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Cabler SS, Storch GA, Weinberg JB, Walton AH, Brengel-Pesce K, Aldewereld Z, Banks RK, Cheynet V, Reeder R, Holubkov R, Berg RA, Wessel D, Pollack MM, Meert K, Hall M, Newth C, Lin JC, Cornell T, Harrison RE, Dean JM, Carcillo JA. Viral DNAemia and DNA Virus Seropositivity and Mortality in Pediatric Sepsis. JAMA Netw Open 2024; 7:e240383. [PMID: 38407904 PMCID: PMC10897747 DOI: 10.1001/jamanetworkopen.2024.0383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 01/05/2024] [Indexed: 02/27/2024] Open
Abstract
Importance Sepsis is a leading cause of pediatric mortality. Little attention has been paid to the association between viral DNA and mortality in children and adolescents with sepsis. Objective To assess the association of the presence of viral DNA with sepsis-related mortality in a large multicenter study. Design, Setting, and Participants This cohort study compares pediatric patients with and without plasma cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus 1 (HSV-1), human herpesvirus 6 (HHV-6), parvovirus B19 (B19V), BK polyomavirus (BKPyV), human adenovirus (HAdV), and torque teno virus (TTV) DNAemia detected by quantitative real-time polymerase chain reaction or plasma IgG antibodies to CMV, EBV, HSV-1, or HHV-6. A total of 401 patients younger than 18 years with severe sepsis were enrolled from 9 pediatric intensive care units (PICUs) in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network. Data were collected from 2015 to 2018. Samples were assayed from 2019 to 2022. Data were analyzed from 2022 to 2023. Main Outcomes and Measures Death while in the PICU. Results Among the 401 patients included in the analysis, the median age was 6 (IQR, 1-12) years, and 222 (55.4%) were male. One hundred fifty-four patients (38.4%) were previously healthy, 108 (26.9%) were immunocompromised, and 225 (56.1%) had documented infection(s) at enrollment. Forty-four patients (11.0%) died in the PICU. Viral DNAemia with at least 1 virus (excluding TTV) was detected in 191 patients (47.6%) overall, 63 of 108 patients (58.3%) who were immunocompromised, and 128 of 293 (43.7%) who were not immunocompromised at sepsis onset. After adjustment for age, Pediatric Risk of Mortality score, previously healthy status, and immunocompromised status at sepsis onset, CMV (adjusted odds ratio [AOR], 3.01 [95% CI, 1.36-6.45]; P = .007), HAdV (AOR, 3.50 [95% CI, 1.46-8.09]; P = .006), BKPyV (AOR. 3.02 [95% CI, 1.17-7.34]; P = .02), and HHV-6 (AOR, 2.62 [95% CI, 1.31-5.20]; P = .007) DNAemia were each associated with increased mortality. Two or more viruses were detected in 78 patients (19.5%), with mortality among 12 of 32 (37.5%) who were immunocompromised and 9 of 46 (19.6%) who were not immunocompromised at sepsis onset. Herpesvirus seropositivity was common (HSV-1, 82 of 246 [33.3%]; CMV, 107 of 254 [42.1%]; EBV, 152 of 251 [60.6%]; HHV-6, 253 if 257 [98.4%]). After additional adjustment for receipt of blood products in the PICU, EBV seropositivity was associated with increased mortality (AOR, 6.10 [95% CI, 1.00-118.61]; P = .049). Conclusions and Relevance The findings of this cohort study suggest that DNAemia for CMV, HAdV, BKPyV, and HHV-6 and EBV seropositivity were independently associated with increased sepsis mortality. Further investigation of the underlying biology of these viral DNA infections in children with sepsis is warranted to determine whether they only reflect mortality risk or contribute to mortality.
