Infectious gastroenteritis is a common acute illness that, despite its self-limiting features, can still be more debilitating and even life-threatening in immunocompromised patients.
In the United States, norovirus is the most common pathogenic microorganism alone that causes acute gastroenteritis in adults in emergency settings and the second most common virus (after rotavirus) that causes severe diarrhea in infants and children.
In developing countries, norovirus is assessed to have caused more than 200,000 deaths in children under 5 years of age. When rotavirus is controlled with vaccine prophylaxis, norovirus is predicted to become the leading cause of diarrhea in all age groups worldwide.
As the number of reported cases grows, norovirus is increasingly recognized as an important cause of chronic gastroenteritis in immunocompromised individuals. A comparison of the characteristics of norovirus-induced gastroenteritis in immunocompetent and immunocompromised individuals reveals that patients who fail to adequately clear the virus from their bodies may be at risk for serious clinical outcomes.
This review summarizes recent advances in norovirus research aimed at helping to prevent and control norovirus gastroenteritis in immunocompromised patients.
Classification and structure of noroviruses
Noroviruses are a group of tiny single-stranded RNA envelope-free viruses belonging to the family Cupaviridae, with six main genetic classifications, named GI to GVI.
and GII contain the majority of human pathogenic noroviruses and can be further classified into 30 different genotypes. One single genotype, GII.4, has caused most norovirus outbreaks since the mid-1990s and has since introduced effective molecular diagnostic surveillance techniques.
The norovirus genome encodes seven nonstructural genes and two structural proteins (Figure 1). Most RT-PCR molecular diagnostic techniques use the highly conserved RNA polymerase sequences in the genome as amplification targets.
VP1 is the major structural protein that self-assembles into virus-like particles (VLPs) and thus is considered a potential vaccine target; VP2 is the smaller structural protein. Noroviruses can use the prominent P2 structural domain of VP1 to bind to the glycosyl group of human tissue blood group antigens (HBGAs), a mechanism thought to be the pathway for viral entry into the epithelial cells of the gastrointestinal tract (Figure 1).
Mutations in the HBGAs allele may be responsible for human susceptibility to norovirus. Each norovirus strain has the ability to bind to HBGAs, and a specific genetic background determines the resistance of an individual to viral infection. For example, people who do not secrete such glycosyl groups (those who do not express such glycosyl groups on the surface of intestinal epithelial cells) are susceptible to norovirus (a class of
GI.1 strain).
Norovirus in immunocompromised individuals
There are
Reports suggest that disease due to norovirus infection can persist for a long time in immunocompromised patients such as those with congenital immunodeficiency, organ transplant recipients receiving immunosuppressive therapy, cancer chemotherapy patients, and HIV-infected patients.
Immunocompromised individuals are exposed to norovirus in a variety of ways: through contact with family members, health care workers, contaminated water and food, and the environment (including nosocomial infectious agents). The overall incidence of norovirus gastroenteritis in hospital and community settings is unclear.
A growing number of studies have shown that immunosuppressive therapy is a risk factor for norovirus infection. It has been reported that 18% of patients receiving allogeneic hematopoietic stem cell transplantation
(HSCT) patients with norovirus infection lasting more than 1 year and most often occur after intensive immunosuppressive therapy for suspected graft-versus-host disease (GVHD). A 2-year survey of patients who received kidney transplants showed that 17% of patients developed chronic norovirus infection with intermittent diarrhea.
Norovirus is highly tolerant to adverse environmental conditions. In immunocompetent adults, the clinical features of norovirus gastroenteritis are acute (24-48 hours) and self-limiting.
However, in immunocompromised individuals, the disease may become chronic and persist for weeks to years (Table 2). For the general population, norovirus infection has a significant winter epidemic character with common disease names of winter vomiting sickness and stomach flu. As a control, in pediatric patients with cancer and in patients treated with HSCT, the incidence of disease remained constant throughout the year.
It is unclear whether norovirus can be transmitted from chronically infected individuals to immunocompetent individuals, the former being considered a source of transmission of norovirus variants. Surveillance studies suggest that most norovirus nosocomial events are caused by community infection and that norovirus hospital outbreaks triggered by immunocompromised patients are less common.
Patients receiving immunosuppressive therapy with symptoms of vomiting and diarrhea may have high viral loads, whereas asymptomatic patients have small viral loads, suggesting that most cases are transmitted from symptomatic patients and that high levels of virus may remain in the patient’s stool even long after symptoms have disappeared.
