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Zong Y, Kamoi K, Miyagaki M, Zhang J, Yang M, Zou Y, Ohno-Matsui K. Applications of Biological Therapy for Latent Infections: Benefits and Risks. Int J Mol Sci 2024; 25:9184. [PMID: 39273134 PMCID: PMC11394918 DOI: 10.3390/ijms25179184] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 08/20/2024] [Accepted: 08/22/2024] [Indexed: 09/15/2024] Open
Abstract
Biological therapies have revolutionized medical treatment by targeting the key mediators or receptors involved in inflammatory responses, thereby effectively suppressing inflammation and achieving beneficial outcomes. They are more advanced than conventional therapies using corticosteroids and immunosuppressants, offering effective solutions for autoimmune diseases, cancer, transplant rejection, and various infectious diseases, including coronavirus disease 2019. Although they exert low immunosuppressive effects, biological therapies can reactivate specific biological targets associated with infections. This review summarizes the currently available biological therapies and discusses their immunosuppressive mechanisms and clinical applications, highlighting the variations in the types and frequencies of infection recurrence induced by different biological agents. Additionally, this review describes the risk factors associated with various biological agents, thus aiding clinicians in selecting the most appropriate biological therapy.
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Affiliation(s)
- Yuan Zong
- Department of Ophthalmology & Visual Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Koju Kamoi
- Department of Ophthalmology & Visual Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Miki Miyagaki
- Department of Ophthalmology & Visual Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Jing Zhang
- Department of Ophthalmology & Visual Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Mingming Yang
- Department of Ophthalmology & Visual Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Yaru Zou
- Department of Ophthalmology & Visual Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Kyoko Ohno-Matsui
- Department of Ophthalmology & Visual Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
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Maresca R, Varca S, Di Vincenzo F, Ainora ME, Mignini I, Papa A, Scaldaferri F, Gasbarrini A, Giustiniani MC, Zocco MA, Laterza L. Cytomegalovirus Infection: An Underrated Target in Inflammatory Bowel Disease Treatment. J Clin Med 2023; 13:130. [PMID: 38202138 PMCID: PMC10779749 DOI: 10.3390/jcm13010130] [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: 12/01/2023] [Revised: 12/20/2023] [Accepted: 12/22/2023] [Indexed: 01/12/2024] Open
Abstract
CMV infection is still a matter of concern in IBD patients, especially regarding the disease's relapse management. Why IBD patients, particularly those affected by ulcerative colitis, are more susceptible to CMV reactivation is not totally explained, although a weakened immune system could be the reason. Various techniques, ranging from serology to histology, can be employed to detect intestinal CMV infection; however, there is currently disagreement in the literature regarding the most effective diagnostic test. Furthermore, CMV involvement in steroid resistance has been broadly discussed, but whether CMV infection is a cause or consequence of the disease severity and, consequently, steroid refractoriness is still debated. Its potential contribution to the lack of response to advanced therapy and small molecules must be more valued and wholly explored. In this review, we look at the actual literature on CMV in IBD patients, and we suggest a pragmatic algorithm for clinical practice management of CMV infection.
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Affiliation(s)
- Rossella Maresca
- CEMAD Digestive Diseases Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Rome, Italy; (R.M.); (S.V.); (F.D.V.); (M.E.A.); (I.M.); (A.P.); (F.S.); (A.G.); (L.L.)
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Simone Varca
- CEMAD Digestive Diseases Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Rome, Italy; (R.M.); (S.V.); (F.D.V.); (M.E.A.); (I.M.); (A.P.); (F.S.); (A.G.); (L.L.)
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Federica Di Vincenzo
- CEMAD Digestive Diseases Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Rome, Italy; (R.M.); (S.V.); (F.D.V.); (M.E.A.); (I.M.); (A.P.); (F.S.); (A.G.); (L.L.)
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Maria Elena Ainora
- CEMAD Digestive Diseases Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Rome, Italy; (R.M.); (S.V.); (F.D.V.); (M.E.A.); (I.M.); (A.P.); (F.S.); (A.G.); (L.L.)
| | - Irene Mignini
- CEMAD Digestive Diseases Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Rome, Italy; (R.M.); (S.V.); (F.D.V.); (M.E.A.); (I.M.); (A.P.); (F.S.); (A.G.); (L.L.)
| | - Alfredo Papa
- CEMAD Digestive Diseases Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Rome, Italy; (R.M.); (S.V.); (F.D.V.); (M.E.A.); (I.M.); (A.P.); (F.S.); (A.G.); (L.L.)
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Franco Scaldaferri
- CEMAD Digestive Diseases Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Rome, Italy; (R.M.); (S.V.); (F.D.V.); (M.E.A.); (I.M.); (A.P.); (F.S.); (A.G.); (L.L.)
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Antonio Gasbarrini
- CEMAD Digestive Diseases Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Rome, Italy; (R.M.); (S.V.); (F.D.V.); (M.E.A.); (I.M.); (A.P.); (F.S.); (A.G.); (L.L.)
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Maria Cristina Giustiniani
- Department of Pathology, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Largo A. Gemelli 8, 00168 Rome, Italy;
| | - Maria Assunta Zocco
- CEMAD Digestive Diseases Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Rome, Italy; (R.M.); (S.V.); (F.D.V.); (M.E.A.); (I.M.); (A.P.); (F.S.); (A.G.); (L.L.)
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Lucrezia Laterza
- CEMAD Digestive Diseases Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Rome, Italy; (R.M.); (S.V.); (F.D.V.); (M.E.A.); (I.M.); (A.P.); (F.S.); (A.G.); (L.L.)
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Ren K, Yong C, Wang Y, Wei H, Zhao K, He B, Cui M, Chen Y, Wang J. Cytomegalovirus Pneumonia in Inflammatory Bowel Disease: Literature Review and Clinical Recommendations. Infect Drug Resist 2023; 16:6195-6208. [PMID: 37724090 PMCID: PMC10505384 DOI: 10.2147/idr.s420244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Accepted: 08/22/2023] [Indexed: 09/20/2023] Open
Abstract
Aim The objective was to elucidate the correlation between CMVP and immunosuppressive therapy in IBD patients, we hope this review could expand on the significance of CMV as an opportunistic pathogen and the potential impact on morbidity and mortality in IBD patients. Methods Records and clinical trajectories linked to CMVP in IBD patients were extracted from the PubMed database, irrespective of language barriers. The reference lists incorporated in these studies were manually inspected. Conclusions were generated using straightforward descriptive analysis. Results In total, 18 IBD patients, including Crohn's disease (CD, 67%) and Ulcerative Colitis (UC, 33%), affected by CMVP were identified from 17 published articles. A minority of these patients (17%) exhibited active disease, whereas the majority (83%) presented with quiescent disease. Fever (100%) and dyspnea (44%) emerged as the most prevalent clinical symptoms. All the patients had undergone immunosuppressive therapy. A significant proportion, up to 89%, had received thiopurine treatment prior to the CMVP diagnosis. Interestingly, none of the patients were subjected to biological therapy. Half of the patients manifested with Hemophagocytic Lymphohistiocytosis (HLH). Almost all patients (94%) were administered antiviral treatment and a substantial 83% experienced full recovery. Immunosuppressive agents were either tapered or discontinued altogether. A subset of patients, 17%, suffered fatal outcomes. Conclusion Our findings underscore the need for heightened suspicion of CMVP in IBD patients who exhibit symptoms such as fever and dyspnea. During the COVID-19 pandemic, CMVP should be considered a potential differential diagnosis. It was observed that CMVP primarily transpires during CD remission. Azathioprine emerged as the predominant immunosuppressant linked to CMV reactivation. The prompt application of effective antiviral therapy can substantially enhance patient outcomes. CMV vaccine might serve as a viable prevention strategy.
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Affiliation(s)
- Keyu Ren
- Department of Gastroenterology, Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266000, People’s Republic of China
| | - Chunming Yong
- Department of Emergency, Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266000, People’s Republic of China
| | - Yanting Wang
- Department of Gastroenterology, Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266000, People’s Republic of China
| | - Hongyun Wei
- Department of Gastroenterology, Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266000, People’s Republic of China
| | - Kun Zhao
- Department of Gastroenterology, Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266000, People’s Republic of China
| | - Baoguo He
- Department of Gastroenterology, Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266000, People’s Republic of China
| | - Mingjuan Cui
- Department of Gastroenterology, Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266000, People’s Republic of China
| | - Yunqing Chen
- Department of Pathology, Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266000, People’s Republic of China
| | - Jin Wang
- Department of Pathology, School of Basic Medicine, Qingdao University, Qingdao, Shandong, 266000, People’s Republic of China
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Craviotto V, Furfaro F, Loy L, Zilli A, Peyrin-Biroulet L, Fiorino G, Danese S, Allocca M. Viral infections in inflammatory bowel disease: Tips and tricks for correct management. World J Gastroenterol 2021; 27:4276-4297. [PMID: 34366605 PMCID: PMC8316900 DOI: 10.3748/wjg.v27.i27.4276] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 04/01/2021] [Accepted: 05/15/2021] [Indexed: 02/06/2023] Open
Abstract
Over the past decades, the treatment of inflammatory bowel diseases (IBD) has become more targeted, anticipating the use of immune-modifying therapies at an earlier stage. This top-down approach has been correlated with favorable short and long-term outcomes, but it has also brought with it concerns regarding potential infectious complications. This large IBD population treated with immune-modifying therapies, especially if combined, has an increased risk of severe infections, including opportunistic infections that are sustained by viral, bacterial, parasitic, and fungal agents. Viral infections have emerged as a focal safety concern in patients with IBD, representing a challenge for the clinician: they are often difficult to diagnose and are associated with significant morbidity and mortality. The first step is to improve effective preventive strategies, such as applying vaccination protocols, adopt adequate prophylaxis and educate patients about potential risk factors. Since viral infections in immunosuppressed patients may present atypical signs and symptoms, the challenges for the gastroenterologist are to suspect, recognize and diagnose such complications. Appropriate treatment of common viral infections allows us to minimize their impact on disease outcomes and patients’ lives. This practical review supports this standard of care to improve knowledge in this subject area.
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Affiliation(s)
- Vincenzo Craviotto
- Humanitas Clinical and Research Center, IRCCS, Rozzano 20089, Milano, Italy
| | - Federica Furfaro
- Humanitas Clinical and Research Center, IRCCS, Rozzano 20089, Milano, Italy
| | - Laura Loy
- Humanitas Clinical and Research Center, IRCCS, Rozzano 20089, Milano, Italy
| | - Alessandra Zilli
- Humanitas Clinical and Research Center, IRCCS, Rozzano 20089, Milano, Italy
| | - Laurent Peyrin-Biroulet
- Department of Hepato-Gastroenterology and Inserm U954, University Hospital of Nancy, Lorraine University, Nancy 54511, France
| | - Gionata Fiorino
- Humanitas Clinical and Research Center, IRCCS, Rozzano 20089, Milano, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele 20090, Milano, Italy
| | - Silvio Danese
- Humanitas Clinical and Research Center, IRCCS, Rozzano 20089, Milano, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele 20090, Milano, Italy
| | - Mariangela Allocca
- Humanitas Clinical and Research Center, IRCCS, Rozzano 20089, Milano, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele 20090, Milano, Italy
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van der Sloot KWJ, Voskuil MD, Visschedijk MC, Festen EAM, van Dullemen HM, Weersma RK, Alizadeh BZ, van Leer-Buter C, Dijkstra G. Latent cytomegalovirus infection does not influence long-term disease outcomes in inflammatory bowel disease, but is associated with later onset of disease. Scand J Gastroenterol 2020; 55:891-896. [PMID: 32633160 DOI: 10.1080/00365521.2020.1786853] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVES Cytomegalovirus (CMV) infection is common in the general population. CMV infection negatively affects disease course in transplant recipients and HIV patients. Whereas primary CMV infections may occur sporadically in seronegative patients, all seropositive patients with inflammatory bowel syndrome (IBD) are at risk for CMV reactivation due to the inflammatory mucosal and use of immunosuppressive medication. It is unclear whether latent CMV infection, and risk of reactivations, influences long-term disease outcomes. In this study, we aim to explore whether CMV infection affects disease outcomes in IBD patients. METHODS We performed a cross-sectional cohort study with 1404 patients with IBD from a single center. Clinical characteristics and disease outcomes were prospectively collected. We scrutinized CMV serology test results and performed additional CMV serology testing if serum was available. RESULTS Out of 699 IBD patients with CMV serology, 303 (43.3%) were seropositive, comparable to the general Dutch population. CMV seropositivity was associated with older age, longer IBD disease duration, non-Western origin, birth outside the Netherlands and a lower educational level (p-values ≤ .004). CMV seropositivity was not associated with more complicated long-term disease outcomes of IBD (p-values > .05). Seropositive patients presented with symptoms and were diagnosed at an older age compared to seronegative patients (p-values < .01). CONCLUSIONS CMV seropositivity does not influence disease outcomes of IBD patients and seems to be associated with a delay in IBD onset. Guidelines regarding CMV screening in patients with IBD are currently based on a low level of evidence. These data support the recommendation that routine CMV serology measurement is not necessary in the clinical care of IBD.
