 12 months after discontinuation of MabCampath^®.^Citation111 Poor response to vaccination is observed in patients with hematologic malignancies who have received alemtuzumab in the previous six months.^Citation77 Immunization requirements should be completed ≥ 6 weeks prior to the initiation of Lemtrada^®. VZV seronegative patients should be immunized ≥ six weeks prior to the initiation of Lemtrada^®.^Citation76
T-Cell Co-stimulation blockers	Live vaccines could be administered ≥ 3 months after discontinuation of abatacept.^Citation112
Monoclonal antibodies targeting α4-integrin and CD 11a	The EMA label recommends discontinuation of efalizumab eight weeks prior to vaccination and resumption of therapy two weeks after vaccination.^Citation78 Routine immunization schedule, including inactivated and live vaccines for infants exposed to natalizumab during pregnancy and lactation, could be considered.^Citation103 Vaccine response to Haemophilus influenzae in infants born from mothers on natalizumab was not impaired.
IL-12 and IL-23-targeted agent	Live vaccines could be administered ≥ 15 weeks after discontinuation of ustekinumab.^Citation113 Vaccine response to Haemophilus influenzae in infants born from mothers on ustekinumab was not impaired. The Canadian Dermatology Association strongly recommends routine immunization schedule, including both inactivated and live vaccines for infants exposed to ustekinumab during pregnancy and lactation.^Citation103
Component 5 (C5)-targeted agents	Unvaccinated patients should receive S. pneumonia and H. influenzae type b vaccine ≥ 2 weeks prior to treatment with eculizumab. Two-dose series with quadrivalent conjugate (MenACWY) at least two months apart and serogroup B (MenB) either two-dose series at least a month apart or three-dose series at 0,1, 2 and 6 months should be administered. Meningococcal immunization should be completed ≥ 2–4 weeks prior to eculizumab administration. Booster doses of tetravalent conjugate vaccine should be repeated every five years based on the duration of therapy.^Citation8
Proteasome Inhibitors	VZV seronegative patients should receive live attenuated vaccine ≥ 1 month prior to initiation of therapy.^Citation11 HSV subunit vaccine could be considered for VZV seropositive patients ≥ 50 years.^Citation11
BCR-ABL Tyrosine kinase inhibitors	ECIL guidelines recommend yearly seasonal influenza vaccine and PCV followed by PPSV 23 (8 weeks later) in CML patients on BCR-ABL tyrosine kinase inhibitors.^Citation23
JAK inhibitors	Vaccination with Shingrix^® should be considered ≥ 2 weeks or (Zostavax^® ≥ 4 weeks) prior to the initiation of tofacitinib.^Citation94
Sphingosine 1-phosphate receptor modulators	Live vaccines are not recommended until at least two months after discontinuation of fingolimod.^Citation97 The EMA label recommends vaccination against HPV prior to the initiation of fingolimod.^Citation97 VZV seronegative, non-immunized patients should receive live attenuated (2 doses of Varivax^® separated by four weeks) ≥ 1 month prior to initiation of therapy.^Citation11,Citation63 Adjuvant herpes zoster subunit (HZ/su) vaccine could be considered for VZV seropositive patients ≥ 50 years.^Citation63 The vaccine should not be administered while the patient is on antiviral agents against VZV. An antiviral agent should be prescribed for vaccinated patients who develop rashes.^Citation63 When treated with pulse dose corticosteroid, vaccination should be postponed for at least one month after the last dose of corticosteroid.^Citation63
Bruton Tyrosine kinase inhibitors	Pneumococcal vaccine and yearly inactivated influenza vaccine is recommended in CLL patients.^Citation23
Monoclonal antibody targeting CD25	Inactivated vaccines could be administered 3 months after induction of basiliximab. Inactivated influenza vaccine could be administered as early as one month after transplant.^Citation114

Abbreviations: CLL, Chronic lymphocytic leukemia; HBV, Hepatitis B virus; HPV,  human papillomavirus; H. influenzae, Haemophilus influenza; ECIL, European Conference on Infections in Leukaemia; EMA, European medicines agency; EULAR; European league against rheumatism; IL-1, interleukin-1; S. pneumonia, Streptococcus pneumonia; TNF, tumor necrosis factor; VZV, varicella-zoster virus.