Diagnosis of norovirus gastroenteritis
Norovirus gastroenteritis is difficult to diagnose based on clinical features alone. Diarrhea is a common complication in transplant patients: 80% of allogeneic HSCT transplant recipients develop gastroenteritis as a result of conditioned therapy, GVHD, medications, or infectious agents.
Symptoms of acute norovirus disease include diarrhea, fever, and projectile vomiting, features that differ from the common complications of GVHD, such as diarrhea and nausea (without vomiting). Although a provisional diagnosis can be made, a reliable diagnostic protocol is still needed to discern infectious diarrhea from clinical complications such as graft rejection and GVHD.
The former disease requires a direct reverse clinical pathway for control (e.g., less immunosuppressive therapy in infectious diarrhea and more therapy in graft rejection or GVHD). Norovirus is excreted in the feces and norovirus-specific antigen and RNA can be detected in fecal samples.
Real-time fluorescence quantitative RT-PCR is a commonly used laboratory test for norovirus gastroenteritis, but a number of other effective tools also exist. CT techniques have been reported to help identify norovirus infection and GVHD because norovirus infection can cause significant small intestinal wall edema, which is uncommon in patients with enterocytomegalovirus infection or GVHD.
Laboratory tests are important for the timely and accurate diagnosis of norovirus infection in intestinal transplant recipients. This is because the pathological features of norovirus infection are similar to those of graft rejection, such as chronic inflammatory changes, apoptosis, and blunting of the villi.
The diagnosis of gastrointestinal GVHD and common HSCT complications also relies on histopathological findings that can be easily mistaken for norovirus infection, as the latter also presents with many apoptotic vesicles.
NEJM Review: Management of Norovirus Gastroenteritis in Immunocompromised Patients
2015-01-23 10:42 Source：NEJM Author：shumufeng
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Editor’s note: Since the beginning of winter in 2012, norovirus has become an explosive epidemic in Europe, the United States, and Japan, infecting millions of people and causing many deaths. In this regard, the New England Journal of Medicine (NEJM) has reviewed the treatment of norovirus, and the article is compiled below for clinicians’ reference.
Infectious gastroenteritis is a common acute disease, although self-limiting features, but still can make immunocompromised patients more weak, or even life-threatening. Norovirus is the main causative agent of gastroenteritis in immunocompetent or hypocompetent individuals (Table 1).
Table 1 Sources of infection in gastroenteritis
In the United States, norovirus is the most common pathogenic microorganism alone that causes acute gastroenteritis in adults in the emergency setting and the second most common virus (after rotavirus) that causes severe diarrhea in infants and children.
In developing countries, norovirus is assessed to have caused more than 200,000 deaths in children under 5 years of age. It is predicted that when rotavirus is controlled by vaccine prophylaxis, norovirus will become the leading cause of diarrhea in all age groups worldwide.
As the number of reported cases grows, norovirus is increasingly recognized as an important cause of chronic gastroenteritis in immunocompromised individuals. Comparing the characteristics of gastroenteritis caused by norovirus in immunocompetent and immunocompromised individuals reveals that patients who are unable to adequately clear the virus from their bodies may have the potential to develop serious clinical outcomes (Table 2).
Table 2
Characteristics of norovirus gastroenteritis in immunocompetent and immunocompromised hosts
This review summarizes recent advances in norovirus research aimed at helping to prevent and control norovirus gastroenteritis in immunocompromised patients.
Classification and structure of noroviruses
Noroviruses are a group of tiny single-stranded RNA envelope-free viruses belonging to the family Cupaviridae, with six main genetic classifications named GI to GVI.
and GII contain the majority of human pathogenic noroviruses and can be further classified into 30 different genotypes. One single genotype, GII.4, has caused most norovirus outbreaks since the mid-1990s and has since introduced effective molecular diagnostic surveillance techniques.
The norovirus genome encodes seven nonstructural genes and two structural proteins (Figure 1). Most RT-PCR molecular diagnostic techniques use the highly conserved RNA polymerase sequences in the genome as amplification targets.
VP1 is the major structural protein that self-assembles into virus-like particles (VLPs) and thus is considered a potential vaccine target; VP2 is the smaller structural protein. Noroviruses can use the prominent P2 structural domain of VP1 to bind to the glycosyl group of human tissue blood group antigens (HBGAs), a mechanism thought to be the pathway for viral entry into the epithelial cells of the gastrointestinal tract (Figure 1).
Mutations in the HBGAs allele may be responsible for human susceptibility to norovirus. Each norovirus strain has the ability to bind to HBGAs, and a specific genetic background determines the resistance of an individual to viral infection. For example, people who do not secrete such glycosyl groups (those who do not express such glycosyl groups on the surface of intestinal epithelial cells) are susceptible to norovirus (a class of
GI.1 strain) is resistant.
