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Norovirus Gastroenteritis in ImmunocompromisedPatients
23190223
http://www.ncbi.nlm.nih.gov/pubmed/23190223
Infectious gastroenteritis is a common, acute illness that is characteristicallyself-limiting, but it can become debilitating and life-threatening inimmunocompromised patients. Noroviruses are major pathogens among the microbesassociated with gastroenteritis in both immunocompetent and immunocompromisedhosts ( Table 1 ). In the United States, noroviruses are the single most commoncause of acute gastroenteritis in adults that results in a visit to thehospital emergency department, and they are second only to rotaviruses as amajor cause of severe diarrhea in infants and young children.
In developing countries, noroviruses are estimated to cause more than200,000 deaths annually among children younger than 5 years of age, and it ispredicted that these viruses will become the predominant cause of diarrhea inall age groups worldwide once rotavirus infection is controlled throughvaccination.Noroviruses are increasingly recognized as an important cause ofchronic gastroenteritis in immunocompromised patients, as reflected by thegrowing number of clinical case reports. A comparison of the known features ofnorovirus gastroenteritis in immunocompetent versus immunocompromised hosts highlights the potentially serious outcome ofthis illness in persons who cannot adequately clear the virus ( Table 2 ). Thepurpose of this review is to summarize recent developments in norovirusresearch that are relevant to the prevention and management of norovirusgastroenteritis in immunocompromised patients.
No r o v i r u s C l a s s i f ica t ion a n d S t r u c t u r e
Noroviruses are small, nonenveloped viruses with a single-stranded RNAgenome that make up the genus norovirus of the family Caliciviridae. They aredivided into six major genogroups designated GI through GVI. GI and GII containthe majority of norovirus strains associated with human disease and are furtherdivided into about 30 genotypes. A single genotype, GII.4, has been associatedwith the majority of global outbreaks since the mid-1990s, when activesurveillance with molecular diagnostic techniques was initiated.
The norovirus genome encodes seven nonstructural and two structuralproteins (Fig. 1). The majority of reverse-transcriptase–polymerase-chain-reaction (RT-PCR) diagnostic assays target the RNApolymerase region of the genome because of its higher sequence conservationamong strains. VP1 is the major structural protein of the virus that self-assembles into viruslike particles (VLPs), which are being evaluated as possible vaccines; VP2 isa minor structural protein. Noroviruses bind saccharides of the human histo–blood group antigens (HBGAs) within their VP1 protruding 2 (P2) domain, aproposed mechanism for facilitating viral entry into the epithelial cells ofthe gastrointestinal tract (Fig. 1). It is thought that susceptibility tonorovirus in humans is determined by allelic variation of HBGAs,13with each norovirus strainpresenting a characteristic HBGA-binding profile. Thus, a certain geneticbackground might confer resistance to theinfection, as in the case of personsclassified asnonsecretors (i.e., persons in whom these carbohydrates are notexpressed on the surface of intestinal epithelial cells), who are resistant toinfection with Norwalk virus, a GI.1 strain.
No r o v i r u s e s i n I m m uno c o m pr o m i s e d Pa t i e n t s
Prolonged norovirus and illness have been reported in persons who are immunosuppressed as a result of congenitalimmunodeficiency, immunosuppressive therapy for the purpose of maintaining anorgan allograft, cancer chemotherapy, and infection with the humanimmunodeficiency virus (HIV). Immunocompromised patients can be exposed to noroviruses frommany sources, including family members, health care workers, contaminated foodor water, and the environment (including nosocomial sources). The overall incidence of norovirus gastroenteritis in hospital and community settings has not yet been determined. An increasing number of studies show thatimmunosuppressive therapy is a risk factor for norovirus infection. Accordingto one report, 18% of patients who underwent allogeneic hematopoietic stem-celltransplantation (HSCT) contracted norovirus over a 1-year period, many afterthey had received intensified immunosuppressive regimens for suspectedgraft-versus-host disease (GVHD).18 A 2-year survey of renal-transplant recipients showed that 17% of the patients were chronically infected with norovirus and had intermittent diarrhea.
