|
1
|
Narsana N, Ha D, Ho DY. Treating Adenovirus Infection in Transplant Populations: Therapeutic Options Beyond Cidofovir? Viruses 2025; 17:599. [PMID: 40431613 PMCID: PMC12116135 DOI: 10.3390/v17050599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2025] [Revised: 04/21/2025] [Accepted: 04/22/2025] [Indexed: 05/29/2025] Open
Abstract
Adenovirus (AdV) infections can lead to significant morbidity and increased mortality in immunocompromised populations such as hematopoietic stem cell and solid organ transplant recipients. This review evaluates currently available and emerging therapies for AdV infections. Cidofovir, while most commonly used, is limited by its variable efficacy and nephrotoxicity. This led to the development of brincidofovir, which has a better safety profile and great in vitro potency against AdV. The use of ribavirin and ganciclovir has been reported in the literature, but their use is limited due to inconsistent efficacy. Immune-based approaches, such as adoptive T-cell therapy, have shown promise in achieving viral clearance and improving survival but remain constrained by challenges related to manufacturing complexity and risks of graft-versus-host disease. This review underscores the need for standardized treatment protocols as well as comparative studies to identify optimal dosing and timing to initiate treatment. Future research should focus on individualized treatment approaches and the development of novel therapeutic agents to address the unmet clinical needs of AdV management.
Collapse
Affiliation(s)
- Niyati Narsana
- Division of Infectious Diseases, UC Davis Medical Center, Sacramento, CA 95817, USA
| | - David Ha
- Stanford Antimicrobial Safety and Sustainability Program, Stanford Health Care, Stanford, CA 94305, USA
- Division of Infectious Diseases & Geographic Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Dora Y. Ho
- Division of Infectious Diseases & Geographic Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| |
Collapse
|
|
2
|
Hissong E, Arora K, Andy C, Jessurun J, Yantiss RK. Histologic Manifestations of Gastrointestinal Adenovirus Infection After Stem Cell Transplant. Am J Surg Pathol 2024; 48:521-527. [PMID: 38329327 DOI: 10.1097/pas.0000000000002197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2024]
Abstract
Adenovirus can cause severe disease in hematopoietic stem cell transplant (HSCT) patients. Histopathologic features of this infection in gastrointestinal biopsies and their distinction from graft-versus-host disease (GVHD) have been incompletely studied. We retrospectively identified patients with gastrointestinal adenovirus infection. H&E-stained sections were reviewed and the histologic features were recorded. The extent of immunostaining was determined using a semiquantitative scale and a maximum number of positive cells per high-power field. Information regarding the clinical course and endoscopic findings were obtained from the electronic medical records. The study group included 32 HSCT patients. Most (81%) presented with diarrhea and detectable virus in the serum. Twenty patients had multiorgan involvement in the gastrointestinal tract, mostly in the duodenum (62%) and colon (56%). Characteristic features included apoptotic epithelial cells with nuclear disarray (84%) and tufted aggregates of degenerating epithelial cells (69%), the latter of which was more commonly seen in the study population more than a control group of HSCT patients with GI involvement by GVHD. Viral inclusions were limited to the superficial epithelium in 59% of samples, and the density of viral inclusions within biopsies was variable (grade 1: 40%, grade 2: 38%, and grade 3: 22%). Following therapy, 10 patients (30%) improved and 14 (42%) had progressive disease. Patients with disease progression were often older (64 vs. 36 years, P =0.01) with higher serologic viral loads, prior history of GVHD, multifocal involvement, and increased number and density of immunoreactive nuclei. Adenovirus infection elicits a spectrum of histologic changes that can simulate or occur in combination with gastrointestinal GVHD. Patients with progressive disease are more likely to have high viral loads and more extensive infection of the gastrointestinal tract.
Collapse
Affiliation(s)
| | | | - Caroline Andy
- Population Health Sciences, Weill Cornell Medicine, New York, NY
| | | | - Rhonda K Yantiss
- Department of Pathology and Laboratory Medicine, Miller School of Medicine, University of Miami, Miami, FL
| |
Collapse
|
|
3
|
Lambert N, El Moussaoui M, Baron F, Maquet P, Darcis G. Virus-Specific T-Cell Therapy for Viral Infections of the Central Nervous System: A Review. Viruses 2023; 15:1510. [PMID: 37515196 PMCID: PMC10383098 DOI: 10.3390/v15071510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 06/29/2023] [Accepted: 07/03/2023] [Indexed: 07/30/2023] Open
Abstract
Opportunistic viral infections of the central nervous system represent a significant cause of morbidity and mortality among an increasing number of immunocompromised patients. Since antiviral treatments are usually poorly effective, the prognosis generally relies on the ability to achieve timely immune reconstitution. Hence, strategies aimed at reinvigorating antiviral immune activity have recently emerged. Among these, virus-specific T-cells are increasingly perceived as a principled and valuable tool to treat opportunistic viral infections. Here we briefly discuss how to develop and select virus-specific T-cells, then review their main indications in central nervous system infections, including progressive multifocal leukoencephalopathy, CMV infection, and adenovirus infection. We also discuss their potential interest in the treatment of progressive multiple sclerosis, or EBV-associated central nervous system inflammatory disease. We finish with the key future milestones of this promising treatment strategy.
Collapse
Affiliation(s)
- Nicolas Lambert
- Department of Neurology, University Hospital of Liège, 4000 Liège, Belgium
| | - Majdouline El Moussaoui
- Department of General Internal Medicine and Infectious Diseases, University Hospital of Liège, 4000 Liège, Belgium
| | - Frédéric Baron
- Department of Hematology, University Hospital of Liège, 4000 Liège, Belgium
| | - Pierre Maquet
- Department of Neurology, University Hospital of Liège, 4000 Liège, Belgium
| | - Gilles Darcis
- Department of General Internal Medicine and Infectious Diseases, University Hospital of Liège, 4000 Liège, Belgium
| |
Collapse
|
|
4
|
Marzaman ANF, Roska TP, Sartini S, Utami RN, Sulistiawati S, Enggi CK, Manggau MA, Rahman L, Shastri VP, Permana AD. Recent Advances in Pharmaceutical Approaches of Antimicrobial Agents for Selective Delivery in Various Administration Routes. Antibiotics (Basel) 2023; 12:822. [PMID: 37237725 PMCID: PMC10215767 DOI: 10.3390/antibiotics12050822] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 04/15/2023] [Accepted: 04/24/2023] [Indexed: 05/28/2023] Open
Abstract
Globally, the increase of pathogenic bacteria with antibiotic-resistant characteristics has become a critical challenge in medical treatment. The misuse of conventional antibiotics to treat an infectious disease often results in increased resistance and a scarcity of effective antimicrobials to be used in the future against the organisms. Here, we discuss the rise of antimicrobial resistance (AMR) and the need to combat it through the discovery of new synthetic or naturally occurring antibacterial compounds, as well as insights into the application of various drug delivery approaches delivered via various routes compared to conventional delivery systems. AMR-related infectious diseases are also discussed, as is the efficiency of various delivery systems. Future considerations in developing highly effective antimicrobial delivery devices to address antibiotic resistance are also presented here, especially on the smart delivery system of antibiotics.
Collapse
Affiliation(s)
- Ardiyah Nurul Fitri Marzaman
- Faculty of Pharmacy, Hasanuddin University, Makassar 90245, Indonesia; (A.N.F.M.); (T.P.R.); (S.S.); (R.N.U.); (S.S.); (C.K.E.); (M.A.M.); (L.R.)
| | - Tri Puspita Roska
- Faculty of Pharmacy, Hasanuddin University, Makassar 90245, Indonesia; (A.N.F.M.); (T.P.R.); (S.S.); (R.N.U.); (S.S.); (C.K.E.); (M.A.M.); (L.R.)
| | - Sartini Sartini
- Faculty of Pharmacy, Hasanuddin University, Makassar 90245, Indonesia; (A.N.F.M.); (T.P.R.); (S.S.); (R.N.U.); (S.S.); (C.K.E.); (M.A.M.); (L.R.)
| | - Rifka Nurul Utami
- Faculty of Pharmacy, Hasanuddin University, Makassar 90245, Indonesia; (A.N.F.M.); (T.P.R.); (S.S.); (R.N.U.); (S.S.); (C.K.E.); (M.A.M.); (L.R.)
| | - Sulistiawati Sulistiawati
- Faculty of Pharmacy, Hasanuddin University, Makassar 90245, Indonesia; (A.N.F.M.); (T.P.R.); (S.S.); (R.N.U.); (S.S.); (C.K.E.); (M.A.M.); (L.R.)
| | - Cindy Kristina Enggi
- Faculty of Pharmacy, Hasanuddin University, Makassar 90245, Indonesia; (A.N.F.M.); (T.P.R.); (S.S.); (R.N.U.); (S.S.); (C.K.E.); (M.A.M.); (L.R.)
| | - Marianti A. Manggau
- Faculty of Pharmacy, Hasanuddin University, Makassar 90245, Indonesia; (A.N.F.M.); (T.P.R.); (S.S.); (R.N.U.); (S.S.); (C.K.E.); (M.A.M.); (L.R.)
| | - Latifah Rahman
- Faculty of Pharmacy, Hasanuddin University, Makassar 90245, Indonesia; (A.N.F.M.); (T.P.R.); (S.S.); (R.N.U.); (S.S.); (C.K.E.); (M.A.M.); (L.R.)
| | - Venkatram Prasad Shastri
- Institute for Macromolecular Chemistry, Albert Ludwigs Universitat Freiburg, 79085 Freiburg, Germany;
| | - Andi Dian Permana
- Faculty of Pharmacy, Hasanuddin University, Makassar 90245, Indonesia; (A.N.F.M.); (T.P.R.); (S.S.); (R.N.U.); (S.S.); (C.K.E.); (M.A.M.); (L.R.)
| |
Collapse
|
|
5
|
Adenovirus Enterocolitis in Hematopoietic Stem Cell Transplant Patients. INFECTIOUS DISEASES IN CLINICAL PRACTICE 2023. [DOI: 10.1097/ipc.0000000000001203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
|
|
6
|
Inamoto Y, Takeda W, Hirakawa T, Sakaguchi H, Nakano N, Uchida N, Doki N, Ikegame K, Katayama Y, Sawa M, Kuriyama T, Hiramoto N, Ota S, Ozawa Y, Kataoka K, Kanda Y, Hino M, Kimura T, Atsuta Y, Fukuda T, Nagafuji K. Adenovirus disease after hematopoietic cell transplantation: A Japanese transplant registry analysis. Am J Hematol 2022; 97:1568-1579. [PMID: 36087061 DOI: 10.1002/ajh.26723] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 08/23/2022] [Accepted: 09/02/2022] [Indexed: 01/31/2023]
Abstract
We analyzed a Japanese registry database to elucidate the incidence, risk factors, and outcomes of adenovirus (AdV) disease after autologous and allogeneic hematopoietic cell transplantation (HCT) in contemporary real-world patients. We evaluated the cumulative incidence of AdV disease, as well as risk factors, survival, and treatment details, among 25 233 patients who underwent autologous HCT and 48 380 patients who underwent allogeneic HCT between 2005 and 2019. The 1-year cumulative incidences of AdV disease after autologous and allogeneic HCT were 0.18% and 1.52%, respectively, in children, and 0.49% and 2.99%, respectively, in adults. Among patients with AdV disease, renourinary infection was the most common manifestation, and viremia or disseminated disease occurred in 6% of those after autologous HCT and 19% of those after allogeneic HCT. In multivariate analysis, age ≥50 years and lymphoma were associated with AdV disease after autologous HCT, while patients age ≥50 years, male patients, lymphoma, HCT-specific comorbidity index ≥3, human leukocyte antigen-mismatched or haploidentical donors, cord blood, in vivo T-cell depletion, HCT from 2005 to 2009, acute graft-versus-host disease (GVHD), and chronic GVHD were associated with AdV disease after allogeneic HCT. The 1-year probabilities of survival after disease diagnosis were 65% in autologous HCT and 44% in allogeneic HCT. Regardless of the AdV disease burden, there was an increased risk of mortality after both autologous and allogeneic HCT. The most commonly used antiviral agents were cidofovir and vidarabine. The probabilities of improvement and survival with currently available agents were suboptimal. AdV disease after HCT remains a challenge. Better antiviral modalities are necessary.