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Affiliation(s)
- Stephanie S. Cabler
- Department of Pediatrics, Washington University in St Louis, St Louis, Missouri
| | - Gregory A. Storch
- Department of Pediatrics, Washington University in St Louis, St Louis, Missouri
| | | | - Andrew H. Walton
- Department of Pediatrics, Washington University in St Louis, St Louis, Missouri
| | | | - Zachary Aldewereld
- Department of Pediatrics and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | | | | | - Ron Reeder
- Department of Pediatrics, University of Utah, Salt Lake City
| | | | - Robert A. Berg
- Department of Anesthesiology, Pediatrics, University of Pennsylvania, Philadelphia
| | - David Wessel
- Department of Pediatrics, George Washington University, Washington, DC
| | - Murray M. Pollack
- Department of Pediatrics, George Washington University, Washington, DC
| | - Kathleen Meert
- Department of Pediatrics, Central Michigan University, Detroit
| | - Mark Hall
- Department of Pediatrics, The Ohio State University, Columbus
| | - Christopher Newth
- Department of Anesthesiology, University of Southern California, Los Angeles
| | - John C. Lin
- Department of Pediatrics, Washington University in St Louis, St Louis, Missouri
| | - Tim Cornell
- Department of Pediatrics, University of Michigan, Ann Arbor
| | | | - J. Michael Dean
- Department of Pediatrics, University of Utah, Salt Lake City
| | - Joseph A. Carcillo
- Department of Pediatrics and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
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Pang V, Seery N, Wesselingh R, Yeh W, Zhong M, Tan T, Dwyer C, Nesbitt C, Rath L, Perera D, Bridge F, Skibina O, Bosco JJ, Jokubaitis V, Marriott M, Butkueven H, Van Der Walt A, Massey J, Sutton I, Monif M. Neutropaenia complications from Ocrelizumab and Rituximab treatment. Mult Scler Relat Disord 2024; 81:105147. [PMID: 38043368 DOI: 10.1016/j.msard.2023.105147] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 11/11/2023] [Accepted: 11/19/2023] [Indexed: 12/05/2023]
Abstract
Ocrelizumab is an anti-CD20 monoclonal antibody (mAb) that has been shown in phase 3 clinical trials to reduce relapses and disease progression in multiple sclerosis (MS) patients. Prior to the approval of ocrelizumab, rituximab, a chimeric anti-CD20 mAb was used to treat MS. Rituximab is still used to treat MS in many countries outside of Australia and remains mainstay of treatment of many non-MS neuroimmunological and systemic inflammatory diseases. Rituximab is currently used in neuromyelitis optica spectrum disorder (NMOSD) and autoimmune encephalitis, in addition to its widespread usage in hematological malignancies and systemic inflammatory diseases. Ocrelizumab is currently approved in Australia for treatment of relapsing-remitting MS (RRMS). Neutropaenia is a rare complication of both ocrelizumab and rituximab treatment. This case series reports 12 patients who have experienced neutropaenia following ocrelizumab or rituximab treatment and aims to characterize the clinical parameters of neutropaenia experienced by these patients, including the severity and duration of neutropaenia, length of hospital admission, the types of subsequent infections experienced and types of treatment necessary before patients reached count recovery. The unpredictability of neutropaenia and potential for serious infections highlight the need for continued hematological monitoring for patients on B-cell depleting therapies and calls for careful patient counselling to provide guidance on whether to continue such therapies in patients who have experienced related neutropaenia.
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Affiliation(s)
- Venus Pang
- Department of Neuroscience Monash University, Melbourne, Australia
| | - Nabil Seery
- Department of Neuroscience Monash University, Melbourne, Australia; Department of Neurology, Alfred Hospital, Melbourne, Australia
| | - Robb Wesselingh
- Department of Neuroscience Monash University, Melbourne, Australia; Department of Neurology, Alfred Hospital, Melbourne, Australia
| | - Wei Yeh
- Department of Neuroscience Monash University, Melbourne, Australia; Department of Neurology, Alfred Hospital, Melbourne, Australia
| | - Michael Zhong
- Department of Neuroscience Monash University, Melbourne, Australia; Department of Neurology, Alfred Hospital, Melbourne, Australia
| | - Tracie Tan
- Department of Neuroscience Monash University, Melbourne, Australia; Department of Neurology, Alfred Hospital, Melbourne, Australia
| | - Chris Dwyer
- Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia
| | - Cassie Nesbitt
- Department of Neuroscience Monash University, Melbourne, Australia; Department of Neurology, Alfred Hospital, Melbourne, Australia
| | - Louise Rath
- Department of Neurology, Alfred Hospital, Melbourne, Australia
| | - Deborah Perera
- Department of Neurology, Alfred Hospital, Melbourne, Australia
| | - Francesca Bridge
- Department of Neuroscience Monash University, Melbourne, Australia; Department of Neurology, Alfred Hospital, Melbourne, Australia
| | - Olga Skibina
- Department of Neurology, Alfred Hospital, Melbourne, Australia
| | - Julian J Bosco
- Department of Allergy, asthma, Immunology, Alfred Hospital, Melbourne, Australia
| | - Vilija Jokubaitis
- Department of Neuroscience Monash University, Melbourne, Australia; Department of Neurology, Alfred Hospital, Melbourne, Australia
| | - Mark Marriott
- Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia
| | - Helmut Butkueven
- Department of Neuroscience Monash University, Melbourne, Australia; Department of Neurology, Alfred Hospital, Melbourne, Australia
| | - Anneke Van Der Walt
- Department of Neuroscience Monash University, Melbourne, Australia; Department of Neurology, Alfred Hospital, Melbourne, Australia
| | - Jennifer Massey
- Department of Neurology, St Vincent's Hospital, Sydney, Australia
| | - Ian Sutton
- Department of Neurology, St Vincent's Hospital, Sydney, Australia
| | - Mastura Monif
- Department of Neuroscience Monash University, Melbourne, Australia; Department of Neurology, Alfred Hospital, Melbourne, Australia; Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia.