Noroviruses are highly resistant to harsh environmental conditions, andthe infectious oraldose is estimated to be less than 20 viral particles. Inimmunocompetent adults, norovirus gastroenteritis is characteristically acute (24 to 48hours in duration) andself-limiting, but in immunocompromised adults, the disease canbecomechronic and can persist for weeks to years5,9( Table 2 ). A markedpredominance of wintertimenorovirus infections has been widely described inthegeneral population, and common names arewinter-vomiting disease and stomachflu. In contrast, in a case–control study of children withcancer and in a caseseries of patients who hadundergone HSCT, the rate of illness was reported tobe unchanged throughout the year.
It is not yet clear whether noroviruses are transmissible toimmunocompetent adults from patients with chronic viral shedding, the latter having been proposed as a possiblereservoir of novel genetic variants. Surveillance studies suggest that most nosocomial norovirus infections are acquired in the community; nosocomial outbreaks in which persons with immunodeficiency disordersare the source are rare.Vomiting and diarrhea have been linked to high viralloads in patients undergoing immunosuppressive therapy, whereas asymptomatic shedding was associated with lower viral loads.These findings, as well as those involving immunocompetent hosts, suggest that in most cases the virus is transmitted from symptomatic persons, even whenhigh levels of the virus are shed in the stool for prolonged periods after symptoms have resolved.
Chronic norovirus gastroenteritis can present specific clinical challenges in patients with an impaired immune response, as compared with immunocompetent hosts. For example, norovirusinduced diarrhea in immunosuppressed renaltransplant recipients is characterizedby dramatic weight loss and lasts considerably longer than treatable bacteria- or parasite-induced diarrhea (i.e., an average of 9 months vs. 1month). The malnutrition, dehydration, and altered intestinal mucosal barrierassociated with prolonged norovirus-related diarrhea can increase morbidity andworsen the outcome of the underlying disease.Noroviruses were reported to be the cause of death in one patient 49 days after theonset of symptoms and in another patient after 1 year of unresolvedgastroenteritis.
Di a g no s i s of No r o v i r u s G a s t r oe n t e r i t is
It is difficult to diagnose norovirus gastroenteritis on the basis ofclinical features alone. Diarrhea is a common complication in transplant recipients: gastroenteritis develops in 80% of patients who have undergone allogeneic HSCT, as a result ofconditioning therapy, GVHD, drugs, or infectious agents. Symptoms of acute norovirus disease can include diarrhea, fever, and projectile vomiting,in contrast to the characteristic combination of diarrhea and nausea (withoutvomiting) observed in GVHD. Although a provisional diagnosis might be made, use of a reliable diagnostic assay is crucial todistinguish infectious diarrhea from clinical complications such as graft rejection and GVHD, since these conditions require diametrically opposed approaches to management (i.e., decreasingimmunosuppression in infectious diarrhea and increasing it in graft rejection andGVHD).Noroviruses are shed in stool, and norovirusspecific antigens and RNA can be detected in stool samples. Regular or quantitativereal-time RT-PCR assay is the most widely used laboratory method for diagnosing norovirus gastroenteritis, but several other assays arenow available.Computed tomography has been reported to aid in discriminating between norovirus infection and GVHD, since norovirus-infected patients have pronounced bowel-wall edemarestricted to the small intestine, which is infrequently seen in patients with intestinal cytomegalovirus infection or GVHD.
Precise and timely diagnosisof norovirus infection by means of laboratory testing is essential in intestinal-transplant recipients,since the pathological characteristics of norovirus infection are similar tothose seen in allograft rejection, with chronic inflammatorychange, apoptotic cells, andblunted villi. The diagnosis of gastrointestinal GVHD, a welldescribed complication ofHSCT, also relies on histopathological findings that could be mistakenfor those associated with norovirus infection, in which numerous apoptotic bodies are observed.