Collapse
Affiliation(s)
- Yoshihiro Inamoto
- Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan
| | - Wataru Takeda
- Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan
| | | | - Hirotoshi Sakaguchi
- Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan
| | - Nobuaki Nakano
- Department of Hematology, Imamura General Hospital, Kagoshima, Japan
| | - Naoyuki Uchida
- Department of Hematology, Toranomon Hospital, Tokyo, Japan
| | - Noriko Doki
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
| | - Kazuhiro Ikegame
- Department of Hematology, Hyogo Medical University Hospital, Nishinomiya, Japan
| | - Yuta Katayama
- Department of Hematology, Hiroshima Red Cross Hospital & Atomic-Bomb Survivors Hospital, Hiroshima, Japan
| | - Masashi Sawa
- Department of Hematology and Oncology, Anjo Kosei Hospital, Anjo, Japan
| | - Takuro Kuriyama
- Department of Hematology, Hamanomachi Hospital, Fukuoka, Japan
| | - Nobuhiro Hiramoto
- Department of Hematology, Kobe City Medical Center General Hospital, Kobe, Japan
| | - Shuichi Ota
- Department of Hematology, Sapporo Hokuyu Hospital, Sapporo, Japan
| | - Yukiyasu Ozawa
- Department of Hematology, Japanese Red Cross Aichi Medical Center Nagoya Daiichi Hospital, Nagoya, Japan
| | - Keisuke Kataoka
- Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.,Division of Molecular Oncology, National Cancer Center Research Institute, Tokyo, Japan
| | - Yoshinobu Kanda
- Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan
| | - Moeko Hino
- Department of Pediatrics, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Takafumi Kimura
- Preparation Department, Japanese Red Cross Kinki Block Blood Center, Osaka, Japan
| | - Yoshiko Atsuta
- Japanese Data Center for Hematopoietic Cell Transplantation, Nagakute, Japan.,Department of Registry Science for Transplant and Cellular Therapy, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Takahiro Fukuda
- Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan
| | - Koji Nagafuji
- Department of Hematology and Oncology, Kurume University School of Medicine, Kurume, Japan
| |
Collapse
|
|
7
|
Mouse Adenovirus Type 1 Persistence Exacerbates Inflammation Induced by Allogeneic Bone Marrow Transplantation. J Virol 2022; 96:e0170621. [PMID: 35045262 DOI: 10.1128/jvi.01706-21] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Bone marrow transplantation (BMT) recipients are at risk for substantial morbidity and mortality from human adenovirus infections, often in the setting of reactivation of persistent virus. Human adenovirus persistence in mucosal lymphocytes has been described, but specific cellular reservoirs of persistence and effects of persistence on host responses to unrelated stimuli are not completely understood. We used mouse adenovirus type 1 (MAV-1) to characterize persistence of an adenovirus in its natural host and test the hypothesis that persistence increases complications of bone marrow transplantation (BMT). Following intranasal infection of C57BL/6J mice, MAV-1 DNA was detected in lung, mediastinal lymph nodes, and liver during acute infection at 7 days post infection (dpi), and at lower levels at 28 dpi that remained stable through 150 dpi. Expression of early and late viral transcripts was detected in those organs at 7 dpi but not at later time points. MAV-1 persistence was not affected by deficiency of IFN-γ. We detected no evidence of MAV-1 reactivation in vivo following allogeneic BMT of persistently infected mice. Persistent infection did not substantially affect mortality, weight loss, or pulmonary inflammation following BMT. However, T cell infiltration and increased expression of pro-inflammatory cytokines consistent with graft-versus-host disease (GVHD) were more pronounced in livers of persistently infected BMT mice than in uninfected BMT mice. These results suggest that MAV-1 persists in multiple sites without detectable evidence of ongoing replication. Our results indicate that MAV-1 persistence alters host responses to an unrelated challenge, even in the absence of detectable reactivation. Importance Long-term persistence in an infected host is an essential step in the life cycle of DNA viruses. Adenoviruses persist in their host following acute infection, but the nature of adenovirus persistence remains incompletely understood. Following intranasal infection of mice, we found that MAV-1 persists for a prolonged period in multiple organs, although we did not detect evidence of ongoing replication. Because BMT recipients are at risk for substantial morbidity and mortality from human adenovirus infections, often in the setting of reactivation of persistent virus in the recipient, we extended our findings using MAV-1 infection in a mouse model of BMT. MAV-1 persistence exacerbated GVHD-like inflammation following allogeneic BMT, even in the absence of virus reactivation. This novel finding suggests that adenovirus persistence has consequences, and it highlights the potential for a persistent adenovirus to influence host responses to unrelated challenges.
Collapse
|
|
8
|
Chandorkar A, Anderson AD, Morris MI, Natori Y, Jimenez A, Komanduri KV, Camargo JF. Viral kinetics and outcomes of adenovirus viremia following allogeneic hematopoietic cell transplantation. Clin Transplant 2021; 35:e14481. [PMID: 34516017 DOI: 10.1111/ctr.14481] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 08/30/2021] [Accepted: 09/07/2021] [Indexed: 11/29/2022]
Abstract
BACKGROUND Adenovirus (AdV) is a serious infection following hematopoietic cell transplantation (HCT). Little is known about AdV viral kinetics and optimal threshold for initiation of pre-emptive therapy. METHODS Single-center retrospective study of 16 consecutive adult HCT recipients with detectable AdV identified over a 5-year period. RESULTS Median time to AdV reactivation after HCT was 176 days (IQR 86-408). Nine patients received cidofovir, although 14/16 had no tissue-invasive disease. Among treated patients, median duration of viremia was shorter when initiating treatment at viral loads < 10,000 copies/ml (28 vs. 52 days). All-cause mortality in this cohort was 44%. All six patients (five of which were untreated) with peak viral loads < 10,000 copies/ml survived; whereas only 30% (3/10) of patients with peak viral loads greater than this threshold survived, despite most (n = 8; 80%) of them receiving cidofovir (P = .01). Three-month survival following diagnosis of AdV viremia was significantly lower with peak viremia > 10,000 copies/ml (100 vs. 17%; P = .005). CONCLUSION AdV is associated with high all-cause mortality, especially for viremia > 10,000 copies/ml. Delaying therapy until viremia reaches AdV levels ≥10,000 copies/ml was associated with more protracted infection and poor outcomes. Larger studies are needed.
Collapse
Affiliation(s)
- Aditya Chandorkar
- Division of Infectious Diseases and International Medicine, University of Minnesota, Minneapolis, Minnesota, USA
| | - Anthony D Anderson
- Department of Pharmacy, Sylvester Comprehensive Cancer Center, Miami, Florida, USA
| | - Michele I Morris
- Immunocompromised Host Service, Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Yoichiro Natori
- Department of Pharmacy, Sylvester Comprehensive Cancer Center, Miami, Florida, USA.,Division of Infectious Diseases, Miami Transplant Institute, Jackson Health System, Miami, Florida, USA
| | - Antonio Jimenez
- Division of Transplantation and Cellular Therapy, Sylvester Comprehensive Cancer Center, Miami, Florida, USA
| | - Krishna V Komanduri
- Division of Transplantation and Cellular Therapy, Sylvester Comprehensive Cancer Center, Miami, Florida, USA
| | - Jose F Camargo
- Department of Pharmacy, Sylvester Comprehensive Cancer Center, Miami, Florida, USA
| |
Collapse
|
|
9
|
Wang X, Patel SA, Haddadin M, Cerny J. Post-allogeneic hematopoietic stem cell transplantation viral reactivations and viremias: a focused review on human herpesvirus-6, BK virus and adenovirus. Ther Adv Infect Dis 2021; 8:20499361211018027. [PMID: 34104434 PMCID: PMC8155777 DOI: 10.1177/20499361211018027] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 04/27/2021] [Indexed: 12/30/2022] Open
Abstract
Human cytomegalovirus and Epstein-Barr virus have been recognized as potential drivers of morbidity and mortality of patients undergoing allogeneic stem cell transplantation for years. Specific protocols for monitoring, prophylaxis and pre-emptive therapy are in place in many transplant settings. In this review, we focus on the next three most frequent viruses, human herpesvirus-6, BK virus and adenovirus, causing reactivation and/or viremia after allogeneic transplant, which are increasingly detected in patients in the post-transplant period owing to emerging techniques of molecular biology, recipients' characteristics, treatment modalities used for conditioning and factors related donors or stem cell source. Given the less frequent detection of an illness related to these viruses, there are often no specific protocols in place for the management of affected patients. While some patients develop significant morbidity (generally older), others may not need therapy at all (generally younger or children). Furthermore, some of the antiviral therapies used are potentially toxic. With the addition of increased risk of secondary infections, risk of graft failure or increased risk of graft-versus-host disease as well as the relationship with other post-transplant complications, the outcomes of patients with these viremias remain unsatisfactory and even long-term survivors experience increased morbidity.
Collapse
Affiliation(s)
- Xin Wang
- Department of Medicine, UMass Memorial Medical Center, Worcester, MA, USA
| | - Shyam A Patel
- Division of Hematology-Oncology, Department of Medicine, UMass Memorial Medical Center, Worcester, MA, USA
| | - Michael Haddadin
- Division of Hematology-Oncology, Department of Medicine, UMass Memorial Medical Center, Worcester, MA, USA
| | - Jan Cerny
- Division of Hematology and Oncology, Department of Medicine, UMass Memorial Medical Center, 55 Lake Avenue North, Worcester, MA, 01655, USA
| |
Collapse
|
|
10
|
Garnica M, Pierrotti LC, Oliveira PVD, Mazzi M, Chebabo A. Metagenomic next-generation sequencing (mNGS) for diagnostically challenging infectious diseases in patients with acute leukemia. Braz J Infect Dis 2021; 25:101548. [PMID: 33639095 PMCID: PMC9392121 DOI: 10.1016/j.bjid.2021.101548] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 01/26/2021] [Accepted: 02/04/2021] [Indexed: 11/10/2022] Open
Abstract
This report shows the contribution of next-generation metagenomic sequencing (mNGS) as an alternative to challenging diagnostic infection in immunosuppressed individuals. Herein, we report three acute leukemia patients who developed severe invasive infections due to different etiologies: fungi, viruses, and protozoa. mNGS improved the diagnosis of the infections and provided the opportunity for adequate therapy. The mNGS is a hypothesis-free diagnostic platform, increasing potential in challenging diseases in hematological patients due to the extended diagnostic panel and the expedite access to the result.
Collapse
Affiliation(s)
- Marcia Garnica
- Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Complexo Hospitalar de Niterói, Niterói, RJ, Brazil.
| | - Ligia Camera Pierrotti
- Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil; Laboratório Dasa, São Paulo, SP, Brazil
| | | | | | - Alberto Chebabo
- Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Laboratório Dasa, São Paulo, SP, Brazil
| |
Collapse
|
|
11
|
Beyond Cytomegalovirus and Epstein-Barr Virus: a Review of Viruses Composing the Blood Virome of Solid Organ Transplant and Hematopoietic Stem Cell Transplant Recipients. Clin Microbiol Rev 2020; 33:33/4/e00027-20. [PMID: 32847820 DOI: 10.1128/cmr.00027-20] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Viral primary infections and reactivations are common complications in patients after solid organ transplantation (SOT) and hematopoietic stem cell transplantation (HSCT) and are associated with high morbidity and mortality. Among these patients, viral infections are frequently associated with viremia. Beyond the usual well-known viruses that are part of the routine clinical management of transplant recipients, numerous other viral signatures or genomes can be identified in the blood of these patients. The identification of novel viral species and variants by metagenomic next-generation sequencing has opened up a new field of investigation and new paradigms. Thus, there is a need to thoroughly describe the state of knowledge in this field with a review of all viral infections that should be scrutinized in high-risk populations. Here, we review the eukaryotic DNA and RNA viruses identified in blood, plasma, or serum samples of pediatric and adult SOT/HSCT recipients and the prevalence of their detection, with a particular focus on recently identified viruses and those for which their potential association with disease remains to be investigated, such as members of the Polyomaviridae, Anelloviridae, Flaviviridae, and Astroviridae families. Current knowledge of the clinical significance of these viral infections with associated viremia among transplant recipients is also discussed. To ensure a comprehensive description in these two populations, individuals described as healthy (mostly blood donors) are considered for comparative purposes. The list of viruses that should be on the clinicians' radar is certainly incomplete and will expand, but the challenge is to identify those of possible clinical significance.