Baddley JW, Cantini F, Goletti D, et al. ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Soluble immune effector molecules [I]: anti-tumor necrosis factor-α agents). Clin Microbiol Infect. 2018;24:S10–S20. doi:10.1016/j.cmi.2017.12.02529459143

 PubMed Web of Science ®Google Scholar

Noreña I, Fernández-Ruiz M, Aguado JM. Viral infections in the biologic therapy era. Expert. Rev Anti Infect Ther. 2018;16(10):781–791. doi:10.1080/14787210.2018.1521270

 PubMed Web of Science ®Google Scholar

Winthrop KL, Mariette X, Silva JT, et al. ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infection diseases perspective (Soluble immune effector molecules [II]: agents targeting interleukins, immunoglobulins and complement factors). Clin Microbiol Infect. 2018;24:S21–S40. doi:10.1016/j.cmi.2018.02.00229447987

 PubMed Web of Science ®Google Scholar

Mikulska M, Lanini S, Gudiol C, et al. ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infection diseases perspective (Agents targeting lymphoid cells surface antigens [I]: CD19, CD20 and CD52). Clin Microbiol Infect. 2018;24:S71–S82.29447988

 PubMed Web of Science ®Google Scholar

Drgona L, Gudiol C, Lanini S, et al. ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infection diseases perspective (Agents targeting lymphoid or myeloid cells surface antigens [II]: CD22, CD30, CD33, CD38, CD40, SLAMF-7 and CCR4). Clin Microbiol Infect. 2018;24:S83–S94. doi:10.1016/j.cmi.2018.03.02229572070

 PubMed Web of Science ®Google Scholar

Wijetilleka S, Jayne DR, Mukhtyar C, et al. Recommendations for the management of secondary hypogammaglobulinaemia due to B cell targeted immunomodulators in autoimmune rheumatic diseases. Rheumatology. 2018;58(5):889–896. doi:10.1093/rheumatology/key394

 Web of Science ®Google Scholar

Barmettler S, Ong MS, Farmer JR, et al. Association of immunoglobulin levels, infection risk, and mortality with rituximab and hypogammaglobulinemia. JAMA Netw Open. 2018;1(7):e184169. doi:10.1001/jamanetworkopen.2018.416930646343

 PubMed Web of Science ®Google Scholar

Loomba R, Liang TJ. Hepatitis B reactivation associated with immune suppressive and biological modifier therapies: current concepts, management strategies, and future directions. Gastroenterology. 2017;152(6):1297–1309. doi:10.1053/j.gastro.2017.02.00928219691

 PubMed Web of Science ®Google Scholar

Redelman-Sidi G, Michielin O, Cervera C, et al. ESCMID study group for infections in compromised hosts (ESGICH) consensus document on the safety of targeted and biological therapies: an infection diseases perspective (Immune checkpoint inhibitors, cell adhesion inhibitors, sphingosine-1-phosphate receptor modulators and proteasome inhibitors). Clin Microbiol Infect. 2018;24:S95–S107. doi:10.1016/j.cmi.2018.01.03029427804

 PubMed Web of Science ®Google Scholar

Reinwald M, Silva JT, Mueller NJ, et al. ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infection diseases perspective (Intracellular signaling pathways: tyrosine kinase and mTOR inhibitors). Clin Microbiol Infect. 2018;24:S53–70. doi:10.1016/j.cmi.2018.02.00929454849

 PubMed Web of Science ®Google Scholar

Subramanian AK, Theodoropoulos NM. Mycobacterium tuberculosis infections in solid organ transplantation: Guidelines from the infectious diseases community of practice of the American Society of Transplantation. Clin Transplant. 2019 9;33(9):e13513. doi:10.1111/ctr.1351330817030

 PubMed Web of Science ®Google Scholar

Danovitch GM, editor. Handbook of Kidney Transplantation. Lippincott Williams & Wilkins; 2017 6, 13.

 Google Scholar

Terrault NA, Lok AS, McMahon BJ, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018;67(4):1560–1599. doi:10.1002/hep.2980029405329

 PubMed Web of Science ®Google Scholar

Winthrop KL. Tumor necrosis factor-alpha inhibitors: bacterial, viral, and fungal infections. Bow Blumberg EA, Bond Sh, editors. UpToDate Inc.2019 Available from: https://www.uptodate.com/contents/tumor-necrosis-factor-alpha-inhibitors-bacterial-viral-and-fungal-infections. Accessed 129, 2020.