Figure 1 Chromosome composition and atomic structure of the norovirus capsid
Norovirus in immunocompromised individuals
There are
Reports have shown that illness due to norovirus infection can persist for a long time in immunocompromised patients such as those with congenital immunodeficiency, organ transplant recipients receiving immunosuppressive therapy, cancer chemotherapy patients, and HIV-infected patients.
Immunocompromised individuals are exposed to norovirus in a variety of ways: through contact with family members, health care workers, contaminated water and food, and the environment (including nosocomial infectious agents). The overall incidence of norovirus gastroenteritis in hospital and community settings is unclear.
A growing number of studies have shown that immunosuppressive therapy is a risk factor for norovirus infection. It has been reported that 18% of patients receiving allogeneic hematopoietic stem cell transplantation
(HSCT) patients with norovirus infection lasting more than 1 year and most often occur after intensive immunosuppressive therapy for suspected graft-versus-host disease (GVHD). A 2-year survey of patients who received kidney transplants showed that 17% of patients developed chronic norovirus infection with intermittent diarrhea.
Norovirus is highly tolerant to adverse environmental conditions. In immunocompetent adults, the clinical features of norovirus gastroenteritis are acute (24-48 hours) and self-limiting.
However, in immunocompromised individuals, the disease may become chronic and persist for weeks to years (Table 2). For the general population, norovirus infection has a significant winter epidemic character with common disease names of winter vomiting sickness and stomach flu. As a control, in pediatric patients with cancer and in patients treated with HSCT, the incidence of disease remained constant throughout the year.
It is unclear whether norovirus can be transmitted from chronically infected individuals to immunocompetent individuals, the former being considered a source of transmission of norovirus variants. Surveillance studies suggest that most norovirus nosocomial events are caused by community infection and that norovirus hospital outbreaks triggered by immunocompromised patients are less common.
Patients receiving immunosuppressive therapy with symptoms of vomiting and diarrhea may have high viral loads, whereas asymptomatic patients have small viral loads, suggesting that most cases are transmitted from symptomatic patients and that high levels of virus may remain in the patient’s stool even long after symptoms have disappeared.
Diagnosis of norovirus gastroenteritis
Norovirus gastroenteritis is difficult to diagnose based on clinical features alone. Diarrhea is a common complication in transplant patients: 80% of allogeneic HSCT transplant recipients develop gastroenteritis as a result of conditioned therapy, GVHD, medications, or infectious agents.
Symptoms of acute norovirus disease include diarrhea, fever, and projectile vomiting, features that differ from the common complications of GVHD, such as diarrhea and nausea (without vomiting). Although a provisional diagnosis can be made, a reliable diagnostic protocol is still needed to discern infectious diarrhea from clinical complications such as graft rejection and GVHD.
The former disease requires a direct reverse clinical pathway for control (e.g., less immunosuppressive therapy in infectious diarrhea and more therapy in graft rejection or GVHD). Norovirus is excreted in the feces and norovirus-specific antigen and RNA can be detected in fecal samples.
Real-time fluorescence quantitative RT-PCR is a commonly used laboratory test for norovirus gastroenteritis, but a number of other effective tools also exist. CT techniques have been reported to help identify norovirus infection and GVHD because norovirus infection can cause significant small intestinal wall edema, which is uncommon in patients with enterocytomegalovirus infection or GVHD.
Laboratory tests are important for the timely and accurate diagnosis of norovirus infection in intestinal transplant recipients. This is because the pathological features of norovirus infection are similar to those of graft rejection, such as chronic inflammatory changes, apoptosis, and blunting of the villi.
The diagnosis of GVHD and common HSCT complications in the gastrointestinal tract also relies on histopathological findings that are highly susceptible to mistaken for norovirus infection because the latter also presents with many apoptotic vesicles.
Figure 2
Distribution of norovirus variants in immunocompetent and immunocompromised hosts
Diversity and evolution of noroviruses in immunocompromised individuals
Norovirus genotypes commonly found in the community show diversity, but GII.4 is the most prevalent one and is commonly found in immunocompromised patients. No strain differences have been reported to correlate with symptoms, severity, or progression to the chronic stage in immunocompromised patients.
Researchers have conducted detailed studies on the evolution and diversity of viral genomes over time in many chronically norovirus-infected patients. Analysis of viral variants in stool samples from infected patients showed that only a single variant was predominant in immunocompetent individuals who were cured during the acute phase of infection, but multiple viral communities were present in immunocompromised patients in the chronic phase of norovirus infection (Figure 2).