Collapse
|
|
12
|
Papanicolaou GA, Dvorak CC, Dadwal S, Maron G, Prasad VK, Giller R, Abdel-Azim H, Sadanand A, Casciano R, Chandak A, Huang S, Nichols G, Brundage T, Vainorius E, Mozaffari E, Hutcheson R. Practice patterns and incidence of adenovirus infection in allogeneic hematopoietic cell transplant recipients: Multicenter survey of transplant centers in the United States. Transpl Infect Dis 2020; 22:e13283. [PMID: 32267590 DOI: 10.1111/tid.13283] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 03/10/2020] [Accepted: 03/22/2020] [Indexed: 01/23/2023]
Abstract
BACKGROUND Adenovirus (AdV) is increasingly recognized as a threat to successful outcomes after allogeneic hematopoietic cell transplantation (allo-HCT). Guidelines have been developed to inform AdV screening and treatment practices, but the extent to which they are followed in clinical practice in the United States is still unknown. The incidence of AdV in the United States is also not well documented. The main objectives of the AdVance US study were thus to characterize current AdV screening and treatment practices in the United States and to estimate the incidence of AdV infection in allo-HCT recipients across multiple pediatric and adult transplant centers. METHODS Fifteen pediatric centers and 6 adult centers completed a practice patterns survey, and 15 pediatric centers and four adult centers completed an incidence survey. RESULTS The practice patterns survey results confirm that pediatric transplant centers are more likely than adult centers to routinely screen for AdV, and are also more likely to have a preemptive AdV treatment approach compared to adult centers. Perceived risk of AdV infection is a determining factor for whether routine screening and preemptive treatment are implemented. Most pediatric centers screen higher-risk patients for AdV weekly, in blood, and have a preemptive AdV treatment approach. The incidence survey results show that from 2015 to 2017, a total of 1230 patients underwent an allo-HCT at the 15 pediatric transplant centers, and 1815 patients underwent an allo-HCT at the 4 adult transplant centers. The incidences of AdV infection, AdV viremia, and AdV viremia ≥ 1000 copies/mL within 6 months after the first allo-HCT were 23%, 16%, and 9%, respectively, for patients at pediatric centers, and 5%, 3%, and 2%, respectively, for patients at adult centers. CONCLUSIONS These findings provide a more recent estimate of the incidence of AdV infection in the United States, as well as a multicenter view of practice patterns around AdV infection screening and intervention criteria, in pediatric and adult allo-HCT recipients.
Collapse
Affiliation(s)
| | | | | | - Gabriela Maron
- St Jude Children's Research Hospital Infectious Diseases Department, Memphis, TN, USA
| | - Vinod K Prasad
- Duke University Medical Center Department of Pediatrics, Durham, NC, USA
| | - Roger Giller
- Bone Marrow Transplant and Cellular Therapeutic Program, Children's Hospital Colorado and University of Colorado School of Medicine, Aurora, CO, USA
| | - Hisham Abdel-Azim
- Division of Hematology, Oncology and Blood & Marrow Transplantation, Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA, USA
| | - Arhanti Sadanand
- Emory University Children's Healthcare of Atlanta, Atlanta, GA, USA
| | | | | | | | | | | | | | | | | |
Collapse
|
|
13
|
Santos CAQ, Rhee Y, Czapka MT, Kazi AS, Proia LA. Make Sure You Have a Safety Net: Updates in the Prevention and Management of Infectious Complications in Stem Cell Transplant Recipients. J Clin Med 2020; 9:jcm9030865. [PMID: 32245201 PMCID: PMC7141503 DOI: 10.3390/jcm9030865] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 03/11/2020] [Indexed: 12/11/2022] Open
Abstract
Hematopoietic stem cell transplant recipients are at increased risk of infection and immune dysregulation due to reception of cytotoxic chemotherapy; development of graft versus host disease, which necessitates treatment with immunosuppressive medications; and placement of invasive catheters. The prevention and management of infections in these vulnerable hosts is of utmost importance and a key “safety net” in stem cell transplantation. In this review, we provide updates on the prevention and management of CMV infection; invasive fungal infections; bacterial infections; Clostridium difficile infection; and EBV, HHV-6, adenovirus and BK infections. We discuss novel drugs, such as letermovir, isavuconazole, meropenem-vaborbactam and bezlotoxumab; weigh the pros and cons of using fluoroquinolone prophylaxis during neutropenia after stem cell transplantation; and provide updates on important viral infections after hematopoietic stem cell transplant (HSCT). Optimizing the prevention and management of infectious diseases by using the best available evidence will contribute to better outcomes for stem cell transplant recipients, and provide the best possible “safety net” for these immunocompromised hosts.
Collapse
|
|
14
|
Generation and infusion of multi-antigen-specific T cells to prevent complications early after T-cell depleted allogeneic stem cell transplantation—a phase I/II study. Leukemia 2019; 34:831-844. [DOI: 10.1038/s41375-019-0600-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 08/21/2019] [Accepted: 08/27/2019] [Indexed: 12/11/2022]
|
|
15
|
Zeng X, Carlin CR. Adenovirus early region 3 RIDα protein limits NFκB signaling through stress-activated EGF receptors. PLoS Pathog 2019; 15:e1008017. [PMID: 31425554 PMCID: PMC6715251 DOI: 10.1371/journal.ppat.1008017] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Revised: 08/29/2019] [Accepted: 08/02/2019] [Indexed: 12/18/2022] Open
Abstract
The host limits adenovirus infections by mobilizing immune systems directed against infected cells that also represent major barriers to clinical use of adenoviral vectors. Adenovirus early transcription units encode a number of products capable of thwarting antiviral immune responses by co-opting host cell pathways. Although the EGF receptor (EGFR) was a known target for the early region 3 (E3) RIDα protein encoded by nonpathogenic group C adenoviruses, the functional role of this host-pathogen interaction was unknown. Here we report that incoming viral particles triggered a robust, stress-induced pathway of EGFR trafficking and signaling prior to viral gene expression in epithelial target cells. EGFRs activated by stress of adenoviral infection regulated signaling by the NFκB family of transcription factors, which is known to have a critical role in the host innate immune response to infectious adenoviruses and adenovirus vectors. We found that the NFκB p65 subunit was phosphorylated at Thr254, shown previously by other investigators to be associated with enhanced nuclear stability and gene transcription, by a mechanism that was attributable to ligand-independent EGFR tyrosine kinase activity. Our results indicated that the adenoviral RIDα protein terminated this pathway by co-opting the host adaptor protein Alix required for sorting stress-exposed EGFRs in multivesicular endosomes, and promoting endosome-lysosome fusion independent of the small GTPase Rab7, in infected cells. Furthermore RIDα expression was sufficient to down-regulate the same EGFR/NFκB signaling axis in a previously characterized stress-activated EGFR trafficking pathway induced by treatment with the pro-inflammatory cytokine TNF-α. We also found that cell stress activated additional EGFR signaling cascades through the Gab1 adaptor protein that may have unappreciated roles in the adenoviral life cycle. Similar to other E3 proteins, RIDα is not conserved in adenovirus serotypes associated with potentially severe disease, suggesting stress-activated EGFR signaling may contribute to adenovirus virulence.
Collapse
Affiliation(s)
- Xuehuo Zeng
- Department of Molecular Biology and Microbiology, School of Medicine, Case Western Reserve University, Cleveland, United States of America
| | - Cathleen R. Carlin
- Department of Molecular Biology and Microbiology, School of Medicine, Case Western Reserve University, Cleveland, United States of America
- Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, United States of America
| |
Collapse
|
|
16
|
Ali S, Krueger J, Richardson SE, Sung L, Waespe N, Renzi S, Chiang K, Allen U, Ali M, Schechter T. The yield of monitoring adenovirus in pediatric hematopoietic stem cell transplant patients. Pediatr Hematol Oncol 2019; 36:161-172. [PMID: 31037986 DOI: 10.1080/08880018.2019.1607961] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Human adenovirus (HAdV) is recognized as a serious pathogen after allogeneic hematopoietic stem cell transplantation (HSCT), causing morbidity and mortality. Currently, there is no universal agreement regarding routine HAdV surveillance after HSCT. We assessed the impact of HAdV weekly monitoring by polymerase chain reaction (PCR) on HAdV viremia rates and the risk factors that influence survival. Three-hundred and fifty-six pediatric allogeneic HSCT were done between 2007 and 2015. Until July 2011, HAdV testing was performed based on clinical suspicion (cohort 1, n = 175) and from August 2011, weekly blood-HAdV monitoring was done (cohort 2, n = 181) until day +100. Twenty-three patients (4 [2.3%] from cohort 1 and 19 [10.5%] from cohort 2, p = .001) were found with HAdV viremia and seven of them died. Both cohorts had a similar incidence of HAdV-associated mortality (3/175; 1.7% in cohort 1 and 4/181; 2.2% in cohort 2). Respiratory failure was the cause of death in all patients. Clinical symptoms appeared prior to or within 5 days of HAdV detection in cohort 2. In summary, weekly monitoring was associated with higher detection of HAdV. The study could not assess survival benefit due to small numbers of HAdV-positive cases. In many instances, symptoms occurred with the development of positive HAdV blood PCR results and hence, symptomatology could have triggered the test. Future studies are needed to provide data that help establishing a uniform approach for regular monitoring of HAdV post-transplant.
Collapse
Affiliation(s)
- Salah Ali
- a Division of Hematology/Oncology/BMT , The Hospital for Sick Children , Toronto , Ontario , Canada
| | - Joerg Krueger
- a Division of Hematology/Oncology/BMT , The Hospital for Sick Children , Toronto , Ontario , Canada.,b Department of Paediatrics , University of Toronto , Toronto , Ontario , Canada
| | - Susan E Richardson
- b Department of Paediatrics , University of Toronto , Toronto , Ontario , Canada.,c Department of Pediatric Laboratory Medicine , The Hospital for Sick Children , Toronto , Ontario , Canada
| | - Lillian Sung
- a Division of Hematology/Oncology/BMT , The Hospital for Sick Children , Toronto , Ontario , Canada.,b Department of Paediatrics , University of Toronto , Toronto , Ontario , Canada
| | - Nicolas Waespe
- a Division of Hematology/Oncology/BMT , The Hospital for Sick Children , Toronto , Ontario , Canada.,d Swiss Childhood Cancer Registry , Institute of Social and Preventive Medicine , University of Bern , Switzerland.,e CANSEARCH Research Laboratory, Department of Pediatrics , Faculty of Medicine , University of Geneva , Switzerland
| | - Samuele Renzi
- a Division of Hematology/Oncology/BMT , The Hospital for Sick Children , Toronto , Ontario , Canada
| | - Ky Chiang
- a Division of Hematology/Oncology/BMT , The Hospital for Sick Children , Toronto , Ontario , Canada.,b Department of Paediatrics , University of Toronto , Toronto , Ontario , Canada
| | - Upton Allen
- b Department of Paediatrics , University of Toronto , Toronto , Ontario , Canada.,f Division of Infectious Diseases, Department of Pediatrics , The Hospital for Sick Children , Toronto , Ontario , Canada
| | - Muhammad Ali
- a Division of Hematology/Oncology/BMT , The Hospital for Sick Children , Toronto , Ontario , Canada.,b Department of Paediatrics , University of Toronto , Toronto , Ontario , Canada
| | - Tal Schechter
- a Division of Hematology/Oncology/BMT , The Hospital for Sick Children , Toronto , Ontario , Canada.,b Department of Paediatrics , University of Toronto , Toronto , Ontario , Canada
| |
Collapse
|
|
17
|
Noroozi-aghideh A, Kheirandish M. Human cord blood-derived viral pathogens as the potential threats to the hematopoietic stem cell transplantation safety: A mini review. World J Stem Cells 2019; 11:73-83. [PMID: 30842806 PMCID: PMC6397803 DOI: 10.4252/wjsc.v11.i2.73] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 01/14/2019] [Accepted: 01/26/2019] [Indexed: 02/06/2023] Open
Abstract
Umbilical cord blood (UCB) is a valuable source of hematopoietic stem cells (HSCs) and potential alternative for bone marrow transplantation for patients who lack human leukocyte antigen (HLA)-matched donors. The main practical advantages of UCB over other HSC sources are the immediate availability, lower incidence of graft-versus-host disease, minimal risk to the donor, and lower requirement for HLA compatibility. However, the use of UCB is limited by delayed engraftment and poor immune reconstitution, leading to a high rate of infection-related mortality. Therefore, severe infectious complications, especially due to viral pathogens remain the leading cause of morbidity and mortality during the post-UCB transplantation (UCBT) period. In this context, careful screening and excluding the viral-contaminated UCB units might be an effective policy to reduce the rate of UCBT-related infection and mortality. Taken together, complete prevention of the transmission of donor-derived viral pathogens in stem cell transplantation is not possible. However, having the knowledge of the transmission route and prevalence of viruses will improve the safety of transplantation. To the best of our knowledge, there are few studies that focused on the risk of virus transmission through the UCB transplant compared to other HSC sources. This review summarizes the general aspects concerning the prevalence, characteristics, and risk factors of viral infections with a focus on the impact of viral pathogens on cord blood transplantation safety.