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Affiliation(s)
- Kimberley W J van der Sloot
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
- Department of Epidemiology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - Michiel D Voskuil
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
- Department of Genetics, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - Marijn C Visschedijk
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - Eleonora A M Festen
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
- Department of Genetics, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - Hendrik M van Dullemen
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - Rinse K Weersma
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - Behrooz Z Alizadeh
- Department of Epidemiology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - Coretta van Leer-Buter
- Department of Medical Microbiology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - Gerard Dijkstra
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
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Reactivation of Epstein-Barr Virus Presenting as Massive Splenomegaly after Initiation of Golimumab Treatment. Case Rep Hematol 2020; 2020:3641813. [PMID: 32328321 PMCID: PMC7171624 DOI: 10.1155/2020/3641813] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 03/13/2020] [Indexed: 02/06/2023] Open
Abstract
Epstein–Barr virus infection is most commonly asymptomatic in the acute setting, where the end result of infection is the adoption of a viral latency phenotype. The virus can reactivate later in life leading to the abnormal proliferation of the infected B, T, or NK cells. Hereby, we report a 71-year-old female with seronegative rheumatoid arthritis who presented with massive splenomegaly, pancytopenia, and positivization of antibodies against double-stranded deoxyribonucleic acid (dsDNA) after initiation of the anti-tumor necrosis factor (TNF) golimumab. The diagnosis of EBV-associated lymphoproliferative disorder (LPD) was demonstrated by elevation of the plasmatic EBV viral load. Withdrawal of the anti-TNF and treatment with the anti-CD20 antibody rituximab were able to revert the clinical abnormalities. EBV-associated LPDs are described after initiation of other anti-TNF agents, such as infliximab, but no reports of golimumab-associated EBV LPD are found in the literature. The mechanisms for this occurrence are not clear, but these are known to involve expression of a panel of viral proteins specific to the viral latency phenotypes.
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Rodríguez-Lago I, Merino O, López de Goicoechea MJ, Aranzamendi M, Zubiaurre L, Muro N, Ortiz de Zárate J, Cilla G, Cabriada JL. Immunosuppression for inflammatory bowel disease does not influence Epstein-Barr viral load in the short-term. GASTROENTEROLOGIA Y HEPATOLOGIA 2019; 42:542-547. [PMID: 31402179 DOI: 10.1016/j.gastrohep.2019.03.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 03/16/2019] [Accepted: 03/23/2019] [Indexed: 10/26/2022]
Abstract
INTRODUCTION Immunomodulators and biologics are two of the main drugs used for the treatment of inflammatory bowel disease (IBD). Some of these agents have been associated with certain infections and lymphoproliferative disorders, including Epstein-Barr virus (EBV) infection. Our aim was to determine the influence of immunosuppression in the EBV viral load in patients with IBD. MATERIALS AND METHODS We prospectively included naïve patients with IBD who were starting immunosuppressive therapy in four IBD Units. All patients were assessed at baseline and four months after starting immunosuppression for clinical disease activity, biomarkers, EBV serology (IgM VCA, IgG VCA and IgG EBNA) and viral load. RESULTS Thirty-two patients were included. At baseline, all patients showed positive results for IgG VCA or IgG EBNA with undetectable EBV viral load. No patient showed detectable EBV viral load after starting the immunosuppressive therapy. CONCLUSION Immunosuppression did not influence on EBV viral load in the short-term in naïve IBD patients.
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Affiliation(s)
| | - Olga Merino
- Hospital Universitario de Cruces, Gastroenterology Department, Barakaldo, Spain
| | | | | | - Leire Zubiaurre
- Hospital de Mendaro, Gastroenterology Department, Mendaro, Spain
| | - Nerea Muro
- Hospital Universitario Donostia, Gastroenterology Department, San Sebastián, Spain
| | | | - Gustavo Cilla
- Hospital Universitario Donostia, Microbiology and CIBERES, San Sebastián, Spain
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Hissong E, Chen Z, Yantiss RK. Cytomegalovirus reactivation in inflammatory bowel disease: an uncommon occurrence related to corticosteroid dependence. Mod Pathol 2019; 32:1210-1216. [PMID: 30952971 DOI: 10.1038/s41379-019-0258-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Revised: 01/30/2019] [Accepted: 01/31/2019] [Indexed: 02/07/2023]
Abstract
Cytomegalovirus promotes mucosal injury in patients with inflammatory bowel disease, historically affecting 10-25% of ulcerative colitis patients with refractory disease. Viral reactivation is likely related to long-term corticosteroid therapy, which is no longer central to maintenance of patients with inflammatory bowel disease. We hypothesize that viral detection rates have decreased in the modern era, reflecting widespread use of immunomodulatory agents to control inflammation. We performed this study to evaluate the relationships between medical regimens and cytomegalovirus detection rates among patients with inflammatory bowel disease. We searched our database for all patients with established inflammatory bowel disease and severe flares diagnosed from 2002 to 2017. Patients maintained with corticosteroid therapy were considered to be corticosteroid-dependent and those treated with other agents were classified as corticosteroid-independent, provided they had not received corticosteroids within 6 months of colonoscopy. Biopsy samples were reviewed for viral inclusions and subjected to cytomegalovirus immunohistochemistry, and rates of viral detection were compared between groups. There were 135 corticosteroid-dependent patients; most had ulcerative colitis flares occurring during the 2002-2009 period. Patients with ulcerative colitis and Crohn disease were equally represented in the corticosteroid-independent group (n = 133) and most were evaluated for disease flares during the 2010-2017 interval. Cytomegalovirus was detected in 13 (8%) cases; 9 (69%) were diagnosed from 2002 to 2009 and all were obtained from corticosteroid-dependent patients (p = < 0.001). We conclude that rates of cytomegalovirus-related enterocolitis are declining among inflammatory bowel disease patients, reflecting a shift away from corticosteroid-based maintenance therapy in favor of more effective agents that do not promote viral reactivation.
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Affiliation(s)
- Erika Hissong
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.
| | - Zhengming Chen
- Division of Biostatistics and Epidemiology, Department of Healthcare Policy and Research, Weill Cornell Medicine, New York, NY, USA
| | - Rhonda K Yantiss
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
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Progressive Multifocal Leukoencephalopathy in Primary Immunodeficiencies. J Clin Immunol 2018; 39:55-64. [PMID: 30552536 DOI: 10.1007/s10875-018-0578-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Accepted: 12/03/2018] [Indexed: 10/27/2022]
Abstract
PURPOSE Progressive multifocal leukoencephalopathy (PML) is a rare but severe demyelinating disease caused by the polyomavirus JC (JCV) in immunocompromised patients. We report a series of patients with primary immune deficiencies (PIDs) who developed PML. METHODS Retrospective observational study including PID patients with PML. Clinical, immunological, imaging features, and outcome are provided for each patient. RESULTS Eleven unrelated patients with PIDs developed PML. PIDs were characterized by a wide range of syndromic or genetically defined defects, mostly with combined B and T cell impairment. Genetic diagnosis was made in 7 patients. Before the development of PML, 10 patients had recurrent infections, 7 had autoimmune and/or inflammatory manifestations, and 3 had a history of malignancies. Immunologic investigations showed CD4+ lymphopenia (median 265, range 50-344) in all cases. Six patients received immunosuppressive therapy in the year before PML onset, including prolonged steroid therapy in 3 cases, rituximab in 5 cases, anti-TNF-α therapy, and azathioprine in 1 case each. Despite various treatments, all but 1 patient died after a median of 8 months following PML diagnosis. CONCLUSION PML is a rare but fatal complication of PIDs. Many cases are secondary to immunosuppressive therapy warranting careful evaluation before initiation subsequent immunosuppression during PIDs.
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ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Soluble immune effector molecules [I]: anti-tumor necrosis factor-α agents). Clin Microbiol Infect 2018; 24 Suppl 2:S10-S20. [DOI: 10.1016/j.cmi.2017.12.025] [Citation(s) in RCA: 126] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2017] [Revised: 12/25/2017] [Accepted: 12/30/2017] [Indexed: 12/14/2022]
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Ramasamy BR, Charles P, Johnson D, Frauman A. Massive splenomegaly due to concurrent primary Epstein-Barr virus and cytomegalovirus infection in a patient on adalimumab. BMJ Case Rep 2017; 2017:bcr-2017-220184. [PMID: 28864556 DOI: 10.1136/bcr-2017-220184] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
A 32-year-old man who was receiving adalimumab for seronegative rheumatoid arthritis presented with a 4-week history of fever, night sweats, fatigue, myalgias and diarrhoea. On examination, he had obvious splenomegaly but no lymphadenopathy or pharyngitis. Full blood count revealed mild neutropenia and significant lymphocytosis, with a blood film showing atypical lymphocytes. Liver function tests were mildly deranged with a mixed hepatitic and obstructive pattern. Ultrasound confirmed massive splenomegaly with a span of 21 cm in the long axis. Serological tests confirmed the presence of both primary Epstein-Barr virus and cytomegalovirus infections. The patient had his adalimumab withheld, was treated with supportive measures and improved over a period of 8 weeks. He remained well 5 months after the onset of illness with complete normalisation of blood count and a resolution of the splenomegaly.