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3
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Grammatikos A, Donati M, Johnston SL, Gompels MM. Peripheral B Cell Deficiency and Predisposition to Viral Infections: The Paradigm of Immune Deficiencies. Front Immunol 2021; 12:731643. [PMID: 34527001 PMCID: PMC8435594 DOI: 10.3389/fimmu.2021.731643] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Accepted: 08/09/2021] [Indexed: 12/11/2022] Open
Abstract
In the era of COVID-19, understanding how our immune system responds to viral infections is more pertinent than ever. Immunodeficiencies with very low or absent B cells offer a valuable model to study the role of humoral immunity against these types of infection. This review looks at the available evidence on viral infections in patients with B cell alymphocytosis, in particular those with X-linked agammaglobulinemia (XLA), Good’s syndrome, post monoclonal-antibody therapy and certain patients with Common Variable Immune Deficiency (CVID). Viral infections are not as infrequent as previously thought in these conditions and individuals with very low circulating B cells seem to be predisposed to an adverse outcome. Particularly in the case of SARS-CoV2 infection, mounting evidence suggests that peripheral B cell alymphocytosis is linked to a poor prognosis.
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Affiliation(s)
- Alexandros Grammatikos
- Department of Immunology, Southmead Hospital, North Bristol National Health Service (NHS) Trust, Bristol, United Kingdom
| | - Matthew Donati
- Severn Infection Sciences and Public Health England National Infection Service South West, Department of Virology, Southmead Hospital, North Bristol NHS Trust, Bristol, United Kingdom
| | - Sarah L Johnston
- Department of Immunology, Southmead Hospital, North Bristol National Health Service (NHS) Trust, Bristol, United Kingdom
| | - Mark M Gompels
- Department of Immunology, Southmead Hospital, North Bristol National Health Service (NHS) Trust, Bristol, United Kingdom
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Escobar-Sevilla J, Bustos Merlo A, Garcia Martínez C, Mediavilla Garcia JD. Severe Refractory Anaemia and Fever of Unknow Origin: Human Parvovirus B19 Reactivation. Eur J Case Rep Intern Med 2020; 7:001596. [PMID: 32908820 DOI: 10.12890/2020_001596] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Accepted: 05/14/2020] [Indexed: 11/05/2022] Open
Abstract
Reactivation of human parvovirus B19 is exceptional and characteristic of immunosuppression, with anaemia being the predominant manifestation although pancytopenia and thrombotic microangiopathy may also occur. We describe a patient with a history of diffuse large B-cell lymphoma with pure erythrocyte aplasia due to reactivation of parvovirus B19, who was treated with corticosteroids and immunoglobulins. LEARNING POINTS Infection with human parvovirus B19 is identified by polymerase chain reaction (PCR) testing of blood and the presence of typical giant proerythroblasts in the bone marrow.Cytomegalovirus infection should be considered in immunosuppressed patients with fever and non-specific symptoms with haematological changes.The treatment of persistent infection in immunosuppressed patients is based on the administration of IV immunoglobulins at high doses.
