© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Transplant Infectious Disease, ISSN 1398-2273
Review
Diarrhea caused by viruses in transplant recipients L.Y. Lee, M.G. Ison. Diarrhea caused by viruses in transplant recipients. Transpl Infect Dis 2014: 16: 347–358. All rights reserved Abstract: Diarrhea is a common complication after solid organ transplantation, and viruses are emerging as important but underestimated causative agents. Viral infections in solid organ transplant (SOT) recipients can result in severe and prolonged diarrhea with significant patient morbidity and graft complications. Cytomegalovirus remains the most common of the viruses to cause diarrhea, but other viruses are being increasingly recognized, including norovirus, rotavirus, and adenovirus. This article reviews the epidemiology, clinical presentation, diagnosis, management, and outcomes of these viral causes of diarrhea in SOT patients.
L.Y. Lee1,2, M.G. Ison1,2,3,4 1
Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA, 2 Northwestern University Transplant Outcomes Research Collaborative, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA, 3Division of Infectious Diseases Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA, 4Division of Organ Transplantation, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA Key words: diarrhea; solid organ transplantation; norovirus; rotavirus; adenovirus; cytomegalovirus Correspondence to: Michael G. Ison, MD, MS, Divisions of Infectious Diseases & Organ Transplantation, Northwestern University Feinberg School of Medicine, 645 N. Michigan Avenue Suite 900, Chicago, IL 60611, USA Tel: 312 695 4186 Fax: 312 695 5088 E-mail: [email protected]
Received 8 August 2013, revised 11 December 2013, accepted for publication 21 December 2013 DOI: 10.1111/tid.12212 Transpl Infect Dis 2014: 16: 347–358
Diarrhea is characterized by a decreased consistency (soft or liquid) of stool and increased frequency (≥3/ day) of bowel movements (1). Diarrhea is frequently observed following solid organ transplantation with a prevalence up to 54% (2–4). In solid organ transplant (SOT) patients, diarrhea has been associated with morbidity, mortality, and graft loss because of severe dehydration, increased creatinine levels, and fluctuating serum levels of immunosuppressive drugs (5–9).
Abbreviations: AdV, adenovirus; CDC, Centers for Disease Control and Prevention; CMV, cytomegalovirus; D, donor; EIA, enzyme immunoassay; GCV, ganciclovir; GE, gastroenteritis; GI, gastrointestinal; HBGAs, histo-blood group antigens; NSP, non-structural protein; OHIG, oral human immunoglobulin; ORF, open reading frames; PCR, polymerase chain reaction; R, recipient; RT-PCR, reverse-transcriptase polymerase chain reaction; SOT, solid organ transplant; valGCV, valganciclovir; VP, structural protein
The etiologic spectrum of diarrhea in SOT recipients is wide and includes both non-infectious and infectious causes. The immunosuppressive drugs given to SOT recipients, especially mycophenolate mofetil, are frequently associated with gastrointestinal (GI) side effects such as diarrhea that can occur at any point post transplant (9–13). Graft-versus-host disease is a rare non-infectious cause of diarrhea that typically develops early after solid organ transplantation (11). Several infections, including bacteria, including Clostridium difficile, viruses, and parasites, result in diarrhea among transplant patients and have been reviewed in detail elsewhere (11). Despite the prevalence of diarrhea among SOT patients, limited data are available regarding its etiology and epidemiology (9, 14). An etiologic cause of diarrhea is documented in the majority of patients (80–83%), with
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infectious agents accounting for 42–77% of the incidences (9, 14). Contemporary diagnostic strategies, such as polymerase chain reaction (PCR), have resulted in higher rates of diagnosis of infectious causes (9, 13, 15). Virally mediated diarrhea is increasingly being recognized as a common complication after solid organ transplantation, and in a study of intestinal transplantation patients, up to 70% of intestinal enteritis was caused by viral infection (16). Currently, cytomegalovirus (CMV) remains the most common viral infection complicating solid organ transplantation, and perhaps for that reason, diarrhea attributed to CMV colitis has been relatively well described in terms of epidemiology, clinical presentation, treatment, and outcomes (17, 18). However, improvements in diagnostic techniques have led to the recognition of other viruses that can cause diarrhea in SOT recipients (19). The most prominent of these emerging viruses include norovirus, adenovirus (AdV), and rotavirus (15, 19). In this review, the epidemiology, clinical presentation, diagnosis, management, and outcomes of these important viral causes of diarrhea in SOT patients will be summarized.