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Affiliation(s)
| | - Patrick Charles
- Department of General Medicine, Austin Health, Heidelberg, Victoria, Australia.,Infectious Diseases Department, Austin Health, Heidelberg, Victoria, Australia
| | - Douglas Johnson
- Department of General Medicine, Austin Health, Heidelberg, Victoria, Australia.,Infectious Diseases Department, Austin Health, Heidelberg, Victoria, Australia
| | - Albert Frauman
- Department of Clinical Pharmacology and Therapeutics, Austin Health, Heidelberg, Victoria, Australia.,Acute Medical Group, Cabrini Hospital, Malvern, Victoria, Australia
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12
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Sondermann W, Baba HA, Körber A. Hepatitis due to EBV-reactivation under infliximab in a psoriasis patient. Dermatol Ther 2017; 30. [PMID: 28771953 DOI: 10.1111/dth.12525] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Revised: 05/30/2017] [Accepted: 06/06/2017] [Indexed: 11/30/2022]
Affiliation(s)
- Wiebke Sondermann
- Department of Dermatology, Venereology, and Allergology, University School of Medicine Essen-Duisburg, Essen, Germany
| | - Hideo A Baba
- Institute of Pathology, University School of Medicine Essen-Duisburg, Essen, Germany
| | - Andreas Körber
- Department of Dermatology, Venereology, and Allergology, University School of Medicine Essen-Duisburg, Essen, Germany
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13
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Campos ST, Portela FA, Tomé L. Cytomegalovirus, inflammatory bowel disease, and anti-TNFα. Int J Colorectal Dis 2017; 32:645-650. [PMID: 28084548 DOI: 10.1007/s00384-017-2752-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/06/2017] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND PURPOSE Anti-TNFα agents emerged in inflammatory bowel disease (IBD) as an effective option in situations that, otherwise, would be refractory to medical therapy. Cytomegalovirus infection may present with a high spectrum of manifestations and lead to high morbidity and mortality. However, its clinical significance in IBD course remains unknown and data on its association with anti-TNFα are limited. AIMS This study aims to evaluate cytomegalovirus (CMV) infection/disease in patients with IBD treated with anti-TNFα; if possible, possible risk factors associated with CMV infection/disease in IBD patients under anti-TNFα as well as the influence of CMV infection/disease in IBD course would be determined. METHODS During three consecutive years, all IBD patients starting infliximab in our department were included. Cytomegalovirus status before anti-TNFα was evaluated. Data regarding IBD, therapeutic and IBD course after infliximab, were recorded. CMV analysis was performed with polymerase chain reaction (PCR)-cytomegalovirus in peripheral blood and colonoscopy with biopsies (histopathology/immunohistochemistry). RESULTS We included 29 patients: female-83%; Crohn's disease-51.8%, ulcerative colitis-44.8%, non-classified colitis-3.4%; 23 cytomegalovirus seropositive. Median follow-up: 19 months (3-36). During follow-up, 14 patients were under combination therapy with azathioprine and 5 did at least 1 cycle of corticosteroids. Twenty-one patients responded to infliximab. We registered 8 exacerbations of IBD. Four patients discontinued infliximab: none had CMV infection. We documented 1 case of intestinal cytomegalovirus infection-detected in biopsies performed per protocol in an asymptomatic UC patient, who responded to valganciclovir without infliximab discontinuation. CONCLUSIONS Infliximab, with/without immunosuppression, does not confer an increased risk of (re)activation of cytomegalovirus. Cytomegalovirus was not responsible neither for significant morbidity nor mortality in IBD.
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Affiliation(s)
- Sara T Campos
- Gastroenterology Department, Centro Hospitalar e Universitário de Coimbra, Praçeta Prof. Mota Pinto, 3000-075, Coimbra, Portugal.
| | - Francisco A Portela
- Gastroenterology Department, Centro Hospitalar e Universitário de Coimbra, Praçeta Prof. Mota Pinto, 3000-075, Coimbra, Portugal
| | - Luís Tomé
- Gastroenterology Department, Centro Hospitalar e Universitário de Coimbra, Praçeta Prof. Mota Pinto, 3000-075, Coimbra, Portugal
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Park SC, Jeen YM, Jeen YT. Approach to cytomegalovirus infections in patients with ulcerative colitis. Korean J Intern Med 2017; 32:383-392. [PMID: 28490715 PMCID: PMC5432807 DOI: 10.3904/kjim.2017.087] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Accepted: 03/06/2017] [Indexed: 12/16/2022] Open
Abstract
Cytomegalovirus (CMV) reactivation is common in patients with severe ulcerative colitis (UC), and may ref lect exacerbation of mucosal inf lammation and/or administration of immunosuppressants. The question of whether CMV is an active pathogen or 'an innocent bystander' in the exacerbation of UC remains controversial. Patients with UC exacerbated by reactivated CMV experience worse prognoses than those without CMV reactivation and antiviral therapy significantly reduces the need for colectomy in patients with severe UC and high-grade CMV infection, indicating that CMV plays a role in UC prognosis. Therefore, the CMV status of patients on immunosuppressants, particularly those with steroid-refractory or -dependent UC, should be tested. When CMV is detected, be performed based on should adequate treatment the extent of the viral load and the presence of certain clinical features including a large ulcer. Anti-tumor necrosis factor agents may be useful for treating CMV colitis complicating UC.
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Affiliation(s)
- Sung Chul Park
- Department of Internal Medicine, Kangwon National University Hospital, Chuncheon, Korea
| | - Yoon Mi Jeen
- Department of Pathology, Soon Chun Hyang University Seoul Hospital, Seoul, Korea
- Correspondence to Yoon Mi Jeen, M.D. Department of Pathology, Soon Chun Hyang University Seoul Hospital, 59 Daesagwan-ro, Yongsan-gu, Seoul 04401, Korea Tel: +82-2-709-9435 Fax: +82-2-709-9441 E-mail:
| | - Yoon Tae Jeen
- Department of Internal Medicine, Korea University Anam Hospital, Seoul, Korea
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Shukla T, Singh S, Tandon P, McCurdy JD. Corticosteroids and Thiopurines, But Not Tumor Necrosis Factor Antagonists, are Associated With Cytomegalovirus Reactivation in Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis. J Clin Gastroenterol 2017; 51:394-401. [PMID: 27875356 DOI: 10.1097/mcg.0000000000000758] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND The association between cytomegalovirus (CMV) reactivation and individual immunosuppressive agents in inflammatory bowel disease (IBD) has not been clearly defined. Therefore, we performed a systematic review and meta-analysis to assess this association. METHODS Multiple electronic databases were searched systematically through July 2015 for observational studies reporting CMV reactivation (based on serum-based or tissue-based tests) in IBD patients stratified by medication exposure. We estimated summary odds ratios (ORs) and 95% confidence intervals (CI) using random-effects model. Study quality was assessed using the Newcastle-Ottawa scale. RESULTS Sixteen observational studies were identified. As compared with nonexposed patients, exposure to corticosteroids (CS) (12 studies, 1180 patients, 52.3% exposed; OR, 2.05; 95% CI, 1.40-2.99) and thiopurines (14 studies, 1273 patients, 24.1% exposed; OR, 1.56; 95% CI, 1.01-2.39) was associated with increased risk of CMV reactivation. In contrast, as compared with patients not exposed to tumor necrosis factor (TNF) antagonists, exposure to TNF antagonists was not associated with an increased risk of CMV reactivation (7 studies, 818 patients, 18.5% exposed; OR, 1.44; 95% CI, 0.93-2.24). The results remained stable for CS and thiopurines when the analysis was limited to hospitalized patients, and by a tissue-based diagnosis. Studies were limited in the ability to assess the impact of concomitant immunosuppressive therapy, duration of medication exposure, and disease severity. CONCLUSIONS On the basis of 16 observational studies, exposure to CS or thiopurines, but not TNF antagonists, was associated with an increased risk of CMV reactivation in IBD patients.
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Affiliation(s)
- Tushar Shukla
- *Division of Gastroenterology and Hepatology, The Ottawa Hospital, Ottawa, ON, Canada †Division of Gastroenterology, University of California San Diego, La Jolla, CA
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McCurdy JD, Enders FT, Khanna S, Bruining DH, Jones A, Killian JM, Tariq R, Smyrk TC, Loftus EV. Increased Rates of Clostridium difficile Infection and Poor Outcomes in Patients with IBD with Cytomegalovirus. Inflamm Bowel Dis 2016; 22:2688-2693. [PMID: 27755270 DOI: 10.1097/mib.0000000000000939] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Clostridium difficile infection (CDI) and Cytomegalovirus (CMV) reactivation are associated with disease exacerbations and poor outcomes in inflammatory bowel disease (IBD). Therefore, we assessed the association between these organisms in patients with IBD and the impact on colectomy. METHODS A retrospective case-control study was conducted to assess CDI prevalence in patients with IBD with a tissue diagnosis of CMV compared with matched IBD controls without CMV from 2005 to 2011. We also assessed the impact of coinfection on colectomy risk for patients coinfected with CMV and CDI compared with IBD patients with CMV alone (CMV controls) or matched IBD patients with CDI alone (CDI controls). Colectomy-free survival was assessed using Kaplan-Meier methods, and statistical significance was determined using Log-rank analysis for unmatched comparisons and by generalized estimating equations in Cox regression for matched comparisons. RESULTS CDI was more common in IBD patients with CMV (n = 12/68; 17.6%) than in matched IBD controls (n = 12/144; 8.25%) (P = 0.046). A nonsignificant increase in high-grade disease (5 or more CMV inclusions by immunohistochemistry) was detected in coinfected patients compared with CMV controls (P = 0.15). Colectomy-free survival at 1 year was 30% (95% confidence interval, 12.0-74.7) for coinfected patients and was significantly less compared with 71.5% (95% confidence interval, 58.0-88.2) of CDI controls (P < 0.001) and was numerically less than 57.1% (95% confidence interval, 44.1-74.0) of CMV controls (P = 0.095). CONCLUSIONS CDI occurs more frequently in IBD patients with CMV reactivation and is associated with poor outcomes. Patients with IBD with CMV should be tested for CDI and managed aggressively.
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Affiliation(s)
- Jeffrey D McCurdy
- *Division of Gastroenterology and Hepatology, University of Ottawa, Ottawa, Ontario, Canada; †Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; ‡Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota; and §Department of Anatomical Pathology, Mayo Clinic, Rochester, Minnesota
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Bontà J, Zeitz J, Frei P, Biedermann L, Sulz MC, Vavricka SR, Scharl S, Fried M, Rogler G, Scharl M. Cytomegalovirus disease in inflammatory bowel disease: epidemiology and disease characteristics in a large single-centre experience. Eur J Gastroenterol Hepatol 2016; 28:1329-34. [PMID: 27482785 DOI: 10.1097/meg.0000000000000716] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
BACKGROUND Patients with inflammatory bowel disease (IBD) show an increased risk of developing cytomegalovirus (CMV) disease because of immunosuppressive medication and malnutrition. Here, we aimed to investigate the prevalence and clinical characteristics of CMV disease in our cohort of IBD patients. PATIENTS AND METHODS We carried out a retrospective analysis of 1023 IBD patients treated at our IBD clinic at the University Hospital Zurich between 2007 and 2014. CMV disease was defined as a positive immunohistochemistry for CMV and 14 patients were identified. RESULTS The prevalence of CMV disease in our IBD cohort was 1.37%. Twelve patients had ulcerative colitis and two had Crohn's disease with colonic involvement. All patients who developed CMV disease received immunosuppressive medication or, as in one case, had HIV infection. The most used immunosuppressive medications were steroids and azathioprine. The most common therapeutic strategy was the consecutive use of ganciclovir and valganciclovir. Ten patients recovered and two were treatment refractory; among these, one required colectomy and two had a relapse. CONCLUSION CMV disease may influence the clinical course of IBD. There is probably an association between CMV disease and IBD-specific medication. Risk factors, epidemiology and therapeutic strategy need to be further investigated.