No r o v i r u s Di v e r s i t ya n d E v ol u t ion i n I m m u no c o m pr o m i s e d Pa t i e n t s
The diversity of norovirus genotypes circulating in the community, whereGII.4 is most prevalent, is reflected in the genotypes detected in personswith an impaired immune system. Therehavebeen no reported strain differences among the norovirus genotypes with regard to symptoms, severity, or progression to chronicity in immunocompromised hosts.
Intrahost variation and evolution of the viral genome over extendedperiods of shedding have been studied in detail in several patients persistentlyinfected with norovirus. An analysis of the viral variants present in the stool of infected persons showed that inimmunocompetent persons in whom the infection resolved during the acute phase,a single major variant predominated, whereas immunocompromised patients with chronic norovirus infection had a diverse viral population (Fig. 2). These dataindicate that a chronic infection without immune pressure al-lows the generationof a diverse norovirus population in the host; however, at present there isnoepidemiologic evidence to suggest that these variants become prevalent asepidemic strains in thcommunity. Despitethe increased viral heterogeneity generated during a chronic norovirusinfection, the amino acid residues that interact withHBGA ligands remainconserved — a finding thaisconsistent with the proposed importance of thiinteraction in the binding of virus to intestinaepithelial cells.The shedding of norovirus by immunocompromised patients for an extended period of time has provided aunique opportunity to monitor the effects of genetic changes that lead to theaccumulation of alterations in the amino acid makeup of the virus. Evolution ofthe norovirus genome in patients infected for extended periods is relativelyrapid (3.3% amino acid substitutions per year), considering that GII.4noroviruses have been shown to have accumulated only a 10% amino acid difference intheir viral capsid after circulating in the community for 31 years.Accuratedetermination of a substitution rate could be useful in assessing whether a patient with chronic shedding continues to have the same norovirus strain or has been reinfected with a new strain; it mayalso help track norovirus transmission among immunocompromised patients in acommon setting. This “time-clock” approach may proveuseful in establishing the role of nosocomial transmission in immunocompromisedpatients and in evaluating the efficacy of treatment because knowledge of therate at which genetic differences are generated can be used to determinewhether a persistent strain is under investigation or a new strain has beenintroduced.
Pr e v e n t ion a n d T r e a t m e n t of No r o v i r u s I n f e c t ion i n I m m u no c o m pr o m i s e d Pa t i e n t s
No vaccines or specific antiviral agents are cur-rently available toprevent or treat norovirus in -fection, but progress has recently been made invaccine development. Norovirus vaccines have been tested in both humans andchimpanzees, and the results of these studies were used to de -terminecorrelates of protection and duration of immune response. It has also beenreported that both T-cell and B-cell responses are neces -sary to clearnorovirus. In a mouse model, CD4+ and CD8+ cells were required for clearance ofmu -rine norovirus in the intestine.37,38 Norovirus clearance in patients with chronicinfection has been shown to be associated with the recovery of T cells; in one study, symptoms improved in patients with HIV infection who had anincreased CD4+ count.
Currently, the treatment of patients with no-rovirus gastroenteritis isprimarily supportive and focuses on prevention and reversal of dehydra -tion. Chronic norovirus infections in transplant recipients mayalso require the adjustment of im -munosuppressive therapy during prolonged ill-ness. Passive antibody therapies havebeen test -ed in individual case studies, and evidence of their efficacy intreating patients with norovirus gastroenteritis is mostly anecdotal. Oraladmin-istration of breast milk or immune globulin hasyielded mixed results, probably reflecting differences in the quality andquantity of norovirusspecific antibodies in the treatment administered. Both immune globulin and breastmilk have been administered successfully through a duodenal tube (in an attempt to bypass theadverse acidic environment of the stomach) to treat prolonged norovirusinfection in a heart-transplant recipient, but this approach failed to clearnorovirus in a patient with agammaglobulinemia.
Certain commonly used antiviral drugs such as ribavirin have failed toclear norovirus in chronically infected patients.40 Nitazoxanide (an antiprotozoaldrug) was reported to significantly reduce the time to resolution of symptomsrelated to both rotavirus- and norovirus-induced diarrhea in immunocompetentpatients, and symptoms of severe norovirus gastroenteritis were described asmarkedly reduced after 1 day of treatment in a patient who underwent HSCT. However,quantification of the exact genomic load in this patient was not reported, andviral shedding persisted for a month after treatment. Further testing will be needed to determine the efficacy of this drug inimmunocompromised patients.