Collapse
Affiliation(s)
- Ali Noroozi-aghideh
- Department of Hematology, Faculty of Paramedicine, Aja University of Medical Sciences, Tehran 14665-1157, Iran
| | - Maryam Kheirandish
- Immunology Department, Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine (IBTO), Tehran 14665-1157, Iran
| |
Collapse
|
|
18
|
Association between adenovirus viral load and mortality in pediatric allo-HCT recipients: the multinational AdVance study. Bone Marrow Transplant 2019; 54:1632-1642. [PMID: 30804489 PMCID: PMC6957460 DOI: 10.1038/s41409-019-0483-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 01/24/2019] [Accepted: 02/09/2019] [Indexed: 02/06/2023]
Abstract
This multivariable analysis from the AdVance multicenter observational study assessed adenovirus (AdV) viremia peak, duration, and overall AdV viral burden-measured as time-averaged area under the viremia curve over 16 weeks (AAUC0-16)-as predictors of all-cause mortality in pediatric allo-HCT recipients with AdV viremia. In the 6 months following allo-HCT, 241 patients had AdV viremia ≥ 1000 copies/ml. Among these, 18% (43/241) died within 6 months of first AdV ≥ 1000 copies/ml. Measures of AdV viral peak, duration, and overall burden of infection consistently correlate with all-cause mortality. In multivariable analyses, controlling for lymphocyte recovery, patients with AdV AAUC0-16 in the highest quartile had a hazard ratio of 11.1 versus the lowest quartile (confidence interval 5.3-23.6); for peak AdV viremia, the hazard ratio was 2.2 for the highest versus lowest quartile. Both the peak level and duration of AdV viremia were correlated with short-term mortality, independent of other known risk factors for AdV-related mortality, such as lymphocyte recovery. AdV AAUC0-16, which assesses both peak and duration of AdV viremia, is highly correlated with mortality under the current standard of care. New therapeutic agents that decrease AdV AAUC0-16 have the potential of reducing mortality in this at-risk patient population.
Collapse
|
|
19
|
Kaeuferle T, Krauss R, Blaeschke F, Willier S, Feuchtinger T. Strategies of adoptive T -cell transfer to treat refractory viral infections post allogeneic stem cell transplantation. J Hematol Oncol 2019; 12:13. [PMID: 30728058 PMCID: PMC6364410 DOI: 10.1186/s13045-019-0701-1] [Citation(s) in RCA: 97] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Accepted: 01/22/2019] [Indexed: 01/13/2023] Open
Abstract
Background Allogeneic hematopoietic stem cell transplantation (HSCT) can expose patients to a transient but marked immunosuppression, during which viral infections are an important cause of morbidity and mortality. Adoptive transfer of virus-specific T cells is an attractive approach to restore protective T -cell immunity in patients with refractory viral infections after allogeneic HSCT. Objectives This narrative review summarizes clinical evidence and developments of almost 30 years of adoptive T -cell transfer. The review is based on evidence extracted from PubMed searches and the clinical and experimental work of the authors. Content Viral infections after HSCT are frequently caused by the endogenous reactivation of persistent pathogens such as cytomegalovirus (CMV), Epstein-Barr virus (EBV), and adenovirus (AdV). Current antiviral medication is not satisfactory and does not treat the underlying pathophysiology which is the lack of specific T -cell immunity. Adoptive transfer of virus-specific T cells could be a potentially curative, pathogen-specific, and non-toxic treatment providing long-term immunity against the virus. The isolation of virus-specific T cells from a healthy donor and infusion into a recipient is known as adoptive T -cell transfer and has been performed in many patients using different treatment protocols. Based on basic research, new isolation protocols aim at a safe and fast availability of cellular products for adoptive T -cell transfer. We summarize preclinical and clinical data on each of the main pathogens and on the technical approaches currently available to target either single antigens or even multiple pathogens. Conclusion Cellular therapy is considered as one of the major recent breakthroughs in medicine. Translation of this individualized treatment into first-line clinical routine is still limited. Main hurdles are availability of the technique, limited compatibility of classical phase III designs with cellular therapy, and regulatory restrictions. Multinational efforts are required to clarify the status of cellular treatment in first-line clinical routine with the overall objective to strengthen evidence-based treatment guidelines for the treatment of refractory viral infections post HSCT.
Collapse
Affiliation(s)
- Theresa Kaeuferle
- Department of Pediatric Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Dr. von Hauner University Children's Hospital, Ludwig Maximilian University Munich, Lindwurmstrasse 4, 80337, Munich, Germany
| | - Ramona Krauss
- Department of Pediatric Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Dr. von Hauner University Children's Hospital, Ludwig Maximilian University Munich, Lindwurmstrasse 4, 80337, Munich, Germany
| | - Franziska Blaeschke
- Department of Pediatric Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Dr. von Hauner University Children's Hospital, Ludwig Maximilian University Munich, Lindwurmstrasse 4, 80337, Munich, Germany
| | - Semjon Willier
- Department of Pediatric Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Dr. von Hauner University Children's Hospital, Ludwig Maximilian University Munich, Lindwurmstrasse 4, 80337, Munich, Germany
| | - Tobias Feuchtinger
- Department of Pediatric Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Dr. von Hauner University Children's Hospital, Ludwig Maximilian University Munich, Lindwurmstrasse 4, 80337, Munich, Germany. .,German Center for Infection Research (DZIF), Munich, Germany.
| |
Collapse
|
|
20
|
Yasuda S, Najima Y, Konishi T, Yamada Y, Takezaki T, Kurosawa S, Sakaguchi M, Harada K, Yoshioka K, Igarashi A, Inamoto K, Toya T, Kobayashi T, Doki N, Kakihana K, Sakamaki H, Sekiya N, Ohashi K. Disseminated adenovirus infection in a patient with relapsed refractory multiple myeloma undergoing autologous stem cell transplantation and pomalidomide/dexamethasone as salvage regimens. J Infect Chemother 2019; 25:371-375. [PMID: 30642772 DOI: 10.1016/j.jiac.2018.11.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Revised: 11/16/2018] [Accepted: 11/29/2018] [Indexed: 01/29/2023]
Abstract
BACKGROUND Disseminated adenovirus (ADV) infection is a fatal complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), however, it is rare following autologous peripheral blood stem cell transplantation (auto-PBSCT) or chemotherapy alone. CASE A 66-year-old Japanese female with relapsed and refractory multiple myeloma (RRMM) received auto-PBSCT, achieving partial response. To obtain a greater response, pomalidomide/dexamethasone was started on day 28 after auto-PBSCT, but was stopped on day 41 due to thrombocytopenia, fever, and gross hematuria. Additionally, she complained of abdominal pain on day 46. Blood tests revealed elevation of transaminases and alkaline phosphatase. There was no evidence of bacterial or fungal infections or progression of MM. ADV titer in urine and serum were 3.41 × 105 copies/mL and 6.76 × 103 copies/mL, respectively. CT scans revealed cystitis, urethritis, and peritonitis. Since more than two organs were infected with ADV, she was diagnosed with disseminated ADV disease. After 5 weeks of supportive care, all symptoms resolved. ADV titer decreased to 5.90 × 102 copies/mL in urine and became negative in serum on day 80. However, she succumbed to the MM a little more than a month later. CONCLUSION Disseminated ADV infection can occur even in non-allogeneic transplant settings, such as in severely immunocompromised patients with MM who receive auto-PBSCT and repeated salvage therapies. Although it is a rare event, the mortality rate of this disease is very high, and hence, early diagnosis and interventions are needed in suspected cases.
Collapse
Affiliation(s)
- Shunichiro Yasuda
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan
| | - Yuho Najima
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan.
| | - Tatsuya Konishi
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan
| | - Yuta Yamada
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan
| | - Toshiaki Takezaki
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan
| | - Shuhei Kurosawa
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan
| | - Masahiro Sakaguchi
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan
| | - Kaito Harada
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan
| | - Kosuke Yoshioka
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan
| | - Aiko Igarashi
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan
| | - Kyoko Inamoto
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan
| | - Takashi Toya
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan
| | - Takeshi Kobayashi
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan
| | - Noriko Doki
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan
| | - Kazuhiko Kakihana
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan
| | - Hisashi Sakamaki
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan
| | - Noritaka Sekiya
- Department of Infection Prevention and Control, Department of Clinical Laboratory, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan
| | - Kazuteru Ohashi
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan
| |
Collapse
|
|
21
|
González-Vicent M, Verna M, Pochon C, Chandak A, Vainorius E, Brundage T, Mozaffari E, Nichols G, Rao K. Current practices in the management of adenovirus infection in allogeneic hematopoietic stem cell transplant recipients in Europe: The AdVance study. Eur J Haematol 2019; 102:210-217. [PMID: 30418684 PMCID: PMC6850370 DOI: 10.1111/ejh.13194] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 10/31/2018] [Accepted: 11/02/2018] [Indexed: 02/03/2023]
Abstract
Objective Adenovirus (AdV) infections are potentially life‐threatening for allogeneic hematopoietic stem cell transplant (allo‐HCT) recipients. The AdVance study aimed to evaluate the incidence, management, and outcomes of AdV infections in European allo‐HCT recipients. Methods As part of the study, physician surveys were conducted to determine current AdV screening and treatment practices at their center. Results All of the 28 respondents who treat pediatric patients reported routine AdV screening practices, with 93% screening all allo‐HCT recipients and others screening those with transplant‐related risk factors. Nearly all centers take a pre‐emptive approach to AdV treatment in both high‐ (89%) and low‐risk patients (75%). Among the 14 respondents who treat adult patients, 5 (36%) reported routine screening practices and few (21%) screen all allo‐HCT recipients unless risk factors are present. In adults, pre‐emptive AdV treatment is uncommon and quantitative AdV thresholds are rare. Typical treatment for all patients with symptomatic AdV infection is off‐label intravenous cidofovir. Conclusions Our findings confirm that screening for AdV is more common in pediatric patients. Antiviral treatment is employed in both pediatric and adult patients, although adults are generally treated when AdV disease is diagnosed. The approach to AdV screening and treatment is risk‐based and consistent with clinical guidelines.
Collapse
Affiliation(s)
| | - Marta Verna
- Pediatric Hematology, MBBM Foundation, Monza, Italy
| | - Cécile Pochon
- Allogeneic Hematopoietic Stem Cell Transplantation Unit, Department of Pediatric Oncohematology, University Hospital of Nancy, Vandoeuvre-lès-Nancy, France
| | | | | | | | | | | | - Kanchan Rao
- Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK
| |
Collapse
|
|
22
|
Impacts and Challenges of Advanced Diagnostic Assays for Transplant Infectious Diseases. PRINCIPLES AND PRACTICE OF TRANSPLANT INFECTIOUS DISEASES 2019. [PMCID: PMC7121269 DOI: 10.1007/978-1-4939-9034-4_47] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The advanced technologies described in this chapter should allow for full inventories to be made of bacterial genes, their time- and place-dependent expression, and the resulting proteins as well as their outcome metabolites. The evolution of these molecular technologies will continue, not only in the microbial pathogens but also in the context of host-pathogen interactions targeting human genomics and transcriptomics. Their performance characteristics and limitations must be clearly understood by both laboratory personnel and clinicians to ensure proper utilization and interpretation.