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Affiliation(s)
- Jonas Bontà
- aDivision of Gastroenterology and Hepatology, University Hospital Zurich bZurich Center for Integrative Human Physiology, University of Zurich cDivision of Gastroenterology and Hepatology, Triemli Hospital dDivision of Gastroenterology and Hepatology, Clinic Bethanien, Zurich eDivision of Gastroenterology and Hepatology, Kantonsspital St Gallen, Switzerland
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Thörn M, Rorsman F, Rönnblom A, Sangfelt P, Wanders A, Eriksson BM, Bondeson K. Active cytomegalovirus infection diagnosed by real-time PCR in patients with inflammatory bowel disease: a prospective, controlled observational study (.). Scand J Gastroenterol 2016; 51:1075-80. [PMID: 27142339 DOI: 10.3109/00365521.2016.1156154] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE It is assumed that cytomegaloviral (CMV) infection in inflammatory bowel disease (IBD) is caused by reactivation due to the immunosuppressive therapy, but the role of CMV as a pathophysiological factor and prognostic marker in IBD is unclear. The aim of this study was to investigate CMV infection in IBD, with real-time polymerase chain reaction (PCR) and immunohistochemistry, with emphasis on newly diagnosed disease. MATERIALS AND METHODS In this prospective, controlled study, 67 patients with IBD and 34 control patients with irritable bowel syndrome (IBS) or rectal bleeding were included. Serology for CMV was analysed along with CMV DNA in plasma, mucosal biopsies, and faeces. Mucosal biopsies were further analysed with histopathology and CMV immunohistochemistry. RESULTS Detection of CMV IgM was more common in patients with IBD, compared to controls, 21% versus 3%. CMV DNA was found in 16% of patients with newly diagnosed, untreated IBD and in 38% of steroid-treated patients. Four of the five patients that needed urgent surgery were CMV-DNA positive in at least one of three sample types. None of the controls had detectable CMV DNA. CONCLUSIONS Active CMV infection was found in high proportions of newly diagnosed untreated patients with IBD, in patients on immunosuppression and in patients in the need of surgery. Low CMV-DNA levels in non-immunosuppressed patients were not a risk factor for the development of more severe IBD, while the detection of CMV DNA in patients on immunosuppressive therapy may foresee disease progression.
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Affiliation(s)
- Mari Thörn
- a Department of Medical Sciences, Section of Gastroenterology and Hepatology , Uppsala University , Uppsala , Sweden
| | - Fredrik Rorsman
- a Department of Medical Sciences, Section of Gastroenterology and Hepatology , Uppsala University , Uppsala , Sweden
| | - Anders Rönnblom
- a Department of Medical Sciences, Section of Gastroenterology and Hepatology , Uppsala University , Uppsala , Sweden
| | - Per Sangfelt
- a Department of Medical Sciences, Section of Gastroenterology and Hepatology , Uppsala University , Uppsala , Sweden
| | - Alkwin Wanders
- b Department of Immunology, Genetics and Pathology , Uppsala University , Uppsala , Sweden
| | - Britt-Marie Eriksson
- c Department of Medical Sciences, Section of Infectious Diseases , Uppsala University , Uppsala , Sweden
| | - Kåre Bondeson
- d Department of Medical Sciences, Clinical Microbiology and Infectious Medicine , Uppsala University , Uppsala , Sweden
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NASPGHAN Clinical Report: Surveillance, Diagnosis, and Prevention of Infectious Diseases in Pediatric Patients With Inflammatory Bowel Disease Receiving Tumor Necrosis Factor-α Inhibitors. J Pediatr Gastroenterol Nutr 2016; 63:130-55. [PMID: 27027903 DOI: 10.1097/mpg.0000000000001188] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Children and adolescents with inflammatory bowel disease (IBD) receiving therapy with tumor necrosis factor α inhibitors (anti-TNFα) pose a unique challenge to health care providers in regard to the associated risk of infection. Published experience in adult populations with distinct autoinflammatory and autoimmune diseases treated with anti-TNFα therapies demonstrates an increased risk of serious infections with intracellular bacteria, mycobacteria, fungi, and some viruses; however, there is a paucity of robust pediatric data. With a rising incidence of pediatric IBD and increasing use of biologic therapies, heightened knowledge and awareness of infections in this population is important for primary care pediatricians, pediatric gastroenterologists, and infectious disease (ID) physicians. This clinical report is the result of a consensus review performed by pediatric ID and gastroenterology physicians detailing relevant published literature regarding infections in pediatric patients with IBD receiving anti-TNFα therapies. The objective of this document is to provide comprehensive information for prevention, surveillance, and diagnosis of infections based on current knowledge, until additional pediatric data are available to inform evidence-based recommendations.
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Rodio DM, Anzivino E, Mischitelli M, Bellizzi A, Scrivo R, Scribano D, Conte G, Prezioso C, Trancassini M, Valesini G, Palamara AT, Pietropaolo V. Increased Prevalence of Human Polyomavirus JC Viruria in Chronic Inflammatory Rheumatic Diseases Patients in Treatment with Anti-TNF α: A 18 Month Follow-Up Study. Front Microbiol 2016; 7:672. [PMID: 27242700 PMCID: PMC4861734 DOI: 10.3389/fmicb.2016.00672] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2016] [Accepted: 04/22/2016] [Indexed: 12/04/2022] Open
Abstract
Chronic inflammatory rheumatic diseases (CIRDs) are immune-mediated pathologies involving joints. To date, TNFα-blocking agents administration is the most promising therapy, although these treatments are associated with an increased Polyomavirus JC (JCPyV) reactivation, the etiological agent of the Progressive Multifocal Leukoencephalopathy (PML). The aim of this study was the recruitment and the analysis of a CIRDs cohort in order to investigate a possible correlation between JCPyV presence and the influence of anti-TNF-α agents on viral loads. Blood and urine samples were collected from 34 CIRDs subjects prior the first anti-TNF-α infusion (T0) and after 3 (T3), 6 (T6), 12 (T12), and 18 (T18) months. Results showed persistent JC viruria significantly higher than JC viremia throughout the 18 month follow-up study (p = 0.002). In JCPyV positive samples, the non-coding control region (NCCR) was analyzed. Results evidenced archetypal structures (type II-S) in all isolates with the exception of a sequence isolated from a plasma sample, that corresponds to the type II-R found in PML subjects. Finally, the viral protein 1 (VP1) genotyping was performed and results showed the prevalence of the European genotypes 1A, 1B, and 4. Since only few studies have been carried out to understand whether there is a PML risk in CIRDs population infected by JCPyV, this study contributes to enrich literature insight on JCPyV biology in this cluster. Further investigations are necessary in order to recognize the real impact of biologics on JCPyV life cycle and to identify possible and specific viral variants related to increased virulence in CIRDs patients.
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Affiliation(s)
- Donatella Maria Rodio
- Department of Public Health and Infectious Diseases, "Sapienza" University of Rome Rome, Italy
| | - Elena Anzivino
- Department of Public Health and Infectious Diseases, "Sapienza" University of Rome Rome, Italy
| | - Monica Mischitelli
- Department of Public Health and Infectious Diseases, "Sapienza" University of Rome Rome, Italy
| | - Anna Bellizzi
- Department of Public Health and Infectious Diseases, Institute Pasteur, Cenci-Bolognetti Foundation, "Sapienza" University of Rome Rome, Italy
| | - Rossana Scrivo
- Department of Internal Medicine and Medical Disciplines, Rheumatology, "Sapienza" University of Rome Rome, Italy
| | - Daniela Scribano
- Department of Experimental and Clinical Sciences, "G. D'Annunzio" University of Chieti Chieti, Italy
| | - Gianlorenzo Conte
- Department of Public Health and Infectious Diseases, "Sapienza" University of Rome Rome, Italy
| | - Carla Prezioso
- Department of Public Health and Infectious Diseases, "Sapienza" University of Rome Rome, Italy
| | - Maria Trancassini
- Department of Public Health and Infectious Diseases, "Sapienza" University of Rome Rome, Italy
| | - Guido Valesini
- Department of Internal Medicine and Medical Disciplines, Rheumatology, "Sapienza" University of Rome Rome, Italy
| | - Anna Teresa Palamara
- Department of Public Health and Infectious Diseases, Institute Pasteur, Cenci-Bolognetti Foundation, "Sapienza" University of RomeRome, Italy; San Raffaele Pisana Scientific Institute for Research, Hospitalization and Health CareRome, Italy
| | - Valeria Pietropaolo
- Department of Public Health and Infectious Diseases, "Sapienza" University of RomeRome, Italy; Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple UniversityPhiladelphia, PA, USA
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Pillet S, Pozzetto B, Roblin X. Cytomegalovirus and ulcerative colitis: Place of antiviral therapy. World J Gastroenterol 2016; 22:2030-2045. [PMID: 26877608 PMCID: PMC4726676 DOI: 10.3748/wjg.v22.i6.2030] [Citation(s) in RCA: 67] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2015] [Revised: 11/19/2015] [Accepted: 12/19/2015] [Indexed: 02/06/2023] Open
Abstract
The link between cytomegalovirus (CMV) infection and inflammatory bowel diseases remains an important subject of debate. CMV infection is frequent in ulcerative colitis (UC) and has been shown to be potentially harmful. CMV reactivation needs to be diagnosed using methods that include in situ detection of viral markers by immunohistochemistry or by nucleic acid amplification techniques. Determination of the density of infection using quantitative tools (numbers of infected cells or copies of the genome) is particularly important. Although CMV reactivation can be considered as an innocent bystander in active flare-ups of refractory UC, an increasing number of studies suggest a deleterious role of CMV in this situation. The presence of colonic CMV infection is possibly linked to a decreased response to steroids and other immunosuppressive agents. Some treatments, notably steroids and cyclosporine A, have been shown to favor CMV reactivation, which seems not to be the case for therapies using anti-tumor necrosis factor drugs. According to these findings, in flare-ups of refractory UC, it is now recommended to look for the presence of CMV reactivation by using quantitative tools in colonic biopsies and to treat them with ganciclovir in cases of high viral load or severe disease.
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Römkens TEH, Bulte GJ, Nissen LHC, Drenth JPH. Cytomegalovirus in inflammatory bowel disease: A systematic review. World J Gastroenterol 2016; 22:1321-30. [PMID: 26811669 PMCID: PMC4716042 DOI: 10.3748/wjg.v22.i3.1321] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 10/12/2015] [Accepted: 11/30/2015] [Indexed: 02/06/2023] Open
Abstract
AIM To identify definitions of cytomegalovirus (CMV) infection and intestinal disease, in inflammatory bowel disease (IBD), to determine the prevalence associated with these definitions. METHODS We conducted a systematic review and interrogated PubMed, EMBASE and Cochrane for literature on prevalence and diagnostics of CMV infection and intestinal disease in IBD patients. As medical headings we used "cytomegalovirus" OR "CMV" OR "cytomegalo virus" AND "inflammatory bowel disease" OR "IBD" OR "ulcerative colitis" OR "colitis ulcerosa" OR "Crohn's disease". Both MeSH-terms and free searches were performed. We included all types of English-language (clinical) trials concerning diagnostics and prevalence of CMV in IBD. RESULTS The search strategy identified 924 citations, and 52 articles were eligible for inclusion. We identified 21 different definitions for CMV infection, 8 definitions for CMV intestinal disease and 3 definitions for CMV reactivation. Prevalence numbers depend on used definition, studied population and region. The highest prevalence for CMV infection was found when using positive serum PCR as a definition, whereas for CMV intestinal disease this applies to the use of tissue PCR > 10 copies/mg tissue. Most patients with CMV infection and intestinal disease had steroid refractory disease and came from East Asia. CONCLUSION We detected multiple different definitions used for CMV infection and intestinal disease in IBD patients, which has an effect on prevalence numbers and eventually on outcome in different trials.