 Google Scholar

Tabanor JA, Lakshminarayanan S. Do patients on biologic drugs for rheumatic disease need PCP prophylaxis? Cleve Clin J Med. 2019;86(7):449–453. doi:10.3949/ccjm.86a.1808431291178

 PubMed Web of Science ®Google Scholar

Baden LR, Swaminathan S, Angarone M, et al. Prevention and treatment of cancer-related infections, Version 2.2016, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2016;14(7):882–913. doi:10.6004/jnccn.2016.009327407129

 PubMed Web of Science ®Google Scholar

Maertens J, Cesaro S, Maschmeyer G, et al. ECIL guidelines for preventing Pneumocystis jirovecii pneumonia in patients with haematological malignancies and stem cell transplant recipients. J Antimicrob Chemother. 2016;71(9):2397–2404. doi:10.1093/jac/dkw15727550992

 PubMed Web of Science ®Google Scholar

Kotton CN, Kumar D, Caliendo AM, et al. The third international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation. Transplantation. 2018;102(6):900–931. doi:10.1097/TP.000000000000219129596116

 PubMed Web of Science ®Google Scholar

Morrison VA. Prevention of infections in patients with chronic lymphocytic leukemia. Bow E, Throner AR, editors. UpToDate Inc. 2019 Available from: https://www.uptodate.com/contents/prevention-of-infections-in-patients-with-chronic-lymphocytic-leukemia. Accessed 129, 2020.

 Google Scholar

Buonomo AR, Zappulo E, Viceconte G, et al. Risk of opportunistic infections in patients treated with alemtuzumab for multiple sclerosis. Expert Opin Drug Saf. 2018;17(7):709–717. doi:10.1080/14740338.2018.148333029848085

 PubMed Web of Science ®Google Scholar

Martin SI, Fishman JA, AST Infection Diseases Community of Practice. Pneumocystis pneumonia in solid organ transplantation. Am J Transplant. 2013;13(s4):272–279. doi:10.1111/ajt.2013.13.issue-s423465020

 PubMed Web of Science ®Google Scholar

Puzanov I, Diab A, Abdallah K, et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer. 2017;5(1):95. doi:10.1186/s40425-017-0300-z29162153

 PubMed Web of Science ®Google Scholar

Arvin AM, Wolinsky JS, Kappos L, et al. Varicella-zoster virus infections in patients treated with fingolimod: risk assessment and consensus recommendations for management. JAMA Neurol. 2015;72(1):31–39. doi:10.1001/jamaneurol.2014.306525419615

 PubMed Web of Science ®Google Scholar

Fishman JA, Gans H; AST Infectious Diseases Community of Practice. Pneumocystis jiroveci in solid organ transplantation: guidelines from the american society of transplantation infectious diseases community of practice. Clin Transplant. 2019;33:e13587.31077616

 PubMed Web of Science ®Google Scholar

Casulo C, Maragulia J, Zelenetz AD. Incidence of hypogammaglobulinemia in patients receiving rituximab and the use of intravenous immunoglobulin for recurrent infections. Clin Lymph Myelom Leuk. 2013;13(2):106–111. doi:10.1016/j.clml.2012.11.011

 PubMed Web of Science ®Google Scholar

Yilmaz E, Mahani MG, Bilen MA, et al. Clinical characteristics of rituximab-induced late onset neutropenia. Am J Hematol. 2010;85(10):810–812. doi:10.1002/ajh.2181820730791

 PubMed Web of Science ®Google Scholar

Salmon JH, Cacoub P, Combe B, et al. Late-onset neutropenia after treatment with rituximab for rheumatoid arthritis and other autoimmune diseases: data from the autoimmunity and rituximab registry. RMD Open. 2015;1(1):e000034. doi:10.1136/rmdopen-2014-00003426509060

 PubMed Web of Science ®Google Scholar

Cohen BA. Late-onset neutropenia following ocrelizumab therapy for multiple sclerosis. Neurology. 2019;92(9):435–436. doi:10.1212/WNL.000000000000692430635476

 PubMed Web of Science ®Google Scholar

Blankenbach K, Schwab N, Hofner B, et al. Natalizumab-associated progressive multifocal leukoencephalopathy in Germany. Neurology. 2019;92(19):e2232–e2233. doi:10.1212/WNL.000000000000745130952796

 PubMed Web of Science ®Google Scholar

Committee for Medicinal Products for Human Use (CHMP). International non- proprietary name: xeljanz EMEA/H/C/004214. Available from: https://www.ema.europa.eu/en/documents/product-information/xeljanz-epar-product-information_en.pdf. Accessed 129, 2020.