Collapse
|
|
23
|
Lee B, Park E, Ha J, Ha IS, Il Cheong H, Kang HG. Disseminated adenovirus infection in a 10-year-old renal allograft recipient. Kidney Res Clin Pract 2018; 37:414-417. [PMID: 30619697 PMCID: PMC6312782 DOI: 10.23876/j.krcp.18.0048] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Revised: 08/06/2018] [Accepted: 08/16/2018] [Indexed: 01/30/2023] Open
Abstract
Disseminated adenovirus infection can result in high mortality and morbidity in immunocompromised patients. Here, we report the case of a 10-year-old renal allograft recipient who presented with hematuria and dysuria. Adenovirus was isolated from his urine. His urinary symptoms decreased after intravenous hydration and reduction of immunosuppressants. However, 2 weeks later he presented with general weakness and laboratory tests indicated renal failure necessitating emergency hemodialysis. Adenovirus was detected in his sputum; therefore, intravenous ganciclovir and immunoglobulin therapy were initiated. Renal biopsy revealed diffuse necrotizing granulomatous tubulointerstitial nephritis compatible with renal involvement of the viral infection. Adenovirus was detected in his serum. Despite cidofovir administration for 2 weeks, adenovirus was also detected in the cerebrospinal fluid, resulting in generalized tonic-clonic seizure. The patient died 7 weeks after the onset of urinary symptoms. Adenovirus should be considered in screening tests for post-renal transplantation patients who present with hemorrhagic cystitis.
Collapse
Affiliation(s)
- Bora Lee
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Eujin Park
- Department of Pediatrics, Hallym University Medical Center, Seoul, Korea
| | - Jongwon Ha
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Il Soo Ha
- Division of Nephrology, Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Hae Il Cheong
- Division of Nephrology, Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Hee Gyung Kang
- Division of Nephrology, Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| |
Collapse
|
|
24
|
Sedláček P, Petterson T, Robin M, Sivaprakasam P, Vainorius E, Brundage T, Chandak A, Mozaffari E, Nichols G, Voigt S. Incidence of Adenovirus Infection in Hematopoietic Stem Cell Transplantation Recipients: Findings from the AdVance Study. Biol Blood Marrow Transplant 2018; 25:810-818. [PMID: 30578939 DOI: 10.1016/j.bbmt.2018.12.753] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Accepted: 12/14/2018] [Indexed: 11/19/2022]
Abstract
Adenovirus (AdV) is an increasingly recognized threat to recipients of allogeneic hematopoietic stem cell transplantation (allo-HCT), particularly when infection is prolonged and unresolved. AdVance is the first multinational, multicenter study to evaluate the incidence of AdV infection in both pediatric and adult allo-HCT recipients across European transplantation centers. Medical records for patients undergoing first allo-HCT between January 2013 and September 2015 at 50 participating centers were reviewed. The cumulative incidence of AdV infection (in any sample using any assay) during the 6 months after allo-HCT was 32% (95% confidence interval [CI], 30.9% to 33.4%) among pediatric allo-HCT recipients (n = 1736) and 6% (95% CI, 4.7% to 6.4%) among adult allo-HCT recipients (n = 2540). The incidence of AdV viremia ≥1000copies/mL (a common threshold for initiation of preemptive treatment) was 14% (95% CI, 13.0% to 14.8%) in pediatric recipients and 1.5% (95% CI, 1.1% to 2.0%) in adult recipients. Baseline risk factors for developing AdV viremia ≥1000copies/mL included younger age, use of T cell depletion, and donor type other than matched related. Baseline demographic factors were broadly comparable across patients of all ages and identified by multivariate analyses. Notably, the incidence of AdV infection decreased stepwise with increasing age; younger adults (age 18 to 34 years) had a similar incidence as older pediatric patients (<18 years). This study provides a contemporary multicenter understanding of the incidence and risk factors for AdV infection following allo-HCT. Our findings may help optimize infection screening and intervention criteria, particularly for younger at-risk adults.
Collapse
Affiliation(s)
- Petr Sedláček
- Hematopoietic Stem Cell Transplant Unit, Department of Pediatric Hematology and Oncology, University Hospital Motol, Prague, Czech Republic
| | - Toni Petterson
- Department of Haemopoietic Stem Cell Bone Marrow Transplantation, The Royal Marsden Hospital, Sutton, London, United Kingdom
| | - Marie Robin
- Service d'Hématologie-Greffe, Hôpital Saint-Louis, Assistance Publique Hôpitaux de Paris, Paris, France
| | - Ponni Sivaprakasam
- Paediatric Bone Marrow Transplant Service, Bristol Royal Hospital for Children, Bristol, United Kingdom
| | | | | | | | | | | | - Sebastian Voigt
- Department of Pediatric Oncology/Hematology/Stem Cell Transplantation, Charité-Universitätsmedizin Berlin, Berlin, Germany.
| |
Collapse
|
|
25
|
A survey on incidence and management of adenovirus infection after allogeneic HSCT. Bone Marrow Transplant 2018; 54:1275-1280. [PMID: 30546071 DOI: 10.1038/s41409-018-0421-0] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2018] [Revised: 11/03/2018] [Accepted: 11/24/2018] [Indexed: 12/25/2022]
Abstract
To determine the current practices on the management of Adenovirus (ADV) infection after allogenic stem cell transplantation, a survey was undertook among EBMT centres. The response rate was 20% (91/446): 46% were adult, 44% were paediatric and 10% were mixed centres, respectively. The overall incidence of ADV infection was 7.1%: 4.1% in adult, 15.4% in paediatric, and 3.6% in mixed population. The determination of ADV-DNA in biological samples was used in 96% of centres; 58% of them monitored asymptomatic patients with a frequency of twice a week in 9%, once a week in 45%, every two weeks in 4% of centres. The treatment of ADV infection was mainly based on the administration of cidofovir (87%), being the schedule of 5 mg/kg/week with probenecid the most used, and the reduction of immunosuppression (84%). The threshold of ADV-DNAemia to start cidofovir in high-risk patients was most frequently >1000 copies/ml. Innovative treatments, such as brincidofovir and adoptive ADV-cytotoxic-T-lymphocytes, were used in 27% and 20% of centres, respectively. Almost all responding centres consider ADV infection serious enough to deserve testing asymptomatic or symptomatic patients. Cidofovir and reduction of immunosuppression represent the main therapeutic options but one fourth of responding centres experimented novel therapies.
Collapse
|
|
26
|
Respiratory Viruses and Other Relevant Viral Infections in the Lung Transplant Recipient. LUNG TRANSPLANTATION 2018. [PMCID: PMC7123387 DOI: 10.1007/978-3-319-91184-7_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
As advances occur in surgical technique, postoperative care, and immunosuppressive therapy, the rate of mortality in the early postoperative period following lung transplantation continues to decline. With the improvements in immediate and early posttransplant mortality, infections and their sequel as well as rejection and chronic allograft dysfunction are increasingly a major cause of posttransplant mortality. This chapter will focus on infections by respiratory viruses and other viral infections relevant to lung transplantation, including data regarding the link between viral infections and allograft dysfunction.
Collapse
|
|
27
|
Hsu JW, Hiemenz JW, Wingard JR, Leather H. Viral Infections in Patients with Hematological Malignancies. NEOPLASTIC DISEASES OF THE BLOOD 2018:1079-1127. [DOI: 10.1007/978-3-319-64263-5_51] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
28
|
|
|
29
|
Chung CJ, Kuo YC, Hsieh YY, Li TC, Lin CC, Liang WM, Liao LN, Li CI, Lin HC. Subject-enabled analytics model on measurement statistics in health risk expert system for public health informatics. Int J Med Inform 2017; 107:18-29. [DOI: 10.1016/j.ijmedinf.2017.08.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2017] [Revised: 08/15/2017] [Accepted: 08/31/2017] [Indexed: 01/13/2023]
|
|
30
|
Ramsay ID, Attwood C, Irish D, Griffiths PD, Kyriakou C, Lowe DM. Disseminated adenovirus infection after allogeneic stem cell transplant and the potential role of brincidofovir - Case series and 10 year experience of management in an adult transplant cohort. J Clin Virol 2017; 96:73-79. [PMID: 29017084 DOI: 10.1016/j.jcv.2017.09.013] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Revised: 08/23/2017] [Accepted: 09/30/2017] [Indexed: 12/16/2022]
Abstract
BACKGROUND Adenovirus infection is a recognized complication following haematopoietic stem cell transplantation. We present a review of our experience of these infections in our transplant cohort over 10 years including 3 patients treated with the novel antiviral brincidofovir. OBJECTIVES We aimed to describe the presentation, response to treatment and outcomes of adult stem cell transplant patients with disseminated adenovirus infection. STUDY DESIGN All adult cases of disseminated adenovirus infection following haematopoietic stem cell transplant in our unit between 2005 and 2015 were identified. Transplant details and data on timing of diagnosis, course of infection, viral co-infection and treatment were collected. RESULTS Of 733 patients transplanted, 10 patients had disseminated infection, including 4 male and 6 female patients with median age of 36.5 (range 19-59) years. 6/10 received an allograft from an unrelated donor. Median post-transplant time to detection of viraemia was 67days (range 20-1140days). Median peak viral load was 3133 copies/ml (352-11,000,000) in survivors received cidofovir alone, one cidofovir then brincidofovir and two brincidofovir alone. 8/10 p and 1,580,000 copies/ml (41,999-3,000.000) in those who died. Five patientsatients had a decrease in viral load following antivirals and/or reduction in immunosuppression including all on brincidofovir. Three died on treatment. CONCLUSIONS Disseminated adenovirus infection is uncommon in adult transplant patients and uncertainties remain surrounding effective treatment. In our cohort, brincidofovir has shown promise in treatment of adenoviral infection. However, randomized controlled studies are required to confirm this impression.
Collapse
Affiliation(s)
| | | | - Dianne Irish
- Department of Virology, Royal Free Hospital London, UK
| | - Paul D Griffiths
- Department of Virology, Royal Free Hospital London, UK; Institute of Immunity and Transplantation, Royal Free Campus, University College London, UK
| | | | - David M Lowe
- Institute of Immunity and Transplantation, Royal Free Campus, University College London, UK; Department of Immunology, Royal Free Hospital London, UK.
| |
Collapse
|
|
31
|
Anti-adenoviral Artificial MicroRNAs Expressed from AAV9 Vectors Inhibit Human Adenovirus Infection in Immunosuppressed Syrian Hamsters. MOLECULAR THERAPY. NUCLEIC ACIDS 2017; 8:300-316. [PMID: 28918031 PMCID: PMC5537171 DOI: 10.1016/j.omtn.2017.07.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Revised: 07/03/2017] [Accepted: 07/03/2017] [Indexed: 12/27/2022]
Abstract
Infections of immunocompromised patients with human adenoviruses (hAd) can develop into life-threatening conditions, whereas drugs with anti-adenoviral efficiency are not clinically approved and have limited efficacy. Small double-stranded RNAs that induce RNAi represent a new class of promising anti-adenoviral therapeutics. However, as yet, their efficiency to treat hAd5 infections has only been investigated in vitro. In this study, we analyzed artificial microRNAs (amiRs) delivered by self-complementary adeno-associated virus (scAAV) vectors for treatment of hAd5 infections in immunosuppressed Syrian hamsters. In vitro evaluation of amiRs targeting the E1A, pTP, IVa2, and hexon genes of hAd5 revealed that two scAAV vectors containing three copies of amiR-pTP and three copies of amiR-E1A, or six copies of amiR-pTP, efficiently inhibited hAd5 replication and improved the viability of hAd5-infected cells. Prophylactic application of amiR-pTP/amiR-E1A- and amiR-pTP-expressing scAAV9 vectors, respectively, to immunosuppressed Syrian hamsters resulted in the reduction of hAd5 levels in the liver of up to two orders of magnitude and in reduction of liver damage. Concomitant application of the vectors also resulted in a decrease of hepatic hAd5 infection. No side effects were observed. These data demonstrate anti-adenoviral RNAi as a promising new approach to combat hAd5 infection.
