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This time in the extended series on gut infections, I will cover a virus. Up until this point all of the infectious organisms covered have been bacteria. Interestingly, while the content of our natural gut microbiome comprises a vast number of bacterial species, it is very likely that this number is miniscule compared to the number of viruses that contribute to this microbiome. Most of the virome, as it is with the bacteriome, is commensal or symbiotic with the host. Nevertheless, some gut viruses are pathogenic to the host. On a global scale, the most important of these is, by far, rotavirus.
The Pathogen. Rotavrius is a double-stranded RNA virus in the Reoviridae family. The genome is comprised of 11 segmented helices of RNA, which correspond to the genes of this virus. In total there are five species of rotavirus, designated rotavirus A though E, with A, B, and C being most important for human infections. Approximately 90% of these infections are due to rotavirus A alone. Thus, this discussion will focus primarily on rotavirus A, although rotavirus B has caused significant outbreaks in China.
There are 3 structural viral proteins and 1 non-structural viral protein that are important factors in the infectivity, pathogenicity, and immunogenicity of this virus. Viral proteins (VP) 4, 6 and 7 are the structural proteins relevant to the above. VP4 is a protein that projects from the capsid and binds to enterocyte receptors, which induces infection of the host cell. Rotavirus infection requires the activity of a protease native to the host gut. This protease alters the structure of VP4 resulting in the newly modified VP5 and VP8 surface proteins, which then initiate infection. VP6 constitutes the primary capsid protein and is a potent antigen, which is important as a diagnostic marker and for identifying rotavirus species. VP7 is a glycoprotein found on the outer surface of the virus that constitutes another important antigen, which is highly immunogenic and responsible for long-term immune memory. Non-structural protein (NSP) 4 is an enterotoxin and is largely responsible for the pathogenicity of the infection because it is an important stimulator of diarrhea.
The virus targets the villi of the epithelium of the small intestine causing a lytic infection. Following infection, the enterotoxin, NSP4, stimulates chloride secretion from the enterocyte followed by increased water secretion into the gut, which follows the gradient. In addition, water reabsorption is inhibited and the net result is watery diarrhea. Because this is a lytic infection, some enterocyte are destroyed, which can lead to temporary nutrient deficiencies due to malabsorption.
The Disease. Simply put, it is watery diarrhea, much like we saw for cholera. However, rotavirus is quite different in terms of its disease ecology and, while potentially quite virulent in children, it is typically not as severe as outbreaks of cholera and does not typically affect adults. Nevertheless, rotavirus is the most important cause of severe diarrhea episodes in children in the world. Nausea and vomiting are also common in clinically apparent disease. Moderate fever can present in many infections, but is not always a clinical feature even in the presence of diarrhea and vomiting. The greatest threat to vulnerable children is dehydration following the large volume fluid loss. Rehydration therapy with a focus on re-establishing the electrolyte balance is imperative. The characteristic signs of the dehydration that attend the severe diarrhea are sunken eyes and cheeks and poor skin turgor. Usually 2% body fluid loss is required before dehydration is clinically recognizable. In addition to the sunken eyes and poor skin turgor mentioned above, irritability, thirst, increased heart rate and respiration, and no urine volume are also characteristic of this stage. In children, less than 10% loss of body fluid marks severe dehydration and is characterized by low blood pressure, diminished pulse, increasingly poor skin turgor, delirium, and frequent loss of consciousness. At this stage the individual is no longer eager to drink and may not even be able to do so. This constitutes a medical emergency and requires immediate oral or intravenous (usually the latter) rehydration therapy. In addition to the dehydration, malabsorption is also a common feature of rotavirus infection due to the death of intestinal epithelial cells.
The Epidemiology and the Landscape. Rotavirus A infections are the second largest single pathogen cause of diarrhea in the world. As with all diarrhea disease, most of these clinically apparent episodes occur in children under 5 years of age, and most severe disease occurs between the ages of 6 months and 2 years. In addition to being a major contributor to overall diarrhea episodes across the world, rotavirus A infections are responsible for the most severe diarrhea episodes in the world. In communities with access to advanced hospital care, rotavirus is responsible for at least 2 million severe cases requiring hospital admission and advanced therapy and management of dehydration. Rotavirus A causes approximately 500,000 deaths per year. Most of these deaths are concentrated in resource poor geographic regions as depicted in this map by the World Health Organization:
While the mortality attributable to rotavirus follows the same lines of geography as that attributable to all other causes of diarrhea, the landscape epidemiology of rotavirus is distinctly different from the other gut pathogens we have covered at Infection Landscapes.