 Google Scholar

Committee for Medicinal Products for Human Use (CHMP). International non- proprietary name: Jakavi - EMEA/H/C/002464. Available from: https://www.ema.europa.eu/en/documents/product-information/jakavi-epar-product-information_en.pdf. Accessed 2 10, 2020.

 Google Scholar

Click B, Regueiro M. Managing Risks with Biologics. Curr Gastroenterol Rep. 2019;21(1):1. doi:10.1007/s11894-019-0669-630635807

 PubMedGoogle Scholar

Committee for Medicinal Products for Human Use (CHMP). International non- proprietary name: gilenya EMEA/H/C/002202. Available from: https://www.ema.europa.eu/en/documents/product-information/gilenya-epar-product-information_en.pdf. Accessed 129, 2020.

 Google Scholar

Furer V, Rondaan C, Heijstek MW, et al. 2019 update of EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases. Ann Rheum Dis. 2020;79(1):39–52. doi:10.1136/annrheumdis-2019-21588231413005

 PubMed Web of Science ®Google Scholar

Rubin LG, Levin MJ, Ljungman P, et al. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis. 2013;58(3):e44–e100.24311479

 PubMed Web of Science ®Google Scholar

Committee for Medicinal Products for Human Use (CHMP). International non- proprietary name: humira EMEA/H/C/000481. Available from: https://www.ema.europa.eu/en/documents/product-information/humira-epar-product-information_en.pdf. Accessed 129, 2020.

 Google Scholar

Committee for Medicinal Products for Human Use (CHMP). International non- proprietary name: enbrel. EMEA/H/C/000262l. Available from: https://www.ema.europa.eu/en/documents/product-information/enbrel-epar-product-information_en.pdf. Accessed 129, 2020.

 Google Scholar

Committee for Medicinal Products for Human Use (CHMP). International non- proprietary name: Simponi. European Medicines Agency. EMEA/H/C/000992. Available from: https://www.ema.europa.eu/en/documents/product-information/simponi-epar-product-information_en.pdf. Accessed 129, 2020.

 Google Scholar

Committee for Medicinal Products for Human Use (CHMP). International non- proprietary name: cimzia. EMEA/H/C/001037. Available from: https://www.ema.europa.eu/en/documents/product-information/cimzia-epar-product-information_en.pdf. Accessed 129, 2020.

 Google Scholar

Committee for Medicinal Products for Human Use (CHMP). International non- proprietary name: remicade. European Medicines Agency EMA/CHMP/47828/2019. Available from: https://www.ema.europa.eu/en/documents/product-information/remicade-epar-product-information_en.pdf. Accessed 129, 2020.

 Google Scholar

Papp KA, Haraoui B, Kumar D, et al. Vaccination guidelines for patients with immune-mediated disorders on immunosuppressive therapies. J Cutan Med Surg. 2019;23(1):50–74. doi:10.1177/120347541881133530463418

 PubMed Web of Science ®Google Scholar

Committee for Medicinal Products for Human Use (CHMP). International non- proprietary name: ilaris ‎EMEA/H/C/001109. Available from: https://www.ema.europa.eu/en/documents/product-information/ilaris-epar-product-information_en.pdf. Accessed 129, 2020.

 Google Scholar

Committee for Medicinal Products for Human Use (CHMP). International non- proprietary name: regeneron EMEA/H/C/001047. Available from: https://www.ema.europa.eu/en/documents/product-information/rilonacept-regeneron-epar-product-information_en.pdf. Accessed 129, 2020.