Collapse
|
|
32
|
Abstract
Adenoviruses are a highly prevalent infection that can cause a range of clinical syndromes in immunocompromised patients, ranging from localized disease of the respiratory tract, gastrointestinal tract, or urinary tract to disseminated disease. Adenovirus infections may develop in this unique population as the result of primary infection or reactivation of latent virus. Disease can be potentially progressive with high rates of mortality in patients with pneumonia and disseminated disease. Fortunately, cidofovir and its lipid ester, brincidofovir, appear to be effective for the treatment of adenovirus, although neither is specifically approved for this indication. Adenovirus should always be considered when immunocompromised patients present with any clinical syndrome that could be compatible with adenoviral infection. Once disease is suspected, cultures or molecular testing of appropriate specimens should be obtained and blood should be sent for adenovirus polymerase chain reaction (PCR) whenever adenovirus is suspected. Monitoring of quantitative viral loads in blood is helpful in predicting response to therapy with a significant drop (>1 log) associated with a higher probability of clinical response.
Collapse
|
|
33
|
Qian C, Campidelli A, Wang Y, Cai H, Venard V, Jeulin H, Dalle JH, Pochon C, D'aveni M, Bruno B, Paillard C, Vigouroux S, Jubert C, Ceballos P, Marie-Cardine A, Galambrun C, Cholle C, Clerc Urmes I, Petitpain N, De Carvalho Bittencourt M, Decot V, Reppel L, Salmon A, Clement L, Bensoussan D. Curative or pre-emptive adenovirus-specific T cell transfer from matched unrelated or third party haploidentical donors after HSCT, including UCB transplantations: a successful phase I/II multicenter clinical trial. J Hematol Oncol 2017; 10:102. [PMID: 28482908 PMCID: PMC5421327 DOI: 10.1186/s13045-017-0469-0] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2017] [Accepted: 04/20/2017] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Allogeneic hematopoietic stem cell transplantation (HSCT), the most widely used potentially curable cellular immunotherapeutic approach in the treatment of hematological malignancies, is limited by life-threatening complications: graft versus host disease (GVHD) and infections especially viral infections refractory to antiviral drugs. Adoptive transfer of virus-specific T cells is becoming an alternative treatment for infections following HSCT. We report here the results of a phase I/II multicenter study which includes a series of adenovirus-specific T cell (ADV-VST) infusion either from the HSCT donor or from a third party haploidentical donor for patients transplanted with umbilical cord blood (UCB). METHODS Fourteen patients were eligible and 11 patients received infusions of ADV-VST generated by interferon (IFN)-γ-based immunomagnetic isolation from a leukapheresis from their original donor (42.9%) or a third party haploidentical donor (57.1%). One patient resolved ADV infection before infusion, and ADV-VST could not reach release or infusion criteria for two patients. Two patients received cellular immunotherapy alone without antiviral drugs as a pre-emptive treatment. RESULTS One patient with adenovirus infection and ten with adenovirus disease were infused with ADV-VST (mean 5.83 ± 8.23 × 103 CD3+IFN-γ+ cells/kg) up to 9 months after transplantation. The 11 patients showed in vivo expansion of specific T cells up to 60 days post-infusion, associated with adenovirus load clearance in ten of the patients (91%). Neither de novo GVHD nor side effects were observed during the first month post-infusion, but GVHD reactivations occurred in three patients, irrespective of the type of leukapheresis donor. For two of these patients, GVHD reactivation was controlled by immunosuppressive treatment. Four patients died during follow-up, one due to refractory ADV disease. CONCLUSIONS Adoptive transfer of rapidly isolated ADV-VST is an effective therapeutic option for achieving in vivo expansion of specific T cells and clearance of viral load, even as a pre-emptive treatment. Our study highlights that third party haploidentical donors are of great interest for ADV-VST generation in the context of UCB transplantation. (N° Clinical trial.gov: NCT02851576, retrospectively registered).
Collapse
Affiliation(s)
- Chongsheng Qian
- Unité de Thérapie cellulaire et Tissus and FR 3209, CHRU de Nancy, Vandoeuvre-Lès-Nancy, F54511, France.,UMR 7365 and FR 3209 CNRS-UL-CHU, Université de Lorraine, Vandoeuvre-Lès-Nancy, F54511, France
| | - Arnaud Campidelli
- Unité de Thérapie cellulaire et Tissus and FR 3209, CHRU de Nancy, Vandoeuvre-Lès-Nancy, F54511, France
| | - Yingying Wang
- Unité de Thérapie cellulaire et Tissus and FR 3209, CHRU de Nancy, Vandoeuvre-Lès-Nancy, F54511, France.,UMR 7365 and FR 3209 CNRS-UL-CHU, Université de Lorraine, Vandoeuvre-Lès-Nancy, F54511, France
| | - Huili Cai
- Laboratoire d'Immunologie and Plateforme Nancytomique, CHRU de Nancy, Vandoeuvre-Lès-Nancy, F54511, France
| | - Véronique Venard
- Laboratoire de Virologie, CHRU de Nancy, Vandoeuvre-Lès-Nancy, F54511, France
| | - Hélène Jeulin
- Laboratoire de Virologie, CHRU de Nancy, Vandoeuvre-Lès-Nancy, F54511, France
| | - Jean Hugues Dalle
- Immuno-Hématologie pédiatrique, Hôpital Robert Debré, Paris, F75935, France
| | - Cécile Pochon
- Unité de Transplantation Médullaire Allogénique, CHRU de Nancy, Vandoeuvre-lès-Nancy, F54511, France
| | - Maud D'aveni
- Unité de Transplantation Médullaire Allogénique, CHRU de Nancy, Vandoeuvre-lès-Nancy, F54511, France
| | - Benedicte Bruno
- Hématologie pédiatrique, Hôpital Jeanne de Flandres CHU de Lille, Lille cedex, F59037, France
| | | | - Stéphane Vigouroux
- Groupe hospitalier Sud Hôpital Haut-Lévêque, Hématologie clinique et thérapie cellulaire, Pessac Cedex, F33604, France
| | - Charlotte Jubert
- Hématologie Oncologie Pédiatrique, Hôpital des Enfants Pellegrin, Bordeaux, F33000, France
| | - Patrice Ceballos
- Hématologie Clinique, Hôpital St Eloi, Montpellier, Cedex 5, F34295, France
| | - Aude Marie-Cardine
- Hématologie et Oncologie Pédiatrique, Hôpital Charles Nicolle-CHU de Rouen, Rouen, F76031, France
| | - Claire Galambrun
- Immuno-hématologie Pédiatrique, CHU de la Timone, Marseille, F13385, France
| | - Clément Cholle
- Faculté de Pharmacie, Département de Microbiologie-Immunologie, Université de Lorraine, Nancy, F54001, France
| | - Isabelle Clerc Urmes
- Plateform of Clinical Research Facility PARC, Unit of Methodology, Data Management and Statistics, CHRU de Nancy, Vandoeuvre-Lès-Nancy, F54511, France
| | - Nadine Petitpain
- Centre Régional de Pharmacovigilance de Lorraine, CHRU de Nancy, Vandoeuvre-Lès-Nancy, F54511, France
| | | | - Véronique Decot
- Unité de Thérapie cellulaire et Tissus and FR 3209, CHRU de Nancy, Vandoeuvre-Lès-Nancy, F54511, France.,UMR 7365 and FR 3209 CNRS-UL-CHU, Université de Lorraine, Vandoeuvre-Lès-Nancy, F54511, France
| | - Loïc Reppel
- Unité de Thérapie cellulaire et Tissus and FR 3209, CHRU de Nancy, Vandoeuvre-Lès-Nancy, F54511, France.,UMR 7365 and FR 3209 CNRS-UL-CHU, Université de Lorraine, Vandoeuvre-Lès-Nancy, F54511, France
| | - Alexandra Salmon
- Unité de Transplantation Médullaire Allogénique, CHRU de Nancy, Vandoeuvre-lès-Nancy, F54511, France
| | - Laurence Clement
- Unité de Transplantation Médullaire Allogénique, CHRU de Nancy, Vandoeuvre-lès-Nancy, F54511, France
| | - Danièle Bensoussan
- Unité de Thérapie cellulaire et Tissus and FR 3209, CHRU de Nancy, Vandoeuvre-Lès-Nancy, F54511, France. .,UMR 7365 and FR 3209 CNRS-UL-CHU, Université de Lorraine, Vandoeuvre-Lès-Nancy, F54511, France. .,Faculté de Pharmacie, Département de Microbiologie-Immunologie, Université de Lorraine, Nancy, F54001, France.
| |
Collapse
|
|
34
|
Brincidofovir for Asymptomatic Adenovirus Viremia in Pediatric and Adult Allogeneic Hematopoietic Cell Transplant Recipients: A Randomized Placebo-Controlled Phase II Trial. Biol Blood Marrow Transplant 2017; 23:512-521. [PMID: 28063938 DOI: 10.1016/j.bbmt.2016.12.621] [Citation(s) in RCA: 113] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Accepted: 07/07/2016] [Indexed: 11/24/2022]
Abstract
Adenovirus infection in immunocompromised patients contributes to significant morbidity and mortality, especially after allogeneic hematopoietic cell transplantation (HCT). Brincidofovir (BCV, CMX001) is an orally bioavailable lipid conjugate of cidofovir that has in vitro activity against adenoviruses and other double-stranded DNA viruses. This randomized placebo-controlled phase II trial evaluated pre-emptive treatment with BCV for the prevention of adenovirus disease in pediatric and adult allogeneic HCT recipients with asymptomatic adenovirus viremia. Allogeneic HCT recipients with adenovirus viremia were randomized 1:1:1 to receive oral BCV 100 mg (2 mg/kg if <50 kg) twice weekly (BIW), BCV 200 mg (4 mg/kg if <50 kg) once weekly (QW), or placebo for 6 to 12 weeks, followed by 4 weeks of post-treatment follow-up. For randomization, subjects were stratified by screening absolute lymphocyte count (<300 cells/mm3 versus ≥300 cells/mm3). Assignment to BCV or placebo was double blinded; dose frequency was unblinded. The primary endpoint was the proportion of subjects experiencing treatment failure, defined as either progression to probable or definitive adenovirus disease or confirmed increasing adenovirus viremia (≥1 log10 copies/mL) during randomized therapy. Between June 2011 and December 2012, 48 subjects were randomized to the BCV BIW (n = 14), BCV QW (n = 16), or placebo (n = 18) groups. The proportion of subjects with treatment failure in the BCV BIW group was 21% (odds ratio, .53; 95% confidence interval [CI], .11 to 2.71; P = .45), 38% (odds ratio, 1.23; 95% CI, .30 to 5.05, P = .779) in the BCV QW group, and 33% in the placebo group. All-cause mortality was lower in the BCV BIW (14%) and BCV QW groups (31%) relative to the placebo group (39%), but these differences were not statistically significant. After 1 week of therapy, 8 of 12 subjects (67%) randomized to BCV BIW had undetectable adenovirus viremia (<100 copies/mL), compared with 4 of 14 subjects (29%) randomized to BCV QW and 5 of 15 subjects (33%) randomized to placebo. In a post hoc analysis of subjects with viremia ≥1000 copies/mL at baseline, 6 of 7 BCV BIW subjects (86%) achieved undetectable viremia compared with 2 of 8 placebo subjects (25%; P = .04). Early treatment discontinuation because of adverse events was more common in subjects treated with BCV than with placebo. Diarrhea was the most common event in all groups (57% BCV BIW, 38% BCV QW, 28% placebo), but it led to treatment discontinuation in only 1 subject receiving BCV QW. Events diagnosed as acute graft-versus-host disease, primarily of the gastrointestinal tract, were more frequent in the BCV BIW group (50%) than in the BCV QW (25%) and placebo (17%) groups. There was no evidence of myelotoxicity or nephrotoxicity in BCV-treated subjects. The results of this trial confirm the antiviral activity of BCV against adenoviruses. Further investigation is ongoing to define the optimal treatment strategy for HCT recipients with serious adenovirus infection and disease.