Finally, it has been suggested that the class of immunosuppressive drugsprovided might affect the clearance of norovirus, since certain drugs also have antiviral properties.30,44 A significant increase in the antiviralproperties of the immunosuppressive therapy administered (as measured by the incidence of cytomegalovirus infections in immunodeficient patients) wasobserved only when a switch was made from an antimetabolite (azathioprine ormycophenolate) to a mammalian target of rapamycin (mTOR) inhibitor (sirolimusor everolimus). The incidence of norovirus gastroenteritis in patients being treated with different types of immunosuppressive agents willrequire more study.
C onc l u s ions
Given the substantial toll that noroviruses can take on the prognosis for and quality of life of patients with a deficientimmune response, appropriate measures should be taken to reduce the risk ofnorovirus infection. First and foremost, rigorous personal hygiene, especiallyhand-washing, is the single most effective measure to combat norovirus transmission.This measure is crucial, given the fact that 80% of hospital surfaces werefound to be contaminated with 21 different noroviruses during environmentalsurveillance in a unit for children with immunodeficiency disorders. Immunocompromised patients should avoid contact with persons who are acutely ill with gastroenteritisand should follow guidelines designed to prevent infections with enteric pathogens.
Such patients should consume foodsconsidered to be safe according to the principles designed to minimize the risk of foodborne diseases. Althoughit is prudent to isolate patients who have chronic norovirus infection, the virulenceof noroviruses shed in the stool in such patients has been called intoquestion, given the absence of reported secondary cases. Finally, norovirustesting can now be included in the care of immunocompromised patients with acute or chronic gastroenteritis of unknown cause.Widespread use of diagnostic assays and continued research will help clarify the precise disease burden andepidemiologic features of norovirus infection in this population and willimprove the clinical care of those infected.
23190223
http://www.ncbi.nlm.nih.gov/pubmed/23190223
Infectious gastroenteritis is a common, acute illness that is characteristicallyself-limiting, but it can become debilitating and life-threatening inimmunocompromised patients. Noroviruses are major pathogens among the microbesassociated with gastroenteritis in both immunocompetent and immunocompromisedhosts ( Table 1 ). In the United States, noroviruses are the single most commoncause of acute gastroenteritis in adults that results in a visit to thehospital emergency department, and they are second only to rotaviruses as amajor cause of severe diarrhea in infants and young children.
In developing countries, noroviruses are estimated to cause more than200,000 deaths annually among children younger than 5 years of age, and it ispredicted that these viruses will become the predominant cause of diarrhea inall age groups worldwide once rotavirus infection is controlled throughvaccination.Noroviruses are increasingly recognized as an important cause ofchronic gastroenteritis in immunocompromised patients, as reflected by thegrowing number of clinical case reports. A comparison of the known features ofnorovirus gastroenteritis in immunocompetent versus immunocompromised hosts highlights the potentially serious outcome ofthis illness in persons who cannot adequately clear the virus ( Table 2 ). Thepurpose of this review is to summarize recent developments in norovirusresearch that are relevant to the prevention and management of norovirusgastroenteritis in immunocompromised patients.
No r o v i r u s C l a s s i f ica t ion a n d S t r u c t u r e
Noroviruses are small, nonenveloped viruses with a single-stranded RNAgenome that make up the genus norovirus of the family Caliciviridae. They aredivided into six major genogroups designated GI through GVI. GI and GII containthe majority of norovirus strains associated with human disease and are furtherdivided into about 30 genotypes. A single genotype, GII.4, has been associatedwith the majority of global outbreaks since the mid-1990s, when activesurveillance with molecular diagnostic techniques was initiated.