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Davis JS, Ferreira D, Paige E, Gedye C, Boyle M. Infectious Complications of Biological and Small Molecule Targeted Immunomodulatory Therapies. Clin Microbiol Rev 2020; 33:e00035-19. [PMID: 32522746 PMCID: PMC7289788 DOI: 10.1128/cmr.00035-19] [Citation(s) in RCA: 73] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The past 2 decades have seen a revolution in our approach to therapeutic immunosuppression. We have moved from relying on broadly active traditional medications, such as prednisolone or methotrexate, toward more specific agents that often target a single receptor, cytokine, or cell type, using monoclonal antibodies, fusion proteins, or targeted small molecules. This change has transformed the treatment of many conditions, including rheumatoid arthritis, cancers, asthma, and inflammatory bowel disease, but along with the benefits have come risks. Contrary to the hope that these more specific agents would have minimal and predictable infectious sequelae, infectious complications have emerged as a major stumbling block for many of these agents. Furthermore, the growing number and complexity of available biologic agents makes it difficult for clinicians to maintain current knowledge, and most review articles focus on a particular target disease or class of agent. In this article, we review the current state of knowledge about infectious complications of biologic and small molecule immunomodulatory agents, aiming to create a single resource relevant to a broad range of clinicians and researchers. For each of 19 classes of agent, we discuss the mechanism of action, the risk and types of infectious complications, and recommendations for prevention of infection.
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Affiliation(s)
- Joshua S Davis
- Department of Infectious Diseases and Immunology, John Hunter Hospital, Newcastle, NSW, Australia
- Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, NT, Australia
- School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia
| | - David Ferreira
- School of Medicine, University of New South Wales, Sydney, NSW, Australia
| | - Emma Paige
- Department of Infectious Diseases, Alfred Hospital, Melbourne, VIC, Australia
| | - Craig Gedye
- School of Medicine, University of New South Wales, Sydney, NSW, Australia
- Department of Oncology, Calvary Mater Hospital, Newcastle, NSW, Australia
| | - Michael Boyle
- Department of Infectious Diseases and Immunology, John Hunter Hospital, Newcastle, NSW, Australia
- School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia
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Shin H, Park S, Lee GW, Koh EH, Kim HY. Parvovirus B19 infection presenting with neutropenia and thrombocytopenia: Three case reports. Medicine (Baltimore) 2019; 98:e16993. [PMID: 31464949 PMCID: PMC6736112 DOI: 10.1097/md.0000000000016993] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
RATIONALE Parvovirus B19 (PV) infection is usually symptomless and can cause benign, short-lived conditions. Anemia associated with PRCA is the most representative hematologic manifestation, but neutropenia and thrombocytopenia have been rarely reported. PATIENT CONCERNS Three patients were admitted to the hospital with neutropenia and thrombocytopenia. The accompanying symptoms were fever, myalgia, rash, or arthralgia, and all patients were previously healthy. DIAGNOSIS Patients were positive for PV PCR and diagnosed with PV infection. Before the diagnosis of PV infection, 2 patients underwent BM study and almost absence of erythroid progenitor cells in BM aspiration were a clue for the PV infection. Other BM findings were hypocellular marrow and a few hemophagocytic histiocytes. INTERVENTIONS Patients received supportive care with follow-up of CBC. OUTCOMES All 3 patients spontaneously recovered from neutropenia and thrombocytopenia within 3 weeks without severe complications. LESSONS The evaluation of PV infection should be considered in situations where there is neutropenia and thrombocytopenia in healthy individuals even without anemia as a differential diagnosis.