Collapse
|
|
35
|
Marr KA. Infections in Hematopoietic Stem Cell Transplant Recipients. Infect Dis (Lond) 2017. [DOI: 10.1016/b978-0-7020-6285-8.00080-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
|
|
36
|
Immunity to Infections after Haploidentical Hematopoietic Stem Cell Transplantation. Mediterr J Hematol Infect Dis 2016; 8:e2016057. [PMID: 27872737 PMCID: PMC5111540 DOI: 10.4084/mjhid.2016.057] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Accepted: 09/21/2016] [Indexed: 02/06/2023] Open
Abstract
The advantage of using a Human Leukocyte Antigen (HLA)-mismatched related donor is that almost every patient who does not have an HLA-identical donor or who urgently needs hematopoietic stem cell transplantation (HSCT) has at least one family member with whom shares one haplotype (haploidentical) and who is promptly available as a donor. The major challenge of haplo-HSCT is intense bi-directional alloreactivity leading to high incidences of graft rejection and graft-versus-host disease (GVHD). Advances in graft processing and pharmacologic prophylaxis of GVHD have reduced these risks and have made haplo-HSCT a viable alternative for patients lacking a matched donor. Indeed, the haplo-HSCT has spread to centers worldwide even though some centers have preferred an approach based on T cell depletion of G-CSF-mobilized peripheral blood progenitor cells (PBPCs), others have focused on new strategies for GvHD prevention, such as G-CSF priming of bone marrow and robust post-transplant immune suppression or post-transplant cyclophosphamide (PTCY). Today, the graft can be a megadose of T-cell depleted PBPCs or a standard dose of unmanipulated bone marrow and/or PBPCs. Although haplo-HSCT modalities are based mainly on high intensity conditioning regimens, recently introduced reduced intensity regimens (RIC) showed promise in decreasing early transplant-related mortality (TRM), and extending the opportunity of HSCT to an elderly population with more comorbidities. Infections are still mostly responsible for toxicity and non-relapse mortality due to prolonged immunosuppression related, or not, to GVHD. Future challenges lie in determining the safest preparative conditioning regimen, minimizing GvHD and promoting rapid and more robust immune reconstitution.
Collapse
|
|
37
|
Occurrence, risk factors and outcome of adenovirus infection in adult recipients of allogeneic hematopoietic stem cell transplantation. J Clin Virol 2016; 82:33-40. [DOI: 10.1016/j.jcv.2016.07.002] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2016] [Revised: 06/25/2016] [Accepted: 07/08/2016] [Indexed: 11/19/2022]
|
|
38
|
Ganapathi L, Arnold A, Jones S, Patterson A, Graham D, Harper M, Levy O. Use of cidofovir in pediatric patients with adenovirus infection. F1000Res 2016; 5:758. [PMID: 27239277 PMCID: PMC4863673 DOI: 10.12688/f1000research.8374.2] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/12/2016] [Indexed: 11/20/2022] Open
Abstract
Background: Adenoviruses contribute to morbidity and mortality among immunocompromised pediatric patients including stem cell and solid organ transplant recipients. Cidofovir (CDV), an antiviral compound approved by the FDA in 1996, is used for treatment of adenoviral (ADV) infections in immunocompromised patients despite concern of potential nephrotoxicity. Methods: We conducted a retrospective 5-year review at Boston Children's Hospital of 16 patients (mean age = 6.5 years) receiving 19 courses of CDV. During therapy all pertinent data elements were reviewed to characterize potential response to therapy and incidence of renal dysfunction. Results: Of the 19 CDV courses prescribed, 16 courses (84%) were in patients who had a positive blood ADV Polymerase chain reaction (PCR) alone or in combination with positive ADV PCR/ Direct Immunofluorescence Assay (DFA) at another site. Respiratory symptoms with or without pneumonia were the most common presentation (10/19, 53%). In the majority of blood positive courses (10/16, 63%), viral clearance was also accompanied by clinical response. This was not the case in four courses where patients expired despite viral clearance, including one in which death was directly attributable to adenovirus. There was reversible renal dysfunction observed during the use of CDV. Conclusions: CDV appeared safe and reasonably tolerated for treatment of ADV in this pediatric population and was associated with viral response and clinical improvement in the majority of patients but reversible renal dysfunction was a side effect. Further studies of the efficacy of CDV for immunocompromised children with ADV infection are warranted.
Collapse
Affiliation(s)
- Lakshmi Ganapathi
- Division of Infectious Diseases, Boston Children's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA
| | - Alana Arnold
- Division of Pharmacy, Boston Children's Hospital, Boston, MA, USA
| | - Sarah Jones
- Division of Pharmacy, Boston Children's Hospital, Boston, MA, USA
| | - Al Patterson
- Division of Pharmacy, Boston Children's Hospital, Boston, MA, USA
| | - Dionne Graham
- Program for Patient Quality and Safety, Boston Children's Hospital, Boston, MA, USA
| | - Marvin Harper
- Division of Infectious Diseases, Boston Children's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA
| | - Ofer Levy
- Division of Infectious Diseases, Boston Children's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA
| |
Collapse
|
|
39
|
Ganapathi L, Arnold A, Jones S, Patterson A, Graham D, Harper M, Levy O. Use of cidofovir in pediatric patients with adenovirus infection. F1000Res 2016; 5:758. [PMID: 27239277 DOI: 10.12688/f1000research.8374.1] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/23/2016] [Indexed: 11/20/2022] Open
Abstract
Background: Adenoviruses contribute to morbidity and mortality among immunocompromised pediatric patients including stem cell and solid organ transplant recipients. Cidofovir (CDV), an antiviral compound approved by the FDA in 1996, is used for treatment of adenoviral (ADV) infections in immunocompromised patients despite concern of potential nephrotoxicity. Methods: We conducted a retrospective 5-year review at Boston Children's Hospital of 16 patients (mean age = 6.5 years) receiving 19 courses of CDV. During therapy all pertinent data elements were reviewed to characterize potential response to therapy and incidence of renal dysfunction. Results: Of the 19 CDV courses prescribed, 16 courses (84%) were in patients who had a positive blood ADV Polymerase chain reaction (PCR) alone or in combination with positive ADV PCR/ Direct Immunofluorescence Assay (DFA) at another site. Respiratory symptoms with or without pneumonia were the most common presentation (10/19, 53%). In the majority of blood positive courses (10/16, 63%), viral clearance was also accompanied by clinical response. This was not the case in four courses where patients expired despite viral clearance, including one in which death was directly attributable to adenovirus. There was reversible renal dysfunction observed during the use of CDV. Conclusions: CDV appeared safe and reasonably tolerated for treatment of ADV in this pediatric population and was associated with viral response and clinical improvement in the majority of patients but reversible renal dysfunction was a side effect. Further studies of the efficacy of CDV for immunocompromised children with ADV infection are warranted.
Collapse
Affiliation(s)
- Lakshmi Ganapathi
- Division of Infectious Diseases, Boston Children's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA
| | - Alana Arnold
- Division of Pharmacy, Boston Children's Hospital, Boston, MA, USA
| | - Sarah Jones
- Division of Pharmacy, Boston Children's Hospital, Boston, MA, USA
| | - Al Patterson
- Division of Pharmacy, Boston Children's Hospital, Boston, MA, USA
| | - Dionne Graham
- Program for Patient Quality and Safety, Boston Children's Hospital, Boston, MA, USA
| | - Marvin Harper
- Division of Infectious Diseases, Boston Children's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA
| | - Ofer Levy
- Division of Infectious Diseases, Boston Children's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA
| |
Collapse
|
|
40
|
Prostaglandin E2 Production and T Cell Function in Mouse Adenovirus Type 1 Infection following Allogeneic Bone Marrow Transplantation. PLoS One 2015; 10:e0139235. [PMID: 26407316 PMCID: PMC4583312 DOI: 10.1371/journal.pone.0139235] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2015] [Accepted: 09/10/2015] [Indexed: 11/19/2022] Open
Abstract
Adenovirus infections are important complications of bone marrow transplantation (BMT). We demonstrate delayed clearance of mouse adenovirus type 1 (MAV-1) from lungs of mice following allogeneic BMT. Virus-induced prostaglandin E2 (PGE2) production was greater in BMT mice than in untransplanted controls, but BMT using PGE2-deficient donors or recipients failed to improve viral clearance, and treatment of untransplanted mice with the PGE2 analog misoprostol did not affect virus clearance. Lymphocyte recruitment to the lungs was not significantly affected by BMT. Intracellular cytokine staining of lung lymphocytes demonstrated impaired production of INF-γ and granzyme B by cells from BMT mice, and production of IFN-γ, IL-2, IL-4, and IL-17 following ex vivo stimulation was impaired in lymphocytes obtained from lungs of BMT mice. Viral clearance was not delayed in untransplanted INF-γ-deficient mice, suggesting that delayed viral clearance in BMT mice was not a direct consequence of impaired IFN-γ production. However, lung viral loads were higher in untransplanted CD8-deficient mice than in controls, suggesting that delayed MAV-1 clearance in BMT mice is due to defective CD8 T cell function. We did not detect significant induction of IFN-β expression in lungs of BMT mice or untransplanted controls, and viral clearance was not delayed in untransplanted type I IFN-unresponsive mice. We conclude that PGE2 overproduction in BMT mice is not directly responsible for delayed viral clearance. PGE2-independent effects on CD8 T cell function likely contribute to the inability of BMT mice to clear MAV-1 from the lungs.
Collapse
|
|
41
|
The effect of cidofovir on adenovirus plasma DNA levels in stem cell transplantation recipients without T cell reconstitution. Biol Blood Marrow Transplant 2014; 21:293-9. [PMID: 25464118 DOI: 10.1016/j.bbmt.2014.10.012] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2014] [Accepted: 10/13/2014] [Indexed: 11/20/2022]
Abstract
Cidofovir is frequently used to treat life-threatening human adenovirus (HAdV) infections in immunocompromised children after hematopoietic stem cell transplantation (HSCT). However, the antiviral effect irrespective of T cell reconstitution remains unresolved. Plasma HAdV DNA levels were monitored by real-time quantitative PCR during 42 cidofovir treatment episodes for HAdV viremia in 36 pediatric allogeneic HSCT recipients. HAdV load dynamics were related to T and natural killer (NK) cell reconstitution measured by flow cytometry. To evaluate the in vivo antiadenoviral effect of cidofovir, we focused on 20 cidofovir treatment episodes lacking concurrent T cell reconstitution. During 2 to 10 weeks of follow-up in the absence of T cells, HAdV load reduction (n = 7) or stabilization (n = 8) was observed in 15 of 20 treatments. Although HAdV load reduction was always accompanied by NK cell expansion, HAdV load stabilization was measured in 2 children lacking both T and NK cell reconstitution. In cases with T cell reconstitution, rapid HAdV load reduction (n = 14) or stabilization (n = 6) was observed in 20 of 22 treatments. In the absence of T cells, cidofovir treatment was associated with HAdV viremia control in the majority of cases. Although the contribution of NK cells cannot be excluded, cidofovir has the potential to mediate HAdV load stabilization in the time pending T cell reconstitution.
Collapse
|
|
42
|
Sandkovsky U, Vargas L, Florescu DF. Adenovirus: current epidemiology and emerging approaches to prevention and treatment. Curr Infect Dis Rep 2014; 16:416. [PMID: 24908344 DOI: 10.1007/s11908-014-0416-y] [Citation(s) in RCA: 91] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Infections caused by adenoviruses are associated with significant morbidity and mortality in both hematopoietic stem cell and solid organ transplant recipients. The risk seems to be highest in allogeneic hematopoietic stem cell transplant recipients as well as heart, lung and small-bowel transplant recipients. Management of these infections may be difficult and includes reduction of immunosuppression whenever possible combined sometimes with antiviral therapy (mainly cidofovir). The currently available antiviral therapy is limited by the need for intravenous administration, potentially significant renal and hematologic toxicities. New emerging therapies such as brincidofovir and transfusion of adenovirus-specific T-lymphocytes may increase the available armamentarium for these potentially life-threatening infections.