This suggests that immunocompromised chronically infected individuals allow multiple norovirus communities to colonize the host, but there is no epidemiological evidence to date that these variants become community endemic strains.
Although an increasing number of viral variants have emerged during long-term norovirus infections, the amino acid residues interacting with the HBGA ligand remain highly conserved. This finding confirms the importance of viral intercalation with intestinal epithelial cells.
The shedding of norovirus in chronically infected immunocompromised individuals provides a rare opportunity to study the accumulation of viral amino acid alterations caused by genetic alterations. The evolution of norovirus in chronically infected patients is relatively rapid (3.3% of amino acids are replaced each year).
GII.4 Norovirus after 31 years of community
After 31 years of community epidemics, only a cumulative 10% of the amino acids in the protein capsid have been replaced. A precise calculation of the replacement rate is necessary to determine whether chronically infected individuals are consistently infected by the same strain of virus or reinfected by a new strain; it can also be used to trace the route of infection of norovirus in immunocompromised patients in the same setting.
Since the genetic mutation rate (amino acid substitution rate) can be used to determine whether the strain being tested is a known strain or a new strain. This “time-locked” pathway may therefore be useful in determining the role of nosocomial infections in immunocompromised patients and in assessing their therapeutic effects.
Prevention and treatment of norovirus infections in immunocompromised patients
There is no effective vaccine or specific antiviral drug for the prevention and treatment of norovirus infections, but vaccine research has made great strides. Norovirus vaccines are available in humans and orangutans, and the results of the studies have been used to determine the protective and persistent nature of the immune response.
Both T- and B-cell responses have been reported to be required for clearance of norovirus. In mouse models, CD4+
and CD8+ cells are essential for clearance of intestinal norovirus in mice. The clearance of norovirus in chronically infected individuals is related to the number of T cells. One study showed that the number of CD4+ cells increased and patients’ symptoms improved.
Currently, supportive treatment for norovirus gastroenteritis focuses on the prevention and reversal of dehydration. For chronic norovirus infection in transplant recipients, adjustments to immunosuppressive treatment regimens are also needed during the course of long-term infection.
Individual case studies have evaluated the efficacy of passive antibody therapy for norovirus gastroenteritis, but most of the research evidence is not controlled. The results of oral breast milk or immunoglobulin treatment studies are complex and likely reflect qualitative and quantitative differences in treatment with different norovirus-specific antibodies.
Both immunoglobulin and breast milk can be successfully absorbed by the duodenum (unlike the acidic environment of the stomach) and thus treat long-term norovirus infection in transplant patients. However, this clinical route does not eradicate norovirus in globulin-deficient patients.
Some commonly used antiviral drugs, such as ribavirin, can also be used to eradicate norovirus in chronically infected patients. In one case of HSCT, the symptoms of severe norovirus gastroenteritis were significantly relieved after 1 day of treatment, but the exact viral load of the case was not reported, and viral shedding continued for one month after treatment. Therefore, further studies are needed to clarify the effect of this drug in immunocompromised patients.
Finally, differences in the type of immunosuppressive drug may also have an impact on norovirus clearance, as some drugs also have antiviral effects. The incidence of norovirus gastroenteritis in patients treated with different immunosuppressive drugs still needs to be confirmed by further studies.
Conclusion
Considering the substantial impairment of the quality of life and prognosis of immunocompromised patients by norovirus infection, appropriate measures should be taken to reduce the risk of norovirus infection.
First and foremost, it is most important to practice good personal hygiene, and frequent hand washing is the simplest and most effective means to combat norovirus transmission. An environmental surveillance of immunodeficient pediatric patients found that 80% of hospital environmental surfaces were contaminated with as many as 21 different noroviruses. Therefore, improvement measures in hygiene practices are decisive.
Secondly, immunocompromised individuals should avoid contact with patients with acute gastroenteritis and should follow guidelines for the prevention of infections with enteric pathogens.
Third, patients should consume only safe foods to avoid the risk of foodborne disease transmission. Although we have reservations about isolating patients with chronic norovirus infection, norovirus in the feces of these patients is still a source of infection that cannot be ignored.
Finally, norovirus screening should be included in the management of immunocompromised individuals presenting with unexplained acute and chronic gastroenteritis. Expanded use of diagnostic techniques and further ongoing studies will help to clarify the precise epidemiological profile of norovirus load and infection in this population and help to improve their clinical treatment options.