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Affiliation(s)
| | - Sungwoo Park
- Division of Hematology-Oncology, Department of Internal Medicine Gyeongsang National University Hospital, Gyeongsang National University School of Medicine
| | - Gyeong-Won Lee
- Division of Hematology-Oncology, Department of Internal Medicine Gyeongsang National University Hospital, Gyeongsang National University School of Medicine
- Institute of Health Science, Gyeongsang National University, Jinju
| | - Eun-Ha Koh
- Department of Laboratory Medicine
- Institute of Health Science, Gyeongsang National University, Jinju
| | - Hyun-Young Kim
- Department of Laboratory Medicine & Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
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Agranulocytosis under biotherapy in rheumatoid arthritis: three cases hypothesis of parvovirus B19 involvement in agranulocytosis observed under tocilizumab and rituximab for the treatment of rheumatoid arthritis. Clin Rheumatol 2016; 35:2615-8. [PMID: 27541023 PMCID: PMC5031743 DOI: 10.1007/s10067-016-3379-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2016] [Accepted: 08/07/2016] [Indexed: 01/04/2023]
Abstract
Leukopenia is a considerably common complication of tocilizumab [TCZ] and rituximab [RTX] therapy. RTX-induced leukopenia typically exhibits delayed onset. While agranulocytosis has been reported linked to RTX treatment of lymphoma, this complication rarely occurs in rheumatoid arthritis (RA) treatment and, to our knowledge, has never been reported in association with TCZ therapy. We herein report four agranulocytosis cases in three patients, with the first two cases suspected to be secondary to human parvovirus B19 (PVB19) infection. Agranulocytosis manifested in the first patient 2 months following a third RTX course. Bone marrow (BM) polymerase chain reaction (PCR) was positive for PVB19. The patient relapsed after three TCZ courses, with her PCR again positive for PVB19. Both episodes resolved under granulocyte-macrophage colony-stimulating factor (GM-CSF). In the second patient, agranulocytosis manifested after the 74th TCZ course. Bone marrow PCR was positive for PVB19, and the evolution was favorable under intravenous immunoglobulin administration. The third case was a 53-year-old female patient with seropositive RA who presented agranulocytosis after the first infusion of her fourth RTX course. Unfortunately, no PCR PVB19 was made on myelogram. Evolution was favorable after 5 days of GM-CSF. PVB19 infection should be investigated in patients suffering from agranulocytosis manifesting during biotherapy. In cases manifesting from the 15th day of RTX treatment onwards, hemogram must be conducted before readministering the infusion.
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Kerr JR. A review of blood diseases and cytopenias associated with human parvovirus B19 infection. Rev Med Virol 2015; 25:224-40. [PMID: 25962796 DOI: 10.1002/rmv.1839] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2015] [Revised: 03/24/2015] [Accepted: 03/25/2015] [Indexed: 12/12/2022]
Abstract
Parvovirus B19 is a single-stranded DNA virus which preferentially targets the erythroblast resulting in red cell aplasia, which is temporary in immunocompetent persons. Since the discovery of B19 virus in 1975, a wide variety of blood diseases and cytopenias affecting several blood cell lineages have been documented during or following B19 infection. These include cytopenias affecting the erythroid, megakaryoblastoid, myeloid and lymphoid lineages, as well as a variety of bicytopenias, pancytopenia, bone marrow necrosis / fat embolism syndrome, myelodysplastic syndrome, leucoerythroblastopenia, and hemophagocytic lymphohistiocytosis. B19 infection may also complicate and precede the course of acute leukemia, the significance of which remains to be determined. This review describes the current state of knowledge of the abnormalities of individual blood cell lineages encountered during parvovirus B19 infection, over the almost 40 years since its discovery, and reveals some very interesting themes, which improve our understanding of the pathogenesis of B19 infection with particular reference to the bone marrow.
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Affiliation(s)
- Jonathan R Kerr
- Escuela de Medicina y Ciencias de la Salud, Universidad del Rosario, Bogotá, Colombia
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Kamei K, Takahashi M, Fuyama M, Saida K, Machida H, Sato M, Ogura M, Ito S. Rituximab-associated agranulocytosis in children with refractory idiopathic nephrotic syndrome: case series and review of literature. Nephrol Dial Transplant 2014; 30:91-6. [PMID: 25085238 DOI: 10.1093/ndt/gfu258] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Agranulocytosis has been reported as a delayed-onset complication of rituximab treatment. However, the exact incidence and risk factors of this complication in patients with nephrotic syndrome remain unknown. METHODS Records of 213 rituximab treatments for 114 patients with refractory nephrotic syndrome between February 2006 and April 2013 were reviewed to identify episodes of agranulocytosis (defined as an absolute neutrophil count of <500 mm(3)). RESULTS Eleven episodes of agranulocytosis were detected in 11 patients. Median time of onset of agranulocytosis was 66 days (range, 54-161 days) after rituximab treatment. Nine patients experienced acute infections and received antibiotics. All but one patient received granulocyte colony-stimulating factor. Agranulocytosis resolved in all cases within a median of 3 days. The incidence of agranulocytosis was 9.6% in total patients and 5.2% in all treatments. Median age of the 11 patients who developed agranulocytosis was 6.4 years at the first rituximab treatment, significantly younger than the median age of the 103 patients who did not (median, 12.5 years; P = 0.0009). Five patients received re-treatment with rituximab. No recurrence of agranulocytosis was observed in any patient. CONCLUSIONS It is important to pay extra attention to this clinically serious delayed-onset complication as it may be accompanied by life-threatening infections such as sepsis. Further clinical studies are needed to clarify its pathogenesis.