The norovirus genome encodes seven nonstructural and two structuralproteins (Fig. 1). The majority of reverse-transcriptase–polymerase-chain-reaction (RT-PCR) diagnostic assays target the RNApolymerase region of the genome because of its higher sequence conservationamong strains. VP1 is the major structural protein of the virus that self-assembles into viruslike particles (VLPs), which are being evaluated as possible vaccines; VP2 isa minor structural protein. Noroviruses bind saccharides of the human histo–blood group antigens (HBGAs) within their VP1 protruding 2 (P2) domain, aproposed mechanism for facilitating viral entry into the epithelial cells ofthe gastrointestinal tract (Fig. 1). It is thought that susceptibility tonorovirus in humans is determined by allelic variation of HBGAs,13with each norovirus strainpresenting a characteristic HBGA-binding profile. Thus, a certain geneticbackground might confer resistance to theinfection, as in the case of personsclassified asnonsecretors (i.e., persons in whom these carbohydrates are notexpressed on the surface of intestinal epithelial cells), who are resistant toinfection with Norwalk virus, a GI.1 strain.
No r o v i r u s e s i n I m m uno c o m pr o m i s e d Pa t i e n t s
Prolonged norovirus and illness have been reported in persons who are immunosuppressed as a result of congenitalimmunodeficiency, immunosuppressive therapy for the purpose of maintaining anorgan allograft, cancer chemotherapy, and infection with the humanimmunodeficiency virus (HIV). Immunocompromised patients can be exposed to noroviruses frommany sources, including family members, health care workers, contaminated foodor water, and the environment (including nosocomial sources). The overall incidence of norovirus gastroenteritis in hospital and community settings has not yet been determined. An increasing number of studies show thatimmunosuppressive therapy is a risk factor for norovirus infection. Accordingto one report, 18% of patients who underwent allogeneic hematopoietic stem-celltransplantation (HSCT) contracted norovirus over a 1-year period, many afterthey had received intensified immunosuppressive regimens for suspectedgraft-versus-host disease (GVHD).18 A 2-year survey of renal-transplant recipients showed that 17% of the patients were chronically infected with norovirus and had intermittent diarrhea.
Noroviruses are highly resistant to harsh environmental conditions, andthe infectious oraldose is estimated to be less than 20 viral particles. Inimmunocompetent adults, norovirus gastroenteritis is characteristically acute (24 to 48hours in duration) andself-limiting, but in immunocompromised adults, the disease canbecomechronic and can persist for weeks to years5,9( Table 2 ). A markedpredominance of wintertimenorovirus infections has been widely described inthegeneral population, and common names arewinter-vomiting disease and stomachflu. In contrast, in a case–control study of children withcancer and in a caseseries of patients who hadundergone HSCT, the rate of illness was reported tobe unchanged throughout the year.
It is not yet clear whether noroviruses are transmissible toimmunocompetent adults from patients with chronic viral shedding, the latter having been proposed as a possiblereservoir of novel genetic variants. Surveillance studies suggest that most nosocomial norovirus infections are acquired in the community; nosocomial outbreaks in which persons with immunodeficiency disordersare the source are rare.Vomiting and diarrhea have been linked to high viralloads in patients undergoing immunosuppressive therapy, whereas asymptomatic shedding was associated with lower viral loads.These findings, as well as those involving immunocompetent hosts, suggest that in most cases the virus is transmitted from symptomatic persons, even whenhigh levels of the virus are shed in the stool for prolonged periods after symptoms have resolved.
Chronic norovirus gastroenteritis can present specific clinical challenges in patients with an impaired immune response, as compared with immunocompetent hosts. For example, norovirusinduced diarrhea in immunosuppressed renaltransplant recipients is characterizedby dramatic weight loss and lasts considerably longer than treatable bacteria- or parasite-induced diarrhea (i.e., an average of 9 months vs. 1month). The malnutrition, dehydration, and altered intestinal mucosal barrierassociated with prolonged norovirus-related diarrhea can increase morbidity andworsen the outcome of the underlying disease.Noroviruses were reported to be the cause of death in one patient 49 days after theonset of symptoms and in another patient after 1 year of unresolvedgastroenteritis.