Rotavirus infection follows fecal-oral transmission, as have most of the pathogens covered so far in this extended series on gut infections. Rotavirus, however, is highly infectious. The infectious dose is 10 to 100 virions. Moreover, there are tens of trillions of virions shed per diarrhea episode in infected individuals. In addition, rotavirus is quite stable outside the human gut in aquatic environments. This combination of properties contributes to one of the most important features of the epidemiology of this virus: it is ubiquitous in all geographic locations where it is consistently maintained in environmental reservoirs. Furthermore, good sanitation and water infrastructure, which are usually sufficient to prevent the bacterial and parasitic gut infections of significance and thus reduce the burden of disease in all settings, are not sufficient to eliminate the burden of disease due to rotavirus in any setting. The simplicity of this epidemiology ensures ongoing infection in populations, which is, contrary to the defining paradigm of this website, irrespective of the landscape. In the absence of vaccination programs, there is little difference in the incidence of rotavirus infections by geography. There is, of course, a difference in mortality attributable to rotavirus by geography, but this is more a function of the presence of resources to treat and manage the severe dehydration that can attend the diarrhea.
Treatment. Oral rehydration salts mixed with water provide an important treatment, but are not always as effective as they are against other diarrhea, thus the particularly high rates of hospitalizations associated with rotavirus infections. The goal is to reestablish the electrolyte balance in the person suffering the diarrhea episode. In order to stave off what can develop into deadly dehydration, the individual must replace the fluid lost, AND the salts lost. This is precisely the goal of oral rehydration therapy. Packets of oral rehydration salts containing sodium chloride, potassium chloride, citrate and glucose can be obtained from almost any pharmacist or chemist in most areas of the world. These are simply mixed with water and consumed by the diarrhea-afflicted person. In addition, as much as can be tolerated by the ill person, normal nutrition intake should be maintained throughout the diarrhea episode. It may seem as though the food will go right through you, but the body does obtain some nutrients and this helps the immune system fight the infection. If dehydration is advanced, and/or if the individual is unable to keep fluids down due to vomiting, then intravenous administration of fluids will likely be necessary.
Control and Prevention. Because sanitation and water infrastructure are not significant in defining the burden of disease attributable to rotavirus, and because the virus' high infectivity and high environmental abundance are significant in defining its epidemiology, prevention of infection is largely determined by a single, highly-effective strategy: vaccination. There are 2 vaccines in use (Rotarix and RotaTeq) and both are shown to be highly effective. They are both live attenuated vaccines and administered orally. It is estimated that a little less than half the annual deaths reported each year (~ 250,000) could be prevented with the universal implementation of vaccination against rotavirus.
Here is a nice summary video by Dr. Manish Patel, a medical epidemiologist at the Centers for Disease Control and Prevention:
Interview with rotavirus expert Dr Manish Patel from GAVI Alliance on Vimeo.
This time in the extended series on gut infections, I will cover a virus. Up until this point all of the infectious organisms covered have been bacteria. Interestingly, while the content of our natural gut microbiome comprises a vast number of bacterial species, it is very likely that this number is miniscule compared to the number of viruses that contribute to this microbiome. Most of the virome, as it is with the bacteriome, is commensal or symbiotic with the host. Nevertheless, some gut viruses are pathogenic to the host. On a global scale, the most important of these is, by far, rotavirus.
The Pathogen. Rotavrius is a double-stranded RNA virus in the Reoviridae family. The genome is comprised of 11 segmented helices of RNA, which correspond to the genes of this virus. In total there are five species of rotavirus, designated rotavirus A though E, with A, B, and C being most important for human infections. Approximately 90% of these infections are due to rotavirus A alone. Thus, this discussion will focus primarily on rotavirus A, although rotavirus B has caused significant outbreaks in China.
There are 3 structural viral proteins and 1 non-structural viral protein that are important factors in the infectivity, pathogenicity, and immunogenicity of this virus. Viral proteins (VP) 4, 6 and 7 are the structural proteins relevant to the above. VP4 is a protein that projects from the capsid and binds to enterocyte receptors, which induces infection of the host cell. Rotavirus infection requires the activity of a protease native to the host gut. This protease alters the structure of VP4 resulting in the newly modified VP5 and VP8 surface proteins, which then initiate infection. VP6 constitutes the primary capsid protein and is a potent antigen, which is important as a diagnostic marker and for identifying rotavirus species. VP7 is a glycoprotein found on the outer surface of the virus that constitutes another important antigen, which is highly immunogenic and responsible for long-term immune memory. Non-structural protein (NSP) 4 is an enterotoxin and is largely responsible for the pathogenicity of the infection because it is an important stimulator of diarrhea.
The virus targets the villi of the epithelium of the small intestine causing a lytic infection. Following infection, the enterotoxin, NSP4, stimulates chloride secretion from the enterocyte followed by increased water secretion into the gut, which follows the gradient. In addition, water reabsorption is inhibited and the net result is watery diarrhea. Because this is a lytic infection, some enterocyte are destroyed, which can lead to temporary nutrient deficiencies due to malabsorption.