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Affiliation(s)
- Koichi Kamei
- Department of Nephrology and Rheumatology, National Center for Child Health and Development, Tokyo, Japan
| | - Masaki Takahashi
- Department of Nephrology and Rheumatology, National Center for Child Health and Development, Tokyo, Japan
| | - Masaki Fuyama
- Department of Nephrology and Rheumatology, National Center for Child Health and Development, Tokyo, Japan
| | - Ken Saida
- Department of Nephrology and Rheumatology, National Center for Child Health and Development, Tokyo, Japan
| | - Hiroyuki Machida
- Department of Nephrology and Rheumatology, National Center for Child Health and Development, Tokyo, Japan
| | - Mai Sato
- Department of Nephrology and Rheumatology, National Center for Child Health and Development, Tokyo, Japan
| | - Masao Ogura
- Department of Nephrology and Rheumatology, National Center for Child Health and Development, Tokyo, Japan
| | - Shuichi Ito
- Department of Nephrology and Rheumatology, National Center for Child Health and Development, Tokyo, Japan
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Yang SH, Hsu C, Cheng AL, Kuo SH. Anti-CD20 monoclonal antibodies and associated viral hepatitis in hematological diseases. World J Hematol 2014; 3:29-43. [DOI: 10.5315/wjh.v3.i2.29] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2013] [Revised: 01/27/2014] [Accepted: 03/18/2014] [Indexed: 02/05/2023] Open
Abstract
Over the past decade, the administration of anti-CD20 monoclonal antibodies such as rituximab has demonstrated various degrees of effectiveness and has improved patients’ outcomes during the treatment of autoimmune hematological disorders and hematological malignancies. However, the depletion of B-cells, the distribution of T-cell populations, and the reconstruction of host immunity resulting from the use of anti-CD20 monoclonal antibodies potentially lead to severe viral infections, such as hepatitis B virus (HBV), hepatitis C virus (HCV), parvovirus B19, and herpes viruses, in patients who are undergoing immune therapy or immunochemotherapy. Of these infections, HBV- and HCV-related hepatitis are a great concern in endemic areas because of the high morbidity and mortality rates in untreated patients. As a result, prophylaxis against HBV infection is becoming a standard of care in these areas. Parvovirus B19, a widespread pathogen that causes red blood cell aplasia in immunocompromised hosts, also causes hepatitis in healthy individuals. Recently, its association with hepatitis was recognized in a patient treated with rituximab. In addition, adenovirus, varicella-zoster virus, hepatitis E virus, and rituximab itself have been linked to the occurrence of hepatitis during or after rituximab treatments. The epidemiologies and pathogeneses of these etiologies remain unknown. Because of the increasing use of anti-CD20 monoclonal antibodies for the treatment of hematological malignancies or autoimmune hematological disorders, it is imperative that physicians understand and balance the risks of hepatotropic virus-associated hepatitis against the benefits of using anti-CD20 monoclonal antibodies.
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11
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12
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Neutropenia in parvovirus B19-associated pure red cell aplasia. Ann Hematol 2010; 90:975-8. [DOI: 10.1007/s00277-010-1108-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2010] [Accepted: 10/11/2010] [Indexed: 10/18/2022]
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13
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Kaneko H, Shimura K, Nishida K, Fujiwara Y, Matsumoto Y, Kuroda J, Horiike S, Yokota S, Ohkawara Y, Taniwaki M. Pure red cell aplasia caused by parvovirus B19 in two patients without chronic hemolysis. J Infect Chemother 2010; 17:268-71. [PMID: 20820839 DOI: 10.1007/s10156-010-0106-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2010] [Accepted: 07/24/2010] [Indexed: 11/26/2022]
Abstract
Infection with human parvovirus B19 (PVB19) induces acquired pure red cell aplasia (PRCA). Chronic hemolytic anemia is well known as an underlying condition. However, additional factors have been recognized to accompany parvoviral PRCA; however, there are only limited reports on iron-deficiency anemia (IDA) and rituximab-induced B-cell dysfunction. We report two patients with PVB19-associated PRCA confirmed by positivity of viral DNA. Although they had no chronic hemolysis, patient 1 had IDA, and patient 2 had remitted small-lymphocytic lymphoma treated with rituximab-containing chemotherapy. Absence of reticulocytes in peripheral blood and marked depletion of erythroid precursors in bone marrow were observed both. Whereas patient 1 received only symptomatic therapy because anemia was not severe, patient 2 was treated with steroids, as PRCA etiology was at first uncertain, and immunological PRCA was not excluded. Both showed rapid increase of reticulocyte counts and recovery from anemia. Although immunoglobulin is considered effective for parvoviral PRCA, notable adverse reactions have been reported. When anemic symptom is not severe, reticulocyte observation only is recommended. The effects of steroids should also be re-evaluated. Optimal treatment according to disease severity remains to be established.