Collapse
Affiliation(s)
- Uriel Sandkovsky
- Division of Infectious Diseases, Transplant Infectious Diseases Program, University of Nebraska Medical Center, Omaha, NE, USA
| | | | | |
Collapse
|
|
43
|
Calkoen FGJ, Vervat C, van Halteren AGS, Welters MJP, Veltrop-Duits LA, Lankester AC, Egeler RM, Ball LM, van Tol MJD. Mesenchymal stromal cell therapy is associated with increased adenovirus-associated but not cytomegalovirus-associated mortality in children with severe acute graft-versus-host disease. Stem Cells Transl Med 2014; 3:899-910. [PMID: 24904175 DOI: 10.5966/sctm.2013-0191] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Beneficial effects of mesenchymal stromal cells (MSCs) in patients with severe steroid-refractory acute graft-versus-host disease (aGvHD) have been reported. However, controversy exists about the effect of MSCs on virus-specific T cells. We evaluated 56 patients with grade II-IV aGvHD who responded to steroids (n = 21) or were steroid refractory receiving either MSCs (n = 22) or other second-line therapy (n = 13). Although the overall incidence of cytomegalovirus (CMV), Epstein-Barr virus, and human adenovirus (HAdV) infections was not significantly increased, HAdV infection was associated with decreased survival in children treated with MSCs. Thus, we investigated in vitro the effects of MSCs on virus-specific T cells. Both CMV-specific and, to a lesser extent, HAdV-specific T-cell activation and proliferation were negatively affected by MSCs either after induction of a response in peripheral blood mononuclear cells (PBMCs) or after restimulation of virus-specific T-cell lines. In patient-derived PBMCs, CMV-specific proliferative responses were greatly decreased on first-line treatment of aGvHD with systemic steroids and slowly recovered after MSC administration and tapering of steroids. HAdV-specific T-cell proliferation could not be detected. In contrast, the proportion of CMV- and HAdV-specific effector T cells, measured as interferon-γ-secreting cells, remained stable or increased after treatment with MSCs. In conclusion, although in vitro experimental conditions indicated a negative impact of MSCs on CMV- and HAdV-specific T-cell responses, no solid evidence was obtained to support such an effect of MSCs on T-cell responses in vivo. Still, the susceptibility of steroid-refractory severe aGvHD patients to viral reactivation warrants critical viral monitoring during randomized controlled trials on second-line treatment including MSCs.
Collapse
Affiliation(s)
- Friso G J Calkoen
- Department of Pediatrics, Immunology Section, Hematology/Oncology and Hematopoietic Stem Cell Transplantation, and Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands; Department of Hematology/Oncology and Hematopoietic Stem Cell Transplantation, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Carly Vervat
- Department of Pediatrics, Immunology Section, Hematology/Oncology and Hematopoietic Stem Cell Transplantation, and Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands; Department of Hematology/Oncology and Hematopoietic Stem Cell Transplantation, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Astrid G S van Halteren
- Department of Pediatrics, Immunology Section, Hematology/Oncology and Hematopoietic Stem Cell Transplantation, and Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands; Department of Hematology/Oncology and Hematopoietic Stem Cell Transplantation, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Marij J P Welters
- Department of Pediatrics, Immunology Section, Hematology/Oncology and Hematopoietic Stem Cell Transplantation, and Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands; Department of Hematology/Oncology and Hematopoietic Stem Cell Transplantation, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Louise A Veltrop-Duits
- Department of Pediatrics, Immunology Section, Hematology/Oncology and Hematopoietic Stem Cell Transplantation, and Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands; Department of Hematology/Oncology and Hematopoietic Stem Cell Transplantation, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Arjan C Lankester
- Department of Pediatrics, Immunology Section, Hematology/Oncology and Hematopoietic Stem Cell Transplantation, and Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands; Department of Hematology/Oncology and Hematopoietic Stem Cell Transplantation, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - R Maarten Egeler
- Department of Pediatrics, Immunology Section, Hematology/Oncology and Hematopoietic Stem Cell Transplantation, and Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands; Department of Hematology/Oncology and Hematopoietic Stem Cell Transplantation, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Lynne M Ball
- Department of Pediatrics, Immunology Section, Hematology/Oncology and Hematopoietic Stem Cell Transplantation, and Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands; Department of Hematology/Oncology and Hematopoietic Stem Cell Transplantation, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Maarten J D van Tol
- Department of Pediatrics, Immunology Section, Hematology/Oncology and Hematopoietic Stem Cell Transplantation, and Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands; Department of Hematology/Oncology and Hematopoietic Stem Cell Transplantation, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| |
Collapse
|
|
44
|
Management of adenovirus in children after allogeneic hematopoietic stem cell transplantation. Adv Hematol 2013; 2013:176418. [PMID: 24288536 PMCID: PMC3830830 DOI: 10.1155/2013/176418] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2013] [Accepted: 09/06/2013] [Indexed: 11/18/2022] Open
Abstract
Adenovirus (ADV) can cause significant morbidity and mortality in children following haematopoietic stem cell transplantation (HSCT), with an incidence of up to 27% and notable associated morbidity and mortality. T-cell depleted grafts and severe lymphopenia are major risk factors for the development of adenovirus disease after HSCT. Current antiviral treatments are at best virostatic and may have significant side effects. Adoptive transfer of donor-derived virus-specific T cells has been shown to be an effective strategy for the prevention and treatment of ADV infection after HSCT. Here we review progress in the field and present a pathway for the management of adenovirus in the posttransplant setting.
Collapse
|
|
45
|
Broad-range PCR-electrospray ionization mass spectrometry for detection and typing of adenovirus and other opportunistic viruses in stem cell transplant patients. J Clin Microbiol 2013; 51:4186-92. [PMID: 24108617 DOI: 10.1128/jcm.01978-13] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
Hematopoietic stem cell transplant patients are highly susceptible to viral infections. Follow-up after transplantation includes weekly screening using single, virus-specific real-time PCR tests, mainly for viruses in the families Herpesviridae and Adenoviridae that contribute to a high morbidity, especially in pediatric populations. The Abbott PLEX-ID platform combines broad-range PCR with electrospray ionization mass spectrometry to enable the simultaneous detection of multiple pathogens in a single assay. The Viral IC Spectrum assay detects human adenoviruses, viruses from the family Herpesviridae (herpes simplex virus 1 [HSV-1], HSV-2, cytomegalovirus [CMV], Epstein-Barr virus [EBV], varicella-zoster virus [VZV], and human herpesvirus 8 [HHV-8]), human enterovirus, polyomaviruses (BK and JC), and parvovirus B19. We evaluated the performance of the Viral IC Spectrum assay with samples from 16 adult and 36 pediatric stem cell transplant patients. The sensitivity of the Viral IC Spectrum assay compared to real-time PCR quantification using the adenovirus Rgene kit for the detection of adenovirus was 96.7% from plasma samples (n = 92) and 78% from stool samples (n = 100). No adenovirus was detected in samples from noninfected patients (n = 30). PLEX-ID species identification was perfectly concordant with species-specific real-time PCR assays. In plasma and stool samples, the level of amplified products measured by PLEX-ID and the quantity in copies/ml (r = 0.82 and 0.78, respectively) were correlated up to 6 log10 copies/ml. In 67.4% of adenovirus-positive plasma samples, at least one other viral infection was detected; these included BK virus (n = 41), CMV (n = 30), EBV (n = 26), JC virus (n = 9), and HSV-1 (n = 6). The results of this study suggest that the Viral IC Spectrum assay performed on the PLEX-ID platform is reliable for adenovirus infection diagnosis in immunocompromised patients.
Collapse
|
|
46
|
Abstract
Modern post-transplant care pathways commonly encompass periods of critical care support. Infectious events account for many of these interactions making critical care physicians integral members of multidisciplinary transplant teams. Despite continuing advances in clinical care and infection prophylaxis, the morbidity and mortality attributable to infection post-transplant remains considerable. Emerging entities constantly add to the breadth of potential opportunistic pathogens. Individualized risk assessments, rapid and thorough diagnostic evaluation, and prompt initiation of appropriate antimicrobial therapies are essential. The approach to managing transplant recipients with infection in critical care is discussed and common and emerging opportunistic pathogens are reviewed.
Collapse
Affiliation(s)
| | - Atul Humar
- Transplant Infectious Diseases, Alberta Transplant Institute, University of Alberta, 6–030 Katz Center for Health Research, 11361–87 Ave, Edmonton, Alberta T6G 2E1, Canada
| |
Collapse
|
|
47
|
Lee N, Qureshi ST. Other viral pneumonias: coronavirus, respiratory syncytial virus, adenovirus, hantavirus. Crit Care Clin 2013; 29:1045-68. [PMID: 24094390 PMCID: PMC7126722 DOI: 10.1016/j.ccc.2013.07.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Severe viral pneumonia is an increasing problem among adults. The incidence and number of viruses known to cause pneumonia and respiratory failure have also expanded in recent years. This article provides an overview of severe respiratory disease caused by coronavirus, respiratory syncytial virus, adenovirus, and hantavirus. These emerging pathogens are easily overlooked and timely diagnosis requires a high index of suspicion and confirmation by molecular testing. Management of individual cases is mainly supportive and requires institution of appropriate infection control measures. Vaccines and effective therapeutics for these potentially devastating respiratory viruses are urgently required.
Collapse
Affiliation(s)
- Nelson Lee
- Division of Infectious Diseases, Department of Medicine and Therapeutics, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, 30-32 Ngan Shing Street, Shatin, New Territories, Hong Kong, China
| | | |
Collapse
|
|
48
|
Ibrišimović M, Lion T, Klein R. Combinatorial targeting of 2 different steps in adenoviral DNA replication by herpes simplex virus thymidine kinase and artificial microRNA expression for the inhibition of virus multiplication in the presence of ganciclovir. BMC Biotechnol 2013; 13:54. [PMID: 23822768 PMCID: PMC3720212 DOI: 10.1186/1472-6750-13-54] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2013] [Accepted: 06/19/2013] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Human adenoviruses are a frequent threat to immunocompromised patients, and disseminated disease is associated with severe morbidity and mortality. Current drugs are not capable of preventing all fatalities, thus indicating the need for alternative treatment strategies. Adenoviruses can be rendered susceptible to antiherpetic prodrugs such as ganciclovir (GCV), upon expression of the herpes simplex virus thymidine kinase (HSV-TK) gene in adenovirus-infected cells. Furthermore, adenoviruses are amenable to post-transcriptional gene silencing via small interfering RNAs (siRNAs) or artificial micro RNAs (amiRNAs). RESULTS In this study, we combined these 2 approaches by constructing a combinatorial gene expression cassette that comprises the HSV-TK gene and multiple copies of an amiRNA directed against the mRNA encoding the adenoviral preterminal protein (pTP). HSV-TK gene expression was controlled by the adenoviral E4 promoter, which is activated in the presence of the adenoviral E1 gene products (i.e., when adenovirus is present in the cell). When inserted into a replication-deficient (E1-, E3-deleted) adenoviral vector, this cassette effectively inhibited the replication of wild-type adenovirus in vitro. The reduction rate mediated by the combinatorial approach was higher compared to that achieved by either of the 2 approaches alone, and these obvious additive effects became most pronounced when the GCV concentration was low. CONCLUSIONS The concept presented here has the potential to aid in the inhibition of wild-type adenovirus replication. Furthermore, the combinatorial expression cassette may constitute a safeguard to potentially control unintended replication of adenoviral vectors and to prevent immune responses provoked by them.
Collapse
Affiliation(s)
- Mirza Ibrišimović
- Children's Cancer Research Institute, St, Anna Kinderkrebsforschung, Zimmermannplatz 10, 1090 Vienna, Austria
| | | | | |
Collapse
|
|
49
|
Digiusto DL, Kiem HP. Current translational and clinical practices in hematopoietic cell and gene therapy. Cytotherapy 2013; 14:775-90. [PMID: 22799276 DOI: 10.3109/14653249.2012.694420] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Clinical trials over the last 15 years have demonstrated that cell and gene therapies for cancer, monogenic and infectious disease are feasible and can lead to long-term benefit for patients. However, these trials have been limited to proof-of-principle and were conducted on modest numbers of patients or over long periods of time. In order for these studies to move towards standard practice and commercialization, scalable technologies for the isolation, ex vivo manipulation and delivery of these cells to patients must be developed. Additionally, regulatory strategies and clinical protocols for the collection, creation and delivery of cell products must be generated. In this article we review recent progress in hematopoietic cell and gene therapy, describe some of the current issues facing the field and discuss clinical, technical and regulatory approaches used to navigate the road to product development.
Collapse
Affiliation(s)
- David L Digiusto
- Department of Virology and Laboratory for Cellular Medicine, Beckman Research Institute of the City of Hope, Duarte, California 91010, USA.
| | | |
Collapse
|
|
50
|
Watanabe A, Carraro E, Camargo C, Puerari D, Guatura S, Granato C, Bellei N. Human adenovirus detection among immunocompetent and immunocompromised patients presenting acute respiratory infection. Rev Soc Bras Med Trop 2013; 46:161-5. [DOI: 10.1590/0037-8682-1699-2013] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2012] [Accepted: 03/14/2013] [Indexed: 11/21/2022] Open
|