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Seroprevalence of Epstein-Barr Virus, Cytomegalovirus, and Polyomaviruses in Children with Inflammatory Bowel Disease. Dig Dis Sci 2015; 60:3399-407. [PMID: 26091801 DOI: 10.1007/s10620-015-3764-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2015] [Accepted: 06/11/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND Young age and thiopurine therapy are risk factors for lymphoproliferative disease among patients with inflammatory bowel disease (IBD). AIMS The aims of this study were to evaluate the prevalence of seropositivity for the Epstein-Barr virus (EBV) and human cytomegalovirus (CMV) among children and adolescents with IBD, to assess the viral load of EBV, CMV, and BK and JC polyomaviruses (BKV, JCV) in these patients, and to assess the influence of different therapeutic regimens on seroprevalence and viral load. METHODS Children who had been followed in our center were tested for EBV, CMV, BKV, and JCV in a cross-sectional study. One hundred and six children were included who had Crohn's disease (68%), ulcerative colitis (29%), and unclassified IBD (3%). RESULTS We found that 64% of patients were EBV seropositive. The proportion of EBV seropositive patients increased during childhood. Azathioprine therapy (p = 0.003) was associated with EBV seropositivity in a multiple logistic regression model, after adjusting for gender, age, and disease activity at determination. We found a significant association between the number of polymerase chain reaction copies and infliximab dose (p = 0.023). We did not find any significant association between CMV serology and CMV, BKV, or JCV viral load, or any other therapeutic regimen or clinical characteristics. CONCLUSIONS Treatment with azathioprine appears to be a risk factor for early EBV seropositivity in children with IBD, and the infliximab dose was associated with a higher EBV viral load.
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Lapsia S, Koganti S, Spadaro S, Rajapakse R, Chawla A, Bhaduri-McIntosh S. Anti-TNFα therapy for inflammatory bowel diseases is associated with Epstein-Barr virus lytic activation. J Med Virol 2015; 88:312-8. [PMID: 26307954 DOI: 10.1002/jmv.24331] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/12/2015] [Indexed: 01/19/2023]
Abstract
Anti-TNFα therapy, known to suppress T-cell immunity, is increasingly gaining popularity for treatment of autoimmune diseases including inflammatory bowel diseases (IBD). T-cell suppression increases the risk of B-cell EBV-lymphoproliferative diseases and lymphomas. Since EBV-lytic activation is essential for development of EBV-lymphomas and there have been reports of EBV-lymphomas in patients treated with anti-TNFα therapy, we investigated if patients treated with anti-TNFα antibodies demonstrate greater EBV-lytic activity in blood. Peripheral blood mononuclear cells from 10 IBD patients solely on anti-TNFα therapy compared to 3 control groups (10 IBD patients not on immunosuppressive therapy, 10 patients with abdominal pain but without IBD, and 10 healthy subjects) were examined for the percentage of T-cells, EBV load and EBV-lytic transcripts. Patients on anti-TNFα therapy had significantly fewer T-cells, greater EBV load, and increased levels of transcripts from EBV-lytic genes of all kinetic classes compared to controls. Furthermore, exposure of EBV-infected B-cell lines to anti-TNFα antibodies resulted in increased levels of BZLF1 mRNA; BZLF1 encodes for ZEBRA, the viral latency-to-lytic cycle switch. Thus, IBD patients treated with anti-TNFα antibodies have greater EBV loads likely due to enhanced EBV-lytic gene expression and anti-TNFα antibodies may be sufficient to activate the EBV lytic cycle. Findings from this pilot study lay the groundwork for additional scientific and clinical investigation into the effects of anti-TNFα therapy on the life cycle of EBV, a ubiquitous oncovirus that causes lymphomas in the setting of immunocompromise.
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Affiliation(s)
- Sameer Lapsia
- Division of Gastroenterology, Department of Pediatrics, Stony Brook University School of Medicine, Stony Brook, New York
| | - Siva Koganti
- Division of Infectious Diseases, Department of Pediatrics, Stony Brook University School of Medicine, Stony Brook, New York
| | - Salvatore Spadaro
- Division of Infectious Diseases, Department of Pediatrics, Stony Brook University School of Medicine, Stony Brook, New York
| | - Ramona Rajapakse
- Division of Gastroenterology, Department of Internal Medicine, Stony Brook University School of Medicine, Stony Brook, New York
| | - Anupama Chawla
- Division of Gastroenterology, Department of Pediatrics, Stony Brook University School of Medicine, Stony Brook, New York
| | - Sumita Bhaduri-McIntosh
- Division of Infectious Diseases, Department of Pediatrics, Stony Brook University School of Medicine, Stony Brook, New York.,Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York
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25
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Abstract
In the more recent years since the introduction of anti-TNF therapy, the treatment strategy in chronic inflammatory bowel disease has developed more towards an early intensive, often double immunosuppression. While this leads to an improved therapeutic success, this intensified therapy also increases the risk for side effects and especially for infectious complications. The early detection of this complication in the immunocompromised patient is often more difficult due to the potential broad spectrum of infectious agents, the often atypical presentation in conjunction with the immunosuppression as well as often similar symptoms regarding intestinal infectious complications common for a flare of the underlying disease. In the first part, this overview will discuss the broad spectrum of potential infectious complications, using pulmonary infections as an example and presenting an algorithm for detection and therapy. In the second part, common intestinal infectious complications will be discussed from diagnosis to therapy.
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Affiliation(s)
- Torsten Kucharzik
- Department of General Internal Medicine and Gastroenterology, University Teaching Hospital Lüneburg, Lüneburg, Germany
| | - Christian Maaser
- Department of Geriatric Medicine, University Teaching Hospital Lüneburg, Lüneburg, Germany
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26
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Pillet S, Jarlot C, Courault M, Del Tedesco E, Chardon R, Saint-Sardos P, Presles E, Phelip JM, Berthelot P, Pozzetto B, Roblin X. Infliximab Does Not Worsen Outcomes During Flare-ups Associated with Cytomegalovirus Infection in Patients with Ulcerative Colitis. Inflamm Bowel Dis 2015; 21:1580-1586. [PMID: 25933392 DOI: 10.1097/mib.0000000000000412] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Immunosuppressive therapies used for treating ulcerative colitis are known to favor chronic and latent viral diseases. This study aimed at evaluating prospectively the association between colonic cytomegalovirus (CMV) reactivation and anti-tumor necrosis factor (TNF) monoclonal antibodies (mabs) by comparison to azathioprine (AZA) in a series of flare-ups occurring in consecutive ulcerative colitis patients. METHODS A total of 109 flare-ups were recorded in 73 patients receiving a maintenance therapy by anti-TNF mabs (n = 69) or AZA (n = 40). The CMV DNA load in colonic tissue was determined by reverse transcription polymerase chain reaction on a pair of biopsies. RESULTS The number of CMV reactivation was of 35% and 38% in patients receiving anti-TNF mabs and AZA, respectively. The median of CMV DNA load was 378 [10-29,800] and 8300 [10-3,25,000] copies/mg of tissue in patients treated by anti-TNF mabs and AZA, respectively (P = 0.11 by Mann-Whitney U test). In a subgroup of 45 patients under anti-TNF mabs requiring an optimized treatment by infliximab, clinical remission (partial Mayo score <3) was not significantly impacted by the presence of CMV reactivation at the time of flare-up (P = 0.52). Twenty of these patients underwent a second colonic biopsy 8 weeks after the initiation of flare-up therapy; except for 3 patients, the colonic CMV DNA load was stable or decreased. CONCLUSIONS Patients under anti-TNF maintenance therapy are not at higher risk of CMV reactivation in case of flare-up. No reciprocal adverse influence was observed between anti-TNF mabs and CMV infection, suggesting that these drugs must be considered for treating flare-ups associated to CMV reactivation.
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Affiliation(s)
- Sylvie Pillet
- *EA-3064, Groupe Immunité des Muqueuses et Agents Pathogènes (GIMAP), Faculty of Medicine of Saint-Etienne, University of Lyon, Lyon, France; †Laboratory of Infectious Agents and Hygiene, University Hospital of Saint-Etienne, France; ‡Department of Gastroenterology, University Hospital of Saint-Etienne, France; and §Inserm, CIE3, F-42055 Saint-Etienne, France
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27
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Busca A, Passera R, Pini M, Zallio F, Dellacasa C, Audisio E, Giaccone L, Maffini E, Costa C, Cavallo R, Bruno B. The use of ATG abrogates the antileukemic effect of cytomegalovirus reactivation in patients with acute myeloid leukemia receiving grafts from unrelated donors. Am J Hematol 2015; 90:E117-21. [PMID: 25752810 DOI: 10.1002/ajh.23998] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2015] [Revised: 02/23/2015] [Accepted: 03/02/2015] [Indexed: 11/12/2022]
Abstract
Several studies provided evidence of a consistent antileukemic effect induced by cytomegalovirus (CMV) replication in acute myeloid leukemia (AML) patients receiving allogeneic hematopoietic stem cell transplantation (HSCT), however the use of antithymocyte globulin (ATG) as graft-versus-host disease prophylaxis, may potentially abrogate the protective effect of CMV infection. To address this issue, we retrospectively analyzed the risk of relapse in a cohort of 101 patients with AML who received grafts from an unrelated donor after a conditioning regimen including ATG. The cumulative incidence of CMV reactivation, evaluated by RT qPCR, was 59% at 12 months, and 93% of CMV reactivations occurred within the first 100 days post HSCT. The 5-year cumulative incidence of relapse in patients with CMV reactivation was 29% compared with 37% for patients without CMV reactivation, and the only factor associated with a reduced 5-year cumulative incidence of relapse was the disease status at HSCT (P < 0.001). In the multivariable model adverse cytogenetics (HR 2.42, 95% CI 1.02-5.72; P = 0.044) and acute GVHD (HR 3.36, 95% CI 1.32-8.54; P = 0.011) were independent risk factors for reducing overall survival (OS), while the presence of chronic GVHD was associated with a better OS (HR 0.37, 95% CI 0.15-0.89; P = 0.027). CMV replication was not an independent risk factor for OS (HR 1.06, 95% CI 0.07-15.75; P = 0.965). In Conclusion, the results of present study suggest that relapse prevention in patients with AML receiving T-cell depleted HSCT using ATG do not benefit from CMV reactivation.
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Affiliation(s)
- Alessandro Busca
- Department of Oncology and Hematology; Stem Cell Transplant Center, AOU Città Della Salute E Della Scienza; Turin Italy
| | - Roberto Passera
- Division of Nuclear Medicine; AOU Città Della Salute E Della Scienza; Turin Italy
| | - Massimo Pini
- Department of Hematology; AO Nazionale Alessandria; Alessandria Italy
| | - Francesco Zallio
- Department of Hematology; AO Nazionale Alessandria; Alessandria Italy
| | - Chiara Dellacasa
- Department of Oncology and Hematology; Stem Cell Transplant Center, AOU Città Della Salute E Della Scienza; Turin Italy
| | - Ernesta Audisio
- Department of Oncology and Hematology; AOU Città Della Salute E Della Scienza; Turin Italy
| | - Luisa Giaccone
- Department of Oncology and Hematology; Stem Cell Transplant Center, AOU Città Della Salute E Della Scienza; Turin Italy
| | - Enrico Maffini
- Department of Oncology and Hematology; AOU Città Della Salute E Della Scienza; Turin Italy
| | - Cristina Costa
- Microbiology and Virology Unit; Laboratory of Virology, AOU Città Della Salute E Della Scienza; Turin Italy
| | - Rossana Cavallo
- Microbiology and Virology Unit; Laboratory of Virology, AOU Città Della Salute E Della Scienza; Turin Italy
| | - Benedetto Bruno
- Department of Oncology and Hematology; Stem Cell Transplant Center, AOU Città Della Salute E Della Scienza; Turin Italy
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28
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Green EKY, Ambrose LR, Webster DP, Atkinson C, Griffiths P, Murray CD, Goodman AL. Intractable diarrhoea despite immune reconstitution in an HIV positive man. J Clin Virol 2015; 69:219-22. [PMID: 26008774 DOI: 10.1016/j.jcv.2015.04.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2014] [Revised: 03/17/2015] [Accepted: 04/06/2015] [Indexed: 10/23/2022]
Affiliation(s)
| | - Lyn R Ambrose
- Institute of Immunity and Transplantation, University College London, Royal Free Hospital, London, UK
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29
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Ciccocioppo R, Racca F, Paolucci S, Campanini G, Pozzi L, Betti E, Riboni R, Vanoli A, Baldanti F, Corazza GR. Human cytomegalovirus and Epstein-Barr virus infection in inflammatory bowel disease: Need for mucosal viral load measurement. World J Gastroenterol 2015; 21:1915-1926. [PMID: 25684960 PMCID: PMC4323471 DOI: 10.3748/wjg.v21.i6.1915] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2014] [Revised: 10/03/2014] [Accepted: 11/19/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the best diagnostic technique and risk factors of the human Cytomegalovirus (HCMV) and Epstein-Barr virus (EBV) infection in inflammatory bowel disease (IBD).