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MESH Headings
- Adult
- Anemia, Iron-Deficiency/complications
- Antibodies, Monoclonal/therapeutic use
- Antibodies, Monoclonal, Murine-Derived/therapeutic use
- DNA, Viral/analysis
- DNA, Viral/genetics
- Female
- Hemolysis
- Humans
- Leukemia, Lymphocytic, Chronic, B-Cell/complications
- Leukemia, Lymphocytic, Chronic, B-Cell/therapy
- Middle Aged
- Parvoviridae Infections/virology
- Parvovirus B19, Human/genetics
- Parvovirus B19, Human/isolation & purification
- Red-Cell Aplasia, Pure/virology
- Rituximab
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Affiliation(s)
- Hiroto Kaneko
- Department of Hematology, Aiseikai-Yamashina Hospital, 19-4 Shichouno-cho, Yamashina-ku, Kyoto, 607-8086, Japan.
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14
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Wolach O, Bairey O, Lahav M. Late-onset neutropenia after rituximab treatment: case series and comprehensive review of the literature. Medicine (Baltimore) 2010; 89:308-318. [PMID: 20827108 DOI: 10.1097/md.0b013e3181f2caef] [Citation(s) in RCA: 120] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Rituximab is a chimeric monoclonal antibody against CD20 that is used mainly for the treatment of CD20-positive lymphoma. Recently, its use has been expanded to include treatment of other nonmalignant diseases such as rheumatologic diseases and autoimmune cytopenia. Correlating with the increased use of rituximab has been an increased number of reports of its late adverse effects. One of these is late-onset neutropenia (LON). Most investigators define LON as grade III-IV neutropenia occurring 3-4 weeks after the last treatment with rituximab, in the absence of an alternative explanation for the neutropenia.We report 6 cases of LON identified in our institution. Four patients were treated for diffuse large B-cell lymphoma, and 2 patients for follicular lymphoma. Median patient age was 68 years (range, 33-83 yr); LON appeared after a median interval of 77 days (range, 42-153 d) and lasted for a median of 5 days (range, 1-45 d). Five of the 6 patients presented with infectious complications, and 4 patients experienced recurrent episodes of neutropenia. One patient presented with LON and concomitant subacute pulmonary disease that was attributed to rituximab therapy.In addition to our own case series we present a systematic review of the literature, which we performed to compile data to describe better the syndrome of LON. Systematic studies, case series, and case reports were extracted. Most studies dealing with LON are retrospective by design and are limited by the heterogeneous populations included in the analysis. The incidence of LON is generally reported to be in the range of 3%-27%. Data regarding populations at risk are not consistent, and in some instances are conflicting.Patients considered at increased risk of LON include patients after autologous stem cell transplantation, patients treated for acquired immunodeficiency syndrome (AIDS)-related lymphoma, and patients treated with purine analogues. Patients who received previous cytotoxic treatment as well as those treated with more intensive chemotherapy or with chemotherapy in combination with radiotherapy are also considered to be at risk of LON. In addition, advanced stages of disease and having received multiple doses of rituximab are risk factors for LON.The mechanism of LON is poorly understood. Direct toxicity is very unlikely. Some speculate that there may be an infectious etiology involved, as well as an antibody-mediated process, but these ideas have not been substantiated. The concept of a lymphocyte subpopulation imbalance leading to LON has been presented based on the demonstration of T-LGL in peripheral blood and bone marrow of patients with LON. Perturbations in stromal-derived factor-1 and in the BAFF cytokine have also been discussed as potential players in the pathogenesis of LON. A recent study correlated specific polymorphism in the immunoglobulin G Fc receptor FCγRIIIa 158 V/F with increased rates of LON.The clinical significance of LON is important because it may affect treatment strategies. Of note, infectious complications are not very frequent and not very severe. Pooling data from the major retrospective studies reveals an infection rate of 16.9%. Most infections were mild and resolved promptly. One death occurred from infection during neutropenia. Repeated episodes of LON are not uncommon, but it is so far impossible to identify those patients at risk of these relapsing episodes of LON. Re-treatment with rituximab after LON may result in recurrent episodes, but the implications and risks are uncertain at the present time. The role of growth factors once LON appears is ill defined, and the decision to use them should be made on a case-by-case basis.