 Google Scholar

Rieger CT, Liss B, Mellinghoff S, et al. Anti-infective vaccination strategies in patients with hematologic malignancies or solid tumors. Guideline of the Infectious Diseases Working Party (AGIHO) of the German Society for Hematology and Medical Oncology (DGHO). Ann Oncol. 2018;29(6):1354–1365. doi:10.1093/annonc/mdy11729688266

 PubMed Web of Science ®Google Scholar

Committee for Medicinal Products for Human Use (CHMP) International non- proprietary name: blincyto EMEA/H/C/003731 https://www.ema.europa.eu/en/documents/product-information/blincyto-epar-product-information_en.pdf. Accessed 129, 2020.

 Google Scholar

Committee for Medicinal Products for Human Use (CHMP). International non- proprietary name: ocrevus EMA/790835/2017. Available from: https://www.ema.europa.eu/en/documents/product-information/ocrevus-epar-product-information_en.pdf. Accessed 129, 2020.

 Google Scholar

Stokmaier D, Winthrop K, Chognot C, et al. Effect of ocrelizumab on vaccine responses in patients with multiple sclerosis (S36. 002).

 Google Scholar

Beaulieu DB, Ananthakrishnan AN, Martin C, et al. Use of biologic therapy by pregnant women with inflammatory bowel disease does not affect infant response to vaccines. Clin Gastroenterol Hepatol. 2018;16(1):99–105. doi:10.1016/j.cgh.2017.08.04128870657

 PubMed Web of Science ®Google Scholar

Committee for Medicinal Products for Human Use (CHMP). International non- proprietary name: arzerra ‎EMEA/H/C/001131. Available from: https://www.ema.europa.eu/en/documents/product-information/arzerra-epar-product-information_en.pdf. Accessed 129, 2020.

 Google Scholar

Committee for Medicinal Products for Human Use (CHMP). International non- proprietary name: Gazyvaro - EMEA/H/C/002799. Available from:https://www.ema.europa.eu/en/documents/product-information/gazyvaro-epar-product-information_en.pdf. Accessed 2 5, 2020.

 Google Scholar

Committee for Medicinal Products for Human Use (CHMP). International non- proprietary name: mabcampath‎ EMEA/H/C/000353. Available from: https://www.ema.europa.eu/en/documents/product-information/mabcampath-epar-product-information_en.pdf. Accessed 129, 2020.

 Google Scholar

Issa NC, Baden LR. Current issues in vaccines for adult patients with hematologic malignancies. J Natl Compr Canc Netw. 2012;10(11):1447–1454. doi:10.6004/jnccn.2012.014723138170

 PubMed Web of Science ®Google Scholar

Berger T, Elovaara I, Fredrikson S, et al. Alemtuzumab use in clinical practice: recommendations from European multiple sclerosis experts. CNS Drugs. 2017;31(1):33–50. doi:10.1007/s40263-016-0394-827882532

 PubMed Web of Science ®Google Scholar

Committee for Medicinal Products for Human Use (CHMP). International non- proprietary name: orenica EMEA/H/C/000701. Available from: https://www.ema.europa.eu/en/documents/product-information/orencia-epar-product-information_en.pdf. Accessed 129, 2020.

 Google Scholar

Committee for Medicinal Products for Human Use (CHMP). International non- proprietary name: raptiva ‎EMEA/H/C/000542. Available from: https://www.ema.europa.eu/en/documents/product-information/raptiva-epar-product-information_en.pdf. Accessed 129, 2020.

 Google Scholar

Committee for Medicinal Products for Human Use (CHMP). International non- proprietary name: stelara EMEA/H/C/000958. Available from: https://www.ema.europa.eu/en/documents/product-information/stelara-epar-product-information_en.pdf. Accessed 129, 2020.

 Google Scholar

Mikulska M, Cesaro S, de Lavallade H, et al. Vaccination of patients with haematological malignancies who did not have transplantations: guidelines from the 2017 European Conference on Infections in Leukaemia (ECIL 7). Lancet Infect Dis. 2019;19(6). doi:10.1016/S1473-3099(18)30601-7

 Web of Science ®Google Scholar

Danziger Isakov L, Kumar D; AST ID Community of Practice. Vaccination of solid organ transplant candidates and recipients: guidelines from the American society of transplantation infectious diseases community of practice. Clin Transplant. 2019;33:e13563.31002409

 PubMed Web of Science ®Google Scholar