The Disease. Simply put, it is watery diarrhea, much like we saw for cholera. However, rotavirus is quite different in terms of its disease ecology and, while potentially quite virulent in children, it is typically not as severe as outbreaks of cholera and does not typically affect adults. Nevertheless, rotavirus is the most important cause of severe diarrhea episodes in children in the world. Nausea and vomiting are also common in clinically apparent disease. Moderate fever can present in many infections, but is not always a clinical feature even in the presence of diarrhea and vomiting. The greatest threat to vulnerable children is dehydration following the large volume fluid loss. Rehydration therapy with a focus on re-establishing the electrolyte balance is imperative. The characteristic signs of the dehydration that attend the severe diarrhea are sunken eyes and cheeks and poor skin turgor. Usually 2% body fluid loss is required before dehydration is clinically recognizable. In addition to the sunken eyes and poor skin turgor mentioned above, irritability, thirst, increased heart rate and respiration, and no urine volume are also characteristic of this stage. In children, less than 10% loss of body fluid marks severe dehydration and is characterized by low blood pressure, diminished pulse, increasingly poor skin turgor, delirium, and frequent loss of consciousness. At this stage the individual is no longer eager to drink and may not even be able to do so. This constitutes a medical emergency and requires immediate oral or intravenous (usually the latter) rehydration therapy. In addition to the dehydration, malabsorption is also a common feature of rotavirus infection due to the death of intestinal epithelial cells.
The Epidemiology and the Landscape. Rotavirus A infections are the second largest single pathogen cause of diarrhea in the world. As with all diarrhea disease, most of these clinically apparent episodes occur in children under 5 years of age, and most severe disease occurs between the ages of 6 months and 2 years. In addition to being a major contributor to overall diarrhea episodes across the world, rotavirus A infections are responsible for the most severe diarrhea episodes in the world. In communities with access to advanced hospital care, rotavirus is responsible for at least 2 million severe cases requiring hospital admission and advanced therapy and management of dehydration. Rotavirus A causes approximately 500,000 deaths per year. Most of these deaths are concentrated in resource poor geographic regions as depicted in this map by the World Health Organization:
While the mortality attributable to rotavirus follows the same lines of geography as that attributable to all other causes of diarrhea, the landscape epidemiology of rotavirus is distinctly different from the other gut pathogens we have covered at Infection Landscapes.
Rotavirus infection follows fecal-oral transmission, as have most of the pathogens covered so far in this extended series on gut infections. Rotavirus, however, is highly infectious. The infectious dose is 10 to 100 virions. Moreover, there are tens of trillions of virions shed per diarrhea episode in infected individuals. In addition, rotavirus is quite stable outside the human gut in aquatic environments. This combination of properties contributes to one of the most important features of the epidemiology of this virus: it is ubiquitous in all geographic locations where it is consistently maintained in environmental reservoirs. Furthermore, good sanitation and water infrastructure, which are usually sufficient to prevent the bacterial and parasitic gut infections of significance and thus reduce the burden of disease in all settings, are not sufficient to eliminate the burden of disease due to rotavirus in any setting. The simplicity of this epidemiology ensures ongoing infection in populations, which is, contrary to the defining paradigm of this website, irrespective of the landscape. In the absence of vaccination programs, there is little difference in the incidence of rotavirus infections by geography. There is, of course, a difference in mortality attributable to rotavirus by geography, but this is more a function of the presence of resources to treat and manage the severe dehydration that can attend the diarrhea.
Treatment. Oral rehydration salts mixed with water provide an important treatment, but are not always as effective as they are against other diarrhea, thus the particularly high rates of hospitalizations associated with rotavirus infections. The goal is to reestablish the electrolyte balance in the person suffering the diarrhea episode. In order to stave off what can develop into deadly dehydration, the individual must replace the fluid lost, AND the salts lost. This is precisely the goal of oral rehydration therapy. Packets of oral rehydration salts containing sodium chloride, potassium chloride, citrate and glucose can be obtained from almost any pharmacist or chemist in most areas of the world. These are simply mixed with water and consumed by the diarrhea-afflicted person. In addition, as much as can be tolerated by the ill person, normal nutrition intake should be maintained throughout the diarrhea episode. It may seem as though the food will go right through you, but the body does obtain some nutrients and this helps the immune system fight the infection. If dehydration is advanced, and/or if the individual is unable to keep fluids down due to vomiting, then intravenous administration of fluids will likely be necessary.
Control and Prevention. Because sanitation and water infrastructure are not significant in defining the burden of disease attributable to rotavirus, and because the virus' high infectivity and high environmental abundance are significant in defining its epidemiology, prevention of infection is largely determined by a single, highly-effective strategy: vaccination. There are 2 vaccines in use (Rotarix and RotaTeq) and both are shown to be highly effective. They are both live attenuated vaccines and administered orally. It is estimated that a little less than half the annual deaths reported each year (~ 250,000) could be prevented with the universal implementation of vaccination against rotavirus.
Here is a nice summary video by Dr. Manish Patel, a medical epidemiologist at the Centers for Disease Control and Prevention:
Interview with rotavirus expert Dr Manish Patel from GAVI Alliance on Vimeo.