Norovirus Basic norovirus virology Noroviruses are non-enveloped, positive-sense, singlestranded RNA viruses belonging to the genus Norovirus, family Caliciviridae (20–22). The Norovirus genus is divided into 5 major genogroups, G-I–G-V, which then further divides into 30+ genotypes (23, 24). Genogroups G-I, G-II, and G-IV have been associated with human disease. Viruses in the G-II.4 genotype have caused the majority of recent norovirus outbreaks globally, with new G-II.4 strains emerging every 2–3 years that result in local epidemics (25–27). The linear RNA strand is organized into 3 open reading frames (ORFs). Structural protein VP1 is the major capsid protein encoded by ORF 2, which has traditionally been the reference region for establishing genotypes (23, 28, 29). VP1 also serves as the major structural protein in noroviruses and has the capability of self-assembling into virus-like particles, and has been a promising candidate for vaccine development as well as the target of laboratory studies (30–32). ORF 1 encodes the 6 non-structural proteins (NSPs) including the highly conserved POL gene coding for an RNAdependent RNA polymerase, a target of reverse-trans-
348
criptase polymerase chain reaction (RT-PCR) assays (20, 23, 28, 29). In humans, norovirus interacts with its host by specifically binding the human histo-blood group antigens (HBGAs) (32–34). HBGAs are complex carbohydrates found on mucosal secretion and epithelial cells, including intestinal epithelial cells (20, 32). Resistance to infection with the G-I.1 strain of norovirus (i.e., Norwalk virus) has been observed in persons lacking HBGA expression on the surface of intestinal epithelial cells (i.e., non-secretors), including those with a mutation in the FUT2 gene (34, 35).
Epidemiology, clinical features, and outcomes of norovirus Noroviruses are the leading cause of acute viral gastroenteritis (GE) in humans, accounting for up to 93% of the non-bacterial acute GE outbreaks (36). Although norovirus can cause infections year round, outbreaks occur most frequently during the winter (21, 37). Noroviruses are spread via the fecal-oral route, although they also transmit by inhalation of aerosols from vomitus or contact with contaminated environmental surfaces (22, 37, 38). Human noroviruses are highly stable in harsh environmental conditions, and with their low infectious dose of
Review
Diarrhea caused by viruses in transplant recipients L.Y. Lee, M.G. Ison. Diarrhea caused by viruses in transplant recipients. Transpl Infect Dis 2014: 16: 347–358. All rights reserved Abstract: Diarrhea is a common complication after solid organ transplantation, and viruses are emerging as important but underestimated causative agents. Viral infections in solid organ transplant (SOT) recipients can result in severe and prolonged diarrhea with significant patient morbidity and graft complications. Cytomegalovirus remains the most common of the viruses to cause diarrhea, but other viruses are being increasingly recognized, including norovirus, rotavirus, and adenovirus. This article reviews the epidemiology, clinical presentation, diagnosis, management, and outcomes of these viral causes of diarrhea in SOT patients.
L.Y. Lee1,2, M.G. Ison1,2,3,4 1
Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA, 2 Northwestern University Transplant Outcomes Research Collaborative, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA, 3Division of Infectious Diseases Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA, 4Division of Organ Transplantation, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA Key words: diarrhea; solid organ transplantation; norovirus; rotavirus; adenovirus; cytomegalovirus Correspondence to: Michael G. Ison, MD, MS, Divisions of Infectious Diseases & Organ Transplantation, Northwestern University Feinberg School of Medicine, 645 N. Michigan Avenue Suite 900, Chicago, IL 60611, USA Tel: 312 695 4186 Fax: 312 695 5088 E-mail: [email protected]
Received 8 August 2013, revised 11 December 2013, accepted for publication 21 December 2013 DOI: 10.1111/tid.12212 Transpl Infect Dis 2014: 16: 347–358
Diarrhea is characterized by a decreased consistency (soft or liquid) of stool and increased frequency (≥3/ day) of bowel movements (1). Diarrhea is frequently observed following solid organ transplantation with a prevalence up to 54% (2–4). In solid organ transplant (SOT) patients, diarrhea has been associated with morbidity, mortality, and graft loss because of severe dehydration, increased creatinine levels, and fluctuating serum levels of immunosuppressive drugs (5–9).