METHODS: A cohort of 40 IBD patients (17 refractory) and 40 controls underwent peripheral blood and endoscopic colonic mucosal sample harvest. Viral infection was assessed by quantitative real-time polymerase chain reaction and immunohistochemistry, and correlations with clinical and endoscopic indexes of activity, and risk factors were investigated.
RESULTS: All refractory patients carried detectable levels of HCMV and/or EBV mucosal load as compared to 13/23 (56.5%) non-refractory and 13/40 (32.5%) controls. The median DNA value was significantly higher in refractory (HCMV 286 and EBV 5.440 copies/105 cells) than in non-refractory (HCMV 0 and EBV 6 copies/105 cells; P < 0.05 and < 0.001) IBD patients and controls (HCMV and EBV 0 copies/105 cells; P < 0.001 for both). Refractory patients showed DNA peak values ≥ 103 copies/105 cells in diseased mucosa in comparison to non-diseased mucosa (P < 0.0121 for HCMV and < 0.0004 for EBV), while non-refractory patients and controls invariably displayed levels below this threshold, thus allowing us to differentiate viral colitis from mucosal infection. Moreover, the mucosal load positively correlated with the values found in the peripheral blood, whilst no correlation with the number of positive cells at immunohistochemistry was found. Steroid use was identified as a significant risk factor for both HCMV (P = 0.018) and EBV (P = 0.002) colitis. Finally, a course of specific antiviral therapy with ganciclovir was successful in all refractory patients with HCMV colitis, whilst refractory patients with EBV colitis did not show any improvement despite steroid tapering and discontinuation of the other medications.
CONCLUSION: Viral colitis appeared to contribute to mucosal lesions in refractory IBD, and its correct diagnosis and management require quantitative real-time polymerase chain reaction assay of mucosal specimens.
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McCurdy JD, Jones A, Enders FT, Killian JM, Loftus EV, Smyrk TC, Bruining DH. A model for identifying cytomegalovirus in patients with inflammatory bowel disease. Clin Gastroenterol Hepatol 2015; 13:131-7; quiz e7. [PMID: 24993369 DOI: 10.1016/j.cgh.2014.05.026] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2014] [Revised: 05/20/2014] [Accepted: 05/28/2014] [Indexed: 01/08/2023]
Abstract
BACKGROUND & AIMS The presentation of cytomegalovirus (CMV) disease in patients with inflammatory bowel disease (IBD) can be similar to that of idiopathic IBD. It is a challenge to identify patients at highest risk for CMV. We investigated risk factors and generated a clinical score to identify patients with IBD at highest risk for CMV disease. METHODS We performed a retrospective case-control study of 68 patients with IBD (66% with ulcerative colitis, 31% with Crohn's disease, and 3% with unclassified IBD) diagnosed with CMV disease on the basis of tissue analysis from January 2005 through December 2011 at Mayo Clinic, Rochester. The patients were each matched with 3 patients with IBD and suspected CMV disease (controls). An a priori set of the most objective variables was used to create a model to identify those with CMV disease. Scores were assigned to each significant factor from the multivariable analysis. Cutoff values that identified patients with CMV with ≥85% sensitivity and specificity were selected. RESULTS Patients with medically refractory IBD (odds ratio [OR], 3.69; P < .001) or endoscopic ulcers (OR, 3.06; P < .001) and those treated with corticosteroids (OR, 2.95; P < .001) or immunomodulators (OR, 1.86; P = .030) but not tumor necrosis factor antagonists (OR, 1.30; P = .376) were more likely to have CMV disease than patients with IBD without these features. In a multivariable model, refractory disease, treatment with immunomodulators, and age older than 30 years were independently associated with CMV disease. Use of tumor necrosis factor antagonists was an insignificant factor even after adjustment. CONCLUSIONS Clinical features can identify patients with IBD at risk for CMV disease. This model may help clinicians stratify patients on the basis of risk when CMV disease is suspected.
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Affiliation(s)
- Jeffrey D McCurdy
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Andrea Jones
- Department of Pathology, Mayo Clinic, Rochester, Minnesota
| | - Felicity T Enders
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota
| | - Jill M Killian
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota
| | - Edward V Loftus
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Thomas C Smyrk
- Department of Pathology, Mayo Clinic, Rochester, Minnesota
| | - David H Bruining
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
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31
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Affiliation(s)
- Tsutomu Ohtsuka
- Department of Dermatology; International University of Health and Welfare Hospital; Nasushiobara Japan
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32
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Novosad SA, Winthrop KL. Beyond Tumor Necrosis Factor Inhibition: The Expanding Pipeline of Biologic Therapies for Inflammatory Diseases and Their Associated Infectious Sequelae. Clin Infect Dis 2014; 58:1587-98. [DOI: 10.1093/cid/ciu104] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
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Targownik LE, Bernstein CN. Infectious and malignant complications of TNF inhibitor therapy in IBD. Am J Gastroenterol 2013; 108:1835-42, quiz 1843. [PMID: 24042192 DOI: 10.1038/ajg.2013.294] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2013] [Accepted: 07/30/2013] [Indexed: 02/08/2023]
Abstract
Tumor necrosis factor (TNF) inhibitors are being increasingly utilized in the management of inflammatory bowel disease (IBD). Although the benefits associated with TNF inhibitor therapy are undeniable, concerns have been raised about the associated risk of infectious and malignant complications. In this narrative review, we will present the evidence from studies that have evaluated the association of TNF inhibitors and both overall and specific infections and malignancy. Overall, although TNF inhibitors may increase the risk of tuberculosis, varicella, and other opportunistic infections, there is little evidence suggesting that anti-TNF agents specifically raise the overall risk of serious infections. Similarly, there is little evidence that TNF antagonists raise the risk of developing malignancy over and above the risks from concomitant therapies and the underlying disease process. However, the risk of nonmelanoma skin cancers may be increased and that is further enhanced by use of combination TNF inhibitor and thiopurine therapy. The risk of non-Hodgkin's lymphoma is statistically increased among combination therapy users. The absolute risk remains a very small but feared risk. It is difficult to fully quantify the risk of these cancers among users of TNF inhibitor therapy in the absence of concurrent thiopurine therapy. We recommend that clinicians remain mindful about the potential risks of infectious and malignant complications in their IBD patients who are using TNF inhibitors, but that further research is required to better study these risks over the long-term course of therapy.
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Affiliation(s)
- Laura E Targownik
- University of Manitoba IBD Clinical and Research Centre and Department of Internal Medicine, Winnipeg, Manitoba, Canada
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34
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Bellizzi A, Anzivino E, Rodio DM, Cioccolo S, Scrivo R, Morreale M, Pontecorvo S, Ferrari F, Di Nardo G, Nencioni L, Carluccio S, Valesini G, Francia A, Cucchiara S, Palamara AT, Pietropaolo V. Human Polyomavirus JC monitoring and noncoding control region analysis in dynamic cohorts of individuals affected by immune-mediated diseases under treatment with biologics: an observational study. Virol J 2013; 10:298. [PMID: 24079660 PMCID: PMC3849738 DOI: 10.1186/1743-422x-10-298] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2013] [Accepted: 09/27/2013] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Progressive multifocal leukoencephalopathy (PML) onset, caused by Polyomavirus JC (JCPyV) in patients affected by immune-mediated diseases during biological treatment, raised concerns about the safety profile of these agents. Therefore, the aims of this study were the JCPyV reactivation monitoring and the noncoding control region (NCCR) and viral protein 1 (VP1) analysis in patients affected by different immune-mediated diseases and treated with biologics. METHODS We performed JCPyV-specific quantitative PCR of biological samples collected at moment of recruitment (t0) and every 4 months (t1, t2, t3, t4). Subsequently, rearrangements' analysis of NCCR and VP1 was carried out. Data were analyzed using χ2 test. RESULTS Results showed that at t0 patients with chronic inflammatory rheumatic diseases presented a JCPyV load in the urine significantly higher (p≤0.05) than in patients with multiple sclerosis (MS) and Crohn's disease (CD). It can also be observed a significant association between JC viruria and JCPyV antibodies after 1 year of natalizumab (p=0.04) in MS patients. Finally, NCCR analysis showed the presence of an archetype-like sequence in all urine samples, whereas a rearranged NCCR Type IR was found in colon-rectal biopsies collected from 2 CD patients after 16 months of infliximab. Furthermore, sequences isolated from peripheral blood mononuclear cells (PBMCs) of 2 MS patients with JCPyV antibody at t0 and t3, showed a NCCR Type IIR with a duplication of a 98 bp unit and a 66 bp insert, resulting in a boxB deletion and 37 T to G transversion into the Spi-B binding site. In all patients, a prevalence of genotypes 1A and 1B, the predominant JCPyV genotypes in Europe, was observed. CONCLUSIONS It has been important to understand whether the specific inflammatory scenario in different immune-mediated diseases could affect JCPyV reactivation from latency, in particular from kidneys. Moreover, for a more accurate PML risk stratification, testing JC viruria seems to be useful to identify patients who harbor JCPyV but with an undetectable JCPyV-specific humoral immune response. In these patients, it may also be important to study the JCPyV NCCR rearrangement: in particular, Spi-B expression in PBMCs could play a crucial role in JCPyV replication and NCCR rearrangement.