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Affiliation(s)
- Ofir Wolach
- From Internal Medicine A (OW, ML), and Institute of Hematology (OB, ML), Davidoff Cancer Center, Rabin Medical Center-Beilinson Hospital, Petah Tikva; and Sackler School of Medicine (OW, OB, ML), Tel Aviv University, Tel Aviv, Israel
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Abstract
After more than 10 years of use, rituximab has proven to be remarkably safe. However, accumulated evidence now suggests that under some circumstances it may significantly increase the risk of infections. This risk is difficult to quantify because of confounding factors (namely, concomitant use of immunosuppressive or chemotherapeutic agents and underlying conditions), as well as under-reporting. Increased number of infections has been documented in patients treated with maintenance rituximab for low-grade lymphoma and in patients with concomitant severe immunodeficiency, whether caused by human immunodeficiency virus (HIV) infection or immunosuppressive agents like fludarabine. From the practical standpoint, the most important infection is hepatitis B reactivation, which may be delayed and result in fulminant liver failure and death. Special care should be placed on screening for hepatitis B virus (HBV) and preemptive antiviral treatment. Some investigators have reported an increase in Pneumocystis pneumonia. Finally, there is increasing evidence of a possible association with progressive multifocal leukoencephalopathy (PML), a lethal encephalitis caused by the polyomavirus JC. This review enumerates the described infectious complications, summarizes the possible underlying mechanisms of the increased risk, and makes recommendations regarding prevention, diagnosis and management.
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Affiliation(s)
- Juan C Gea-Banacloche
- Experimental Transplantation and Immunology Branch, National Cancer Institute, Bethesda, MD 20892, USA.
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Hirayama Y, Kohda K, Konuma Y, Hirata Y, Kuroda H, Fujimi Y, Shirao S, Kobune M, Takimoto R, Matsunaga T, Kato J. Late onset neutropenia and immunoglobulin suppression of the patients with malignant lymphoma following autologous stem cell transplantation with rituximab. Intern Med 2009; 48:57-60. [PMID: 19122357 DOI: 10.2169/internalmedicine.48.1368] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND Recently, decrease of immunoglobulin concentrations or neutrophil counts were reported in some cases several months after administration of rituximab. We examined a number of episodes of late onset neutropenia or immunoglobulin decrease in patients with malignant lymphoma who were in complete remission following autologous transplantation with or without rituximab. METHOD Patients with follicular lymphoma and diffuse large B cell lymphoma transplanted with or without rituximab in our institutes were analyzed. Immunoglobulin concentrations and neutrophil counts after transplantation, both with and without rituximab were measured serially. RESULTS Four weeks after transplantation, blood samples revealed lower concentrations of IgG and IgA in the rituximab group than in the non-rituximab group. Neutrophil numbers did not fall below 0.5x10(9) /L four weeks or more after transplantation in the non-rituximab group. Neutrophil numbers dropped below 0.5x10(9) /L in 6 of 14 cases in the rituximab group. CONCLUSION Although the present study was retrospective and disease composition and pre-transplantation regimens differed between the two groups, the addition of rituximab to autologous transplantation might bring about a decrease of immunoglobulin levels and transient LON.
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Affiliation(s)
- Yasuo Hirayama
- Department of Hematology and Oncology, Asahikawa Red Cross Hospital, Asahikawa.
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Current awareness: Pharmacoepidemiology and drug safety. Pharmacoepidemiol Drug Saf 2007. [DOI: 10.1002/pds.1378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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