Abbreviations: AdV, adenovirus; CDC, Centers for Disease Control and Prevention; CMV, cytomegalovirus; D, donor; EIA, enzyme immunoassay; GCV, ganciclovir; GE, gastroenteritis; GI, gastrointestinal; HBGAs, histo-blood group antigens; NSP, non-structural protein; OHIG, oral human immunoglobulin; ORF, open reading frames; PCR, polymerase chain reaction; R, recipient; RT-PCR, reverse-transcriptase polymerase chain reaction; SOT, solid organ transplant; valGCV, valganciclovir; VP, structural protein
The etiologic spectrum of diarrhea in SOT recipients is wide and includes both non-infectious and infectious causes. The immunosuppressive drugs given to SOT recipients, especially mycophenolate mofetil, are frequently associated with gastrointestinal (GI) side effects such as diarrhea that can occur at any point post transplant (9–13). Graft-versus-host disease is a rare non-infectious cause of diarrhea that typically develops early after solid organ transplantation (11). Several infections, including bacteria, including Clostridium difficile, viruses, and parasites, result in diarrhea among transplant patients and have been reviewed in detail elsewhere (11). Despite the prevalence of diarrhea among SOT patients, limited data are available regarding its etiology and epidemiology (9, 14). An etiologic cause of diarrhea is documented in the majority of patients (80–83%), with
347
Lee & Ison: Viral diarrhea in SOT
infectious agents accounting for 42–77% of the incidences (9, 14). Contemporary diagnostic strategies, such as polymerase chain reaction (PCR), have resulted in higher rates of diagnosis of infectious causes (9, 13, 15). Virally mediated diarrhea is increasingly being recognized as a common complication after solid organ transplantation, and in a study of intestinal transplantation patients, up to 70% of intestinal enteritis was caused by viral infection (16). Currently, cytomegalovirus (CMV) remains the most common viral infection complicating solid organ transplantation, and perhaps for that reason, diarrhea attributed to CMV colitis has been relatively well described in terms of epidemiology, clinical presentation, treatment, and outcomes (17, 18). However, improvements in diagnostic techniques have led to the recognition of other viruses that can cause diarrhea in SOT recipients (19). The most prominent of these emerging viruses include norovirus, adenovirus (AdV), and rotavirus (15, 19). In this review, the epidemiology, clinical presentation, diagnosis, management, and outcomes of these important viral causes of diarrhea in SOT patients will be summarized.
Norovirus Basic norovirus virology Noroviruses are non-enveloped, positive-sense, singlestranded RNA viruses belonging to the genus Norovirus, family Caliciviridae (20–22). The Norovirus genus is divided into 5 major genogroups, G-I–G-V, which then further divides into 30+ genotypes (23, 24). Genogroups G-I, G-II, and G-IV have been associated with human disease. Viruses in the G-II.4 genotype have caused the majority of recent norovirus outbreaks globally, with new G-II.4 strains emerging every 2–3 years that result in local epidemics (25–27). The linear RNA strand is organized into 3 open reading frames (ORFs). Structural protein VP1 is the major capsid protein encoded by ORF 2, which has traditionally been the reference region for establishing genotypes (23, 28, 29). VP1 also serves as the major structural protein in noroviruses and has the capability of self-assembling into virus-like particles, and has been a promising candidate for vaccine development as well as the target of laboratory studies (30–32). ORF 1 encodes the 6 non-structural proteins (NSPs) including the highly conserved POL gene coding for an RNAdependent RNA polymerase, a target of reverse-trans-
348
criptase polymerase chain reaction (RT-PCR) assays (20, 23, 28, 29). In humans, norovirus interacts with its host by specifically binding the human histo-blood group antigens (HBGAs) (32–34). HBGAs are complex carbohydrates found on mucosal secretion and epithelial cells, including intestinal epithelial cells (20, 32). Resistance to infection with the G-I.1 strain of norovirus (i.e., Norwalk virus) has been observed in persons lacking HBGA expression on the surface of intestinal epithelial cells (i.e., non-secretors), including those with a mutation in the FUT2 gene (34, 35).
Epidemiology, clinical features, and outcomes of norovirus Noroviruses are the leading cause of acute viral gastroenteritis (GE) in humans, accounting for up to 93% of the non-bacterial acute GE outbreaks (36). Although norovirus can cause infections year round, outbreaks occur most frequently during the winter (21, 37). Noroviruses are spread via the fecal-oral route, although they also transmit by inhalation of aerosols from vomitus or contact with contaminated environmental surfaces (22, 37, 38). Human noroviruses are highly stable in harsh environmental conditions, and with their low infectious dose of