Di a g no s i s of No r o v i r u s G a s t r oe n t e r i t is
It is difficult to diagnose norovirus gastroenteritis on the basis ofclinical features alone. Diarrhea is a common complication in transplant recipients: gastroenteritis develops in 80% of patients who have undergone allogeneic HSCT, as a result ofconditioning therapy, GVHD, drugs, or infectious agents. Symptoms of acute norovirus disease can include diarrhea, fever, and projectile vomiting,in contrast to the characteristic combination of diarrhea and nausea (withoutvomiting) observed in GVHD. Although a provisional diagnosis might be made, use of a reliable diagnostic assay is crucial todistinguish infectious diarrhea from clinical complications such as graft rejection and GVHD, since these conditions require diametrically opposed approaches to management (i.e., decreasingimmunosuppression in infectious diarrhea and increasing it in graft rejection andGVHD).Noroviruses are shed in stool, and norovirusspecific antigens and RNA can be detected in stool samples. Regular or quantitativereal-time RT-PCR assay is the most widely used laboratory method for diagnosing norovirus gastroenteritis, but several other assays arenow available.Computed tomography has been reported to aid in discriminating between norovirus infection and GVHD, since norovirus-infected patients have pronounced bowel-wall edemarestricted to the small intestine, which is infrequently seen in patients with intestinal cytomegalovirus infection or GVHD.
Precise and timely diagnosisof norovirus infection by means of laboratory testing is essential in intestinal-transplant recipients,since the pathological characteristics of norovirus infection are similar tothose seen in allograft rejection, with chronic inflammatorychange, apoptotic cells, andblunted villi. The diagnosis of gastrointestinal GVHD, a welldescribed complication ofHSCT, also relies on histopathological findings that could be mistakenfor those associated with norovirus infection, in which numerous apoptotic bodies are observed.
No r o v i r u s Di v e r s i t ya n d E v ol u t ion i n I m m u no c o m pr o m i s e d Pa t i e n t s
The diversity of norovirus genotypes circulating in the community, whereGII.4 is most prevalent, is reflected in the genotypes detected in personswith an impaired immune system. Therehavebeen no reported strain differences among the norovirus genotypes with regard to symptoms, severity, or progression to chronicity in immunocompromised hosts.
Intrahost variation and evolution of the viral genome over extendedperiods of shedding have been studied in detail in several patients persistentlyinfected with norovirus. An analysis of the viral variants present in the stool of infected persons showed that inimmunocompetent persons in whom the infection resolved during the acute phase,a single major variant predominated, whereas immunocompromised patients with chronic norovirus infection had a diverse viral population (Fig. 2). These dataindicate that a chronic infection without immune pressure al-lows the generationof a diverse norovirus population in the host; however, at present there isnoepidemiologic evidence to suggest that these variants become prevalent asepidemic strains in thcommunity. Despitethe increased viral heterogeneity generated during a chronic norovirusinfection, the amino acid residues that interact withHBGA ligands remainconserved — a finding thaisconsistent with the proposed importance of thiinteraction in the binding of virus to intestinaepithelial cells.The shedding of norovirus by immunocompromised patients for an extended period of time has provided aunique opportunity to monitor the effects of genetic changes that lead to theaccumulation of alterations in the amino acid makeup of the virus. Evolution ofthe norovirus genome in patients infected for extended periods is relativelyrapid (3.3% amino acid substitutions per year), considering that GII.4noroviruses have been shown to have accumulated only a 10% amino acid difference intheir viral capsid after circulating in the community for 31 years.Accuratedetermination of a substitution rate could be useful in assessing whether a patient with chronic shedding continues to have the same norovirus strain or has been reinfected with a new strain; it mayalso help track norovirus transmission among immunocompromised patients in acommon setting. This “time-clock” approach may proveuseful in establishing the role of nosocomial transmission in immunocompromisedpatients and in evaluating the efficacy of treatment because knowledge of therate at which genetic differences are generated can be used to determinewhether a persistent strain is under investigation or a new strain has beenintroduced.