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Affiliation(s)
- Anna Bellizzi
- Department of Public Health and Infectious Diseases, Sapienza University, P.le Aldo Moro, 5, 00185 Rome, Italy
| | - Elena Anzivino
- Department of Public Health and Infectious Diseases, Sapienza University, P.le Aldo Moro, 5, 00185 Rome, Italy
| | - Donatella Maria Rodio
- Department of Public Health and Infectious Diseases, Sapienza University, P.le Aldo Moro, 5, 00185 Rome, Italy
| | - Sara Cioccolo
- Department of Public Health and Infectious Diseases, Sapienza University, P.le Aldo Moro, 5, 00185 Rome, Italy
| | - Rossana Scrivo
- Department of Internal Medicine and Medical Disciplines, Rheumatology, Sapienza University of Rome, Rome, Italy
| | - Manuela Morreale
- Department of Medico-Surgical Sciences and Biotechnologies, Section of Neurology, Sapienza University of Rome, Rome, Italy
| | - Simona Pontecorvo
- Department of Neurology and Psychiatry, Sapienza University of Rome, Rome, Italy
| | - Federica Ferrari
- Department of Pediatrics, Pediatric Gastroenterology and Liver Unit, Sapienza University of Rome, Rome, Italy
| | - Giovanni Di Nardo
- Department of Pediatrics, Pediatric Gastroenterology and Liver Unit, Sapienza University of Rome, Rome, Italy
| | - Lucia Nencioni
- Department of Public Health and Infectious Diseases, Institute Pasteur, Cenci-Bolognetti Foundation, Sapienza University of Rome, Rome, Italy
| | - Silvia Carluccio
- Department of Biomedical, Surgery and Dental Sciences, University of Milan, via Pascal 36, 20123 Milan, Italy
| | - Guido Valesini
- Department of Internal Medicine and Medical Disciplines, Rheumatology, Sapienza University of Rome, Rome, Italy
| | - Ada Francia
- Department of Neurology and Psychiatry, Sapienza University of Rome, Rome, Italy
| | - Salvatore Cucchiara
- Department of Pediatrics, Pediatric Gastroenterology and Liver Unit, Sapienza University of Rome, Rome, Italy
| | - Anna Teresa Palamara
- Department of Public Health and Infectious Diseases, Institute Pasteur, Cenci-Bolognetti Foundation, Sapienza University of Rome, Rome, Italy
- San Raffaele Pisana Scientific Institute for Research, Hospitalization and Health Care, Rome, Italy
| | - Valeria Pietropaolo
- Department of Public Health and Infectious Diseases, Sapienza University, P.le Aldo Moro, 5, 00185 Rome, Italy
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania, USA
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Katz S. My treatment approach to the management of ulcerative colitis. Mayo Clin Proc 2013; 88:841-53. [PMID: 23910410 DOI: 10.1016/j.mayocp.2013.05.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2013] [Revised: 04/19/2013] [Accepted: 05/02/2013] [Indexed: 12/17/2022]
Abstract
Ulcerative colitis diagnosis and management represent a challenge for clinicians. The disguises of ischemia and acute infectious colitis continue to confound the diagnosis. The therapeutic options have remarkably expanded in the way of immunomodulators, biologics, or ileoanal pouch surgery, yet all carry potential considerable risks. These risks can confuse and impair patient acceptance, particularly elderly patients and men younger than 30 years. Predictors of outcome of medical and surgical therapy have improved but are far from complete. Nevertheless, therapies focused on the specific patient's condition continue to offer hope.
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Affiliation(s)
- Seymour Katz
- Department of Medicine, New York University School of Medicine, New York, NY; North Shore University Hospital-Long Island Jewish Health System, Manhasset, NY; and St Francis Hospital, Roslyn, NY.
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Fries W, Cottone M, Cascio A. Systematic review: macrophage activation syndrome in inflammatory bowel disease. Aliment Pharmacol Ther 2013; 37:1033-1045. [PMID: 23565820 DOI: 10.1111/apt.12305] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2012] [Revised: 10/19/2012] [Accepted: 03/13/2013] [Indexed: 12/16/2022]
Abstract
BACKGROUND Recently, there have been increasingly frequent reports on the occurrence of macrophage activation syndrome (MAS) in patients with inflammatory bowel disease (IBD). Clinically, MAS is characterized mainly by fever, hepatosplenomegaly, cytopenia, and elevated circulating ferritin and CD25. Mortality, even if diagnosed rapidly, is high. AIM To identify all reports on MAS in IBD and to establish data on triggering agents, immunosuppression leading to MAS, and mortality. METHODS A language unrestricted search on Pubmed and Scopus relating to the past 30 years was carried out by matching the following search-terms: h(a)emophagocytic lymphohistiocytosis OR h(a)emophagocytic lymphohistiocytic syndrome OR macrophage activation syndrome OR opportunistic infections OR cytomegalovirus OR Epstein-Barr virus AND Crohn's disease OR ulcerative colitis OR inflammatory bowel disease(s). RESULTS Fifty cases were identified with an overall mortality of 30%. Virus-related MAS associated with cytomegalovirus or Epstein-Barr virus infections represents the main type of MAS, but in isolated cases bacterial infections precipitated the syndrome. In four cases (8%), a lymphoma was present at the time of MAS diagnosis or developed shortly thereafter. Thiopurine monotherapy was given before MAS onset in 56% of the patients, whereas multiple immunosuppression, including biologics, was administered to 24%. CONCLUSIONS In IBD patients, the syndrome appears to be triggered by infections, but genetic susceptibility may contribute to its development. Since immunosuppressive therapy represents the backbone of therapeutic interventions in IBD, with the risk of new, or the reactivation of latent infections, even more frequent cases of macrophage activation syndrome may be expected.
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Affiliation(s)
- W Fries
- Clinical Unit for Chronic Bowel Disorders, Department of Internal Medicine, IBD-unit Messina, University of Messina, Messina, Italy.
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Kopylov U, Sasson G, Geyshis B, Oikawa MT, Barshack I, Eliakim R, Ben-Horin S. Cytomegalovirus positive ulcerative colitis: A single center experience and literature review. World J Gastrointest Pathophysiol 2013; 4:18-23. [PMID: 23596551 PMCID: PMC3627461 DOI: 10.4291/wjgp.v4.i1.18] [Citation(s) in RCA: 16] [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: 11/08/2012] [Revised: 01/19/2013] [Accepted: 02/06/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To compare the clinical outcome of cytomegalovirus (CMV)-positive ulcerative colitis (UC) patients with and without antiviral therapy.
METHODS: This was a retrospective case-controlled study. The database of UC patients in our institution was scanned for documented presence of CMV on colonic biopsies. Demographics, clinical data, endoscopy findings and pathology reports were extracted from the patients’ charts and electronic records. When available, the data from colonoscopies preceding and following the diagnosis of colonic CMV infection were also extracted. The primary outcomes of the study were colectomy/death during hospitalization and the secondary outcomes were colectomy/death through the course of the follow-up.
RESULTS: Thirteen patients were included in the study, 7 (53.5%) of them were treated with gancyclovir and 6 (46.5%) were not. Patients treated with antivirals presented with a more severe disease and 57% of them were treated with cyclosporine or infliximab before initiation of gancyclovir, while none of the patients without antivirals required rescue therapy. One patient died and another patient underwent urgent colectomy during hospitalization, both of them from the gancyclovir-treatment group. For the entire follow-up time (13 ± 13 mo), a total of 3 colectomies and one death occurred, all among the antiviral-treated patients (for colectomy: 3/7 vs 0/6 patients, P = 0.19; for combined adverse outcome: 4/7 vs 0/6 patients, P = 0.07). In 9/13 patients, immunohistochemistry for CMV was performed on biopsies obtained during a subsequent colonoscopy and was positive in one patient only.
CONCLUSION: Gancyclovir-treated patients had a more severe disease and outcome, probably unrelated to antiviral therapy. Immunohistochemistry-CMV-positive patients with mild disease may recover without antiviral therapy.
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Comar M, Delbue S, Lepore L, Martelossi S, Radillo O, Ronfani L, D'Agaro P, Ferrante P. Latent viral infections in young patients with inflammatory diseases treated with biological agents: Prevalence of JC virus genotype 2. J Med Virol 2013; 85:716-22. [DOI: 10.1002/jmv.23525] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/19/2012] [Indexed: 11/11/2022]
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Garrido E, Carrera E, Manzano R, Lopez-Sanroman A. Clinical significance of cytomegalovirus infection in patients with inflammatory bowel disease. World J Gastroenterol 2013; 19:17-25. [PMID: 23326158 PMCID: PMC3545225 DOI: 10.3748/wjg.v19.i1.17] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2012] [Revised: 08/03/2012] [Accepted: 08/14/2012] [Indexed: 02/06/2023] Open
Abstract
Cytomegalovirus (CMV) infection is common in humans. The virus then enters a “latency phase” and can reactivate to different stimuli such as immunosuppression. The clinical significance of CMV infection in inflammatory bowel disease is different in Crohn’s disease (CD) and ulcerative colitis (UC). CMV does not interfere in the clinical course of CD. However, CMV reactivation is frequent in severe or steroid-resistant UC. It is not known whether the virus exacerbates the disease or simply appears as a bystander of a severe disease. Different methods are used to diagnose CMV colitis. Diagnosis is classically based on histopathological identification of viral-infected cells or CMV antigens in biopsied tissues using haematoxylin-eosin or immunohistochemistry, other tests on blood or tissue samples are currently being investigated. Polymerase chain reaction performed in colonic mucosa has a high sensitivity and a positive result could be associated with a worse prognosis disease; further studies are needed to determine the most appropriate strategy with positive CMV-DNA in colonic mucosa. Specific endoscopic features have not been described in active UC and CMV infection. CMV colitis is usually treated with ganciclovir for several weeks, there are different opinions about whether or not to stop immunosuppressive therapy. Other antiviral drugs may be used. Multicenter controlled studies would needed to determine which subgroup of UC patients would benefit from early antiviral treatment.
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Pola S, Patel D, Ramamoorthy S, McLemore E, Fahmy M, Rivera-Nieves J, Chang JT, Evans E, Docherty M, Talamini M, Sandborn WJ. Strategies for the care of adults hospitalized for active ulcerative colitis. Clin Gastroenterol Hepatol 2012; 10:1315-1325.e4. [PMID: 22835577 PMCID: PMC4226798 DOI: 10.1016/j.cgh.2012.07.006] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2012] [Revised: 06/15/2012] [Accepted: 07/11/2012] [Indexed: 02/07/2023]
Abstract
Ulcerative colitis is a chronic inflammatory disease of the colon; as many as 25% of patients with this disease require hospitalization. The goals of hospitalization are to assess disease severity, exclude infection, administer rapidly acting and highly effective medication regimens, and determine response. During hospitalization, patients should be given venous thromboembolism prophylaxis and monitored for the development of toxic megacolon. Patients who do not respond to intravenous corticosteroids should be considered for rescue therapy with infliximab or cyclosporine. Patients who are refractory to medical therapies or who develop toxic megacolon should be evaluated promptly for colectomy. Patients who do respond to medical therapies should be discharged on an appropriate maintenance regimen when they meet discharge criteria. We review practical evidence-based management principles and propose a day-by-day algorithm for managing patients hospitalized for ulcerative colitis.
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Affiliation(s)
- Suresh Pola
- Inflammatory Bowel Disease Center, Division of Gastroenterology, University of California San Diego Health System, La Jolla, CA, USA
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Bharat A, Xie F, Baddley JW, Beukelman T, Chen L, Calabrese L, Delzell E, Grijalva CG, Patkar NM, Saag K, Winthrop KL, Curtis JR. Incidence and risk factors for progressive multifocal leukoencephalopathy among patients with selected rheumatic diseases. Arthritis Care Res (Hoboken) 2012; 64:612-5. [PMID: 22162369 DOI: 10.1002/acr.21564] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVE To ascertain the incidence of progressive multifocal leukoencephalopathy (PML) in patients with selected rheumatic diseases, to describe the characteristics of PML cases occurring in this setting, and to evaluate the extent to which such cases occurred in the context of biologic therapies such as rituximab or tumor necrosis factor antagonists. METHODS We conducted a large population-based study to describe the incidence and risk factors for PML among patients with rheumatoid arthritis, psoriatic arthritis, psoriasis, juvenile idiopathic arthritis, inflammatory bowel disease, and ankylosing spondylitis using national inpatient and outpatient administrative data from the entire Center for Medicare and Medicaid Services from 2000-2009. Suspected PML cases were identified using hospital discharge diagnosis codes. Risk factors for PML were evaluated using outpatient data ≥6 months prior to PML diagnosis. RESULTS Among 2,030,578 patients with autoimmune diseases of interest, a total of 53 PML cases were identified (2.6 per 100,000 patients). Most PML cases had human immunodeficiency virus (HIV) and/or cancer. Nine PML cases had evidence for biologic use prior to PML hospitalization, of which 3 had neither HIV nor malignancy and were exposed to biologics within 12 (rituximab) or 6 months (all other biologics) prior to PML diagnosis. PML occurred at an estimated incidence of 0.2 per 100,000 patients with autoimmune diseases who did not have HIV or malignancy. CONCLUSION PML occurs at a very low incidence among patients with rheumatic diseases but can occur even in the absence of HIV or malignancy.