Pr e v e n t ion a n d T r e a t m e n t of No r o v i r u s I n f e c t ion i n I m m u no c o m pr o m i s e d Pa t i e n t s
No vaccines or specific antiviral agents are cur-rently available toprevent or treat norovirus in -fection, but progress has recently been made invaccine development. Norovirus vaccines have been tested in both humans andchimpanzees, and the results of these studies were used to de -terminecorrelates of protection and duration of immune response. It has also beenreported that both T-cell and B-cell responses are neces -sary to clearnorovirus. In a mouse model, CD4+ and CD8+ cells were required for clearance ofmu -rine norovirus in the intestine.37,38 Norovirus clearance in patients with chronicinfection has been shown to be associated with the recovery of T cells; in one study, symptoms improved in patients with HIV infection who had anincreased CD4+ count.
Currently, the treatment of patients with no-rovirus gastroenteritis isprimarily supportive and focuses on prevention and reversal of dehydra -tion. Chronic norovirus infections in transplant recipients mayalso require the adjustment of im -munosuppressive therapy during prolonged ill-ness. Passive antibody therapies havebeen test -ed in individual case studies, and evidence of their efficacy intreating patients with norovirus gastroenteritis is mostly anecdotal. Oraladmin-istration of breast milk or immune globulin hasyielded mixed results, probably reflecting differences in the quality andquantity of norovirusspecific antibodies in the treatment administered. Both immune globulin and breastmilk have been administered successfully through a duodenal tube (in an attempt to bypass theadverse acidic environment of the stomach) to treat prolonged norovirusinfection in a heart-transplant recipient, but this approach failed to clearnorovirus in a patient with agammaglobulinemia.
Certain commonly used antiviral drugs such as ribavirin have failed toclear norovirus in chronically infected patients.40 Nitazoxanide (an antiprotozoaldrug) was reported to significantly reduce the time to resolution of symptomsrelated to both rotavirus- and norovirus-induced diarrhea in immunocompetentpatients, and symptoms of severe norovirus gastroenteritis were described asmarkedly reduced after 1 day of treatment in a patient who underwent HSCT. However,quantification of the exact genomic load in this patient was not reported, andviral shedding persisted for a month after treatment. Further testing will be needed to determine the efficacy of this drug inimmunocompromised patients.
Finally, it has been suggested that the class of immunosuppressive drugsprovided might affect the clearance of norovirus, since certain drugs also have antiviral properties.30,44 A significant increase in the antiviralproperties of the immunosuppressive therapy administered (as measured by the incidence of cytomegalovirus infections in immunodeficient patients) wasobserved only when a switch was made from an antimetabolite (azathioprine ormycophenolate) to a mammalian target of rapamycin (mTOR) inhibitor (sirolimusor everolimus). The incidence of norovirus gastroenteritis in patients being treated with different types of immunosuppressive agents willrequire more study.
C onc l u s ions
Given the substantial toll that noroviruses can take on the prognosis for and quality of life of patients with a deficientimmune response, appropriate measures should be taken to reduce the risk ofnorovirus infection. First and foremost, rigorous personal hygiene, especiallyhand-washing, is the single most effective measure to combat norovirus transmission.This measure is crucial, given the fact that 80% of hospital surfaces werefound to be contaminated with 21 different noroviruses during environmentalsurveillance in a unit for children with immunodeficiency disorders. Immunocompromised patients should avoid contact with persons who are acutely ill with gastroenteritisand should follow guidelines designed to prevent infections with enteric pathogens.
Such patients should consume foodsconsidered to be safe according to the principles designed to minimize the risk of foodborne diseases. Althoughit is prudent to isolate patients who have chronic norovirus infection, the virulenceof noroviruses shed in the stool in such patients has been called intoquestion, given the absence of reported secondary cases. Finally, norovirustesting can now be included in the care of immunocompromised patients with acute or chronic gastroenteritis of unknown cause.Widespread use of diagnostic assays and continued research will help clarify the precise disease burden andepidemiologic features of norovirus infection in this population and willimprove the clinical care of those infected.