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Affiliation(s)
- A Bharat
- University of Alabama at Birmingham, AL, USA
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Pillet S, Pozzetto B, Jarlot C, Paul S, Roblin X. Management of cytomegalovirus infection in inflammatory bowel diseases. Dig Liver Dis 2012; 44:541-548. [PMID: 22538204 DOI: 10.1016/j.dld.2012.03.018] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2012] [Accepted: 03/20/2012] [Indexed: 12/11/2022]
Abstract
Cytomegalovirus is a deoxyribonucleic acid virus that infects a large part of the human population; after primary infection, it develops a latent state and can be reactivated, notably after a decrease in host immune defences. In patients with inflammatory bowel diseases, cytomegalovirus is frequently involved, either as an agent of colitis or through local asymptomatic reactivation. Due to the immune context of inflammatory bowel diseases and to the immunosuppressive therapies that are used to treat them, cytomegalovirus entertains complex relationships with these diseases. Whereas Crohn's disease seems little impacted by cytomegalovirus, this agent interferes strongly with the natural progression of ulcerative colitis. While immune treatments have a clear influence on the occurrence of cytomegalovirus colitis in ulcerative colitis (favourable for steroids and cyclosporine and rather inhibitory for infliximab), the role of cytomegalovirus infection on ulcerative colitis is more debated with roles ranging from innocent bystander to key pathogen suggested. There is however growing evidence for a participation of intestinal cytomegalovirus infection in the resistance of ulcerative colitis to steroids and the investigation of cytomegalovirus infection in intestinal biopsies by immunohistochemistry or quantitative polymerase chain reaction assay is strongly recommended. In several studies, treatment of cytomegalovirus infection by ganciclovir was shown to restore the response to immunomodulatory therapies and even to prevent the need for colectomy. All of these recently acquired data need to be validated by randomised clinical trials conducted on a large panel of ulcerative colitis patients.
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Affiliation(s)
- Sylvie Pillet
- EA 3064, University of Lyon, 42023 Saint-Etienne, France
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Assessment of the risk of polyomavirus JC reactivation in patients with immune-mediated diseases during long-term treatment with infliximab. J Neurovirol 2012; 18:55-61. [DOI: 10.1007/s13365-012-0078-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2011] [Revised: 01/02/2012] [Accepted: 01/09/2012] [Indexed: 11/28/2022]
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Gentile G, Foà R. Viral infections associated with the clinical use of monoclonal antibodies. Clin Microbiol Infect 2011; 17:1769-75. [DOI: 10.1111/j.1469-0691.2011.03680.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Sipponen T, Turunen U, Lautenschlager I, Nieminen U, Arola J, Halme L. Human herpesvirus 6 and cytomegalovirus in ileocolonic mucosa in inflammatory bowel disease. Scand J Gastroenterol 2011; 46:1324-33. [PMID: 21879802 DOI: 10.3109/00365521.2011.605466] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVES Reactivation of a latent cytomegalovirus (CMV) may occur in inflammatory bowel disease (IBD). Data of human herpesvirus 6 (HHV-6)--a close relative to CMV--in active IBD are scarce. The aim of this study was to detect HHV-6 and CMV antigens in the mucosa of active and inactive IBD. MATERIAL AND METHODS 79 IBD patients (47 ulcerative colitis (UC) and 32 Crohn's disease (CD)) were recruited and endoscopic and histological disease activity was scored. Control group consisted of 15 non-IBD patients with normal colonoscopy. Immunohistochemical stainings for HHV-6B and CMV antigens were performed on biopsy specimens from the ileum and colorectum. The intensity of HHV-6B and CMV expression was graded as negative, mild, moderate, or intense. RESULTS HHV-6B antigen was positive in 35 (44%) and CMV in 64 (81%). Of controls, 6 (40%) were mildly positive for HHV-6 and 6 (40%) for CMV. In IBD, both CMV and HHV-6B intensity correlated with endoscopic disease severity (CMV p = 0.010 and HHV-6 p = 0.048). Simultaneous HHV-6B and CMV antigen expression occurred in 29 (37%) and associated with endoscopic activity (p = 0.006) and to a number of immunosuppressives (p = 0.033). A significant difference in HHV-6B positivity was found between endoscopically active and inactive UC (p = 0.040). Both CMV and HHV-6B intensity correlated with histological severity in the rectal biopsy specimens (for CMV p = 0.040 and for HHV-6B p = 0.027). CONCLUSIONS Both viruses occurred ubiquitously in the IBD mucosa. Coexistence of viruses was common and associated with disease activity and use of immunosuppressives. HHV-6B intensity correlated with endoscopic severity in UC.
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Affiliation(s)
- Taina Sipponen
- Department of Medicine, Division of Gastroenterology, Helsinki University Central Hospital, Helsinki, Finland.
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Pham T, Bachelez H, Berthelot JM, Blacher J, Bouhnik Y, Claudepierre P, Constantin A, Fautrel B, Gaudin P, Goëb V, Gossec L, Goupille P, Guillaume-Czitrom S, Hachulla E, Huet I, Jullien D, Launay O, Lemann M, Maillefert JF, Marolleau JP, Martinez V, Masson C, Morel J, Mouthon L, Pol S, Puéchal X, Richette P, Saraux A, Schaeverbeke T, Soubrier M, Sudre A, Tran TA, Viguier M, Vittecoq O, Wendling D, Mariette X, Sibilia J. TNF alpha antagonist therapy and safety monitoring. Joint Bone Spine 2011; 78 Suppl 1:15-185. [PMID: 21703545 DOI: 10.1016/s1297-319x(11)70001-x] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVES To develop and/or update fact sheets about TNFα antagonists treatments, in order to assist physicians in the management of patients with inflammatory joint disease. METHODS 1. selection by a committee of rheumatology experts of the main topics of interest for which fact sheets were desirable; 2. identification and review of publications relevant to each topic; 3. development and/or update of fact sheets based on three levels of evidence: evidence-based medicine, official recommendations, and expert opinion. The experts were rheumatologists and invited specialists in other fields, and they had extensive experience with the management of chronic inflammatory diseases, such as rheumatoid. They were members of the CRI (Club Rhumatismes et Inflammation), a section of the Société Francaise de Rhumatologie. Each fact sheet was revised by several experts and the overall process was coordinated by three experts. RESULTS Several topics of major interest were selected: contraindications of TNFα antagonists treatments, the management of adverse effects and concomitant diseases that may develop during these therapies, and the management of everyday situations such as pregnancy, surgery, and immunizations. After a review of the literature and discussions among experts, a consensus was developed about the content of the fact sheets presented here. These fact sheets focus on several points: 1. in RA and SpA, initiation and monitoring of TNFα antagonists treatments, management of patients with specific past histories, and specific clinical situations such as pregnancy; 2. diseases other than RA, such as juvenile idiopathic arthritis; 3. models of letters for informing the rheumatologist and general practitioner; 4. and patient information. CONCLUSION These TNFα antagonists treatments fact sheets built on evidence-based medicine and expert opinion will serve as a practical tool for assisting physicians who manage patients on these therapies. They will be available continuously at www.cri-net.com and updated at appropriate intervals.
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Affiliation(s)
- Thao Pham
- Rheumatology Department, CHU Sainte-Marguerite, Marseille, France.
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Granulomatous inflammation in cartilage-hair hypoplasia: Risks and benefits of anti–TNF-α mAbs. J Allergy Clin Immunol 2011; 128:847-53. [DOI: 10.1016/j.jaci.2011.05.024] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2010] [Revised: 05/17/2011] [Accepted: 05/17/2011] [Indexed: 11/19/2022]
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Bellizzi A, Anzivino E, Ferrari F, Di Nardo G, Colosimo MT, Fioriti D, Mischitelli M, Chiarini F, Cucchiara S, Pietropaolo V. Polyomavirus JC reactivation and noncoding control region sequence analysis in pediatric Crohn's disease patients treated with infliximab. J Neurovirol 2011; 17:303-313. [PMID: 21547609 DOI: 10.1007/s13365-011-0036-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2011] [Revised: 04/01/2011] [Accepted: 04/25/2011] [Indexed: 10/18/2022]
Abstract
The recent introduction of monoclonal antibodies in Crohn's disease (CD) management has been associated with the development of serious complications, such as the progressive multifocal leukoencephalopathy (PML), caused by JC polyomavirus (JCV) reactivation. Therefore, the aims of our study have been the investigation of the possible JCV reactivation in pediatric CD patients treated or not with infliximab, performing quantitative PCR in urine, plasma, and intestinal biopsies at the time of recruitment (t0) and every 4 months in 1 year of follow-up (t1, t2, and t3), and the analysis of the JCV noncoding control region (NCCR) to detect cellular transcription factors binding site mutations. Results obtained showed that, in urine and ileal specimens, JCV load significantly increased in infliximab-treated patients after 1 year of treatment (t3), while viremia was significantly higher at t1. JCV NCCR sequence analysis showed a structure similar to CY archetype in 65/80 analyzed sequences, but the remaining 15/80, obtained exclusively from plasma and biopsies, evidenced a CY NCCR organization with two recurrent nucleotide changes, the 37-T to G transversion in box A Spi-B binding site and the 217-G to A transition in box F, and a box D deletion. These rearrangements were always found at t3 within seven infliximab-treated CD patients, who presented a very severe disease at t0. We can conclude that our rearranged NCCR sequences could be considered a marker of JCV virulence during mAb treatment, although none of our examined patients developed PML, and further studies on a larger cohort of patients should be performed.
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MESH Headings
- Adolescent
- Anti-Inflammatory Agents/administration & dosage
- Anti-Inflammatory Agents/adverse effects
- Antibodies, Monoclonal/administration & dosage
- Antibodies, Monoclonal/adverse effects
- Base Sequence
- Binding Sites
- Case-Control Studies
- Child
- Cohort Studies
- Crohn Disease/complications
- Crohn Disease/drug therapy
- Crohn Disease/immunology
- Crohn Disease/pathology
- Crohn Disease/virology
- DNA, Viral/genetics
- Female
- Follow-Up Studies
- Humans
- Infliximab
- JC Virus/genetics
- JC Virus/pathogenicity
- Leukoencephalopathy, Progressive Multifocal/drug therapy
- Leukoencephalopathy, Progressive Multifocal/etiology
- Leukoencephalopathy, Progressive Multifocal/immunology
- Leukoencephalopathy, Progressive Multifocal/pathology
- Leukoencephalopathy, Progressive Multifocal/virology
- Male
- Molecular Sequence Data
- Mutagenesis/drug effects
- Mutation
- Promoter Regions, Genetic
- Real-Time Polymerase Chain Reaction
- Sequence Analysis, DNA
- Virus Activation/drug effects
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Affiliation(s)
- Anna Bellizzi
- Department of Health Sciences and Infectious Diseases, Sapienza University, P.le Aldo Moro, 5, 00185, Rome, Italy
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Ciccocioppo R, Baldanti F, Russo M, Chezzi L, Viola F, Aloi M, Cucchiara S, Corazza GR. Human herpes virus-6 chromosomal integration misled the management of Crohn's disease. Inflamm Bowel Dis 2011; 17:E113-5. [PMID: 21648023 DOI: 10.1002/ibd.21790] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2011] [Accepted: 05/09/2011] [Indexed: 12/12/2022]
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