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''Rotavirus'' is a genus of double-stranded RNA viruses in the family ''Reoviridae''. Rotaviruses are the most common cause of
diarrhoeal disease Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery defecation, bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration of ...
among infants and young children. Nearly every child in the world is infected with a rotavirus at least once by the age of five.
Immunity Immunity may refer to: Medicine * Immunity (medical), resistance of an organism to infection or disease * ''Immunity'' (journal), a scientific journal published by Cell Press Biology * Immune system Engineering * Radiofrequence immunity desc ...
develops with each infection, so subsequent infections are less severe. Adults are rarely affected. There are nine species of the genus, referred to as A, B, C, D, F, G, H, I and J. ''Rotavirus A'', the most common species, causes more than 90% of rotavirus infections in humans. The virus is transmitted by the faecal-oral route. It infects and damages the
cells Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Locations * Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery w ...
that line the
small intestine The small intestine or small bowel is an organ in the gastrointestinal tract where most of the absorption of nutrients from food takes place. It lies between the stomach and large intestine, and receives bile and pancreatic juice through the p ...
and causes
gastroenteritis Gastroenteritis, also known as infectious diarrhea and gastro, is an inflammation of the gastrointestinal tract including the stomach and intestine. Symptoms may include diarrhea, vomiting, and abdominal pain. Fever, lack of energy, and dehydra ...
(which is often called "stomach flu" despite having no relation to
influenza Influenza, commonly known as "the flu", is an infectious disease caused by influenza viruses. Symptoms range from mild to severe and often include fever, runny nose, sore throat, muscle pain, headache, coughing, and fatigue. These symptoms ...
). Although rotavirus was discovered in 1973 by Ruth Bishop and her colleagues by electron micrograph images and accounts for approximately one third of hospitalisations for severe diarrhoea in infants and children, its importance has historically been underestimated within the public health community, particularly in developing countries. In addition to its impact on human health, rotavirus also infects other animals, and is a pathogen of livestock. Rotaviral enteritis is usually an easily managed disease of childhood, but among children under 5 years of age rotavirus caused an estimated 151,714 deaths from diarrhoea in 2019. In the United States, before initiation of the rotavirus vaccination programme in the 2000s, rotavirus caused about 2.7million cases of severe gastroenteritis in children, almost 60,000 hospitalisations, and around 37 deaths each year. Following rotavirus vaccine introduction in the United States, hospitalisation rates have fallen significantly. Public health campaigns to combat rotavirus focus on providing oral rehydration therapy for infected children and vaccination to prevent the disease. The incidence and severity of rotavirus infections has declined significantly in countries that have added rotavirus vaccine to their routine childhood immunisation policies.


Virology


Types of rotavirus

There are nine species of rotavirus, referred to as A, B, C, D, F, G, H, I and J. Humans are primarily infected by the species ''rotavirus A''. A–I species cause disease in other animals, species H in pigs, D, F and G in birds, I in cats and J in bats. Within ''rotavirus A'' there are different strains, called serotypes. As with
influenza Influenza, commonly known as "the flu", is an infectious disease caused by influenza viruses. Symptoms range from mild to severe and often include fever, runny nose, sore throat, muscle pain, headache, coughing, and fatigue. These symptoms ...
virus, a dual classification system is used based on two proteins on the surface of the virus. The
glycoprotein Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycos ...
VP7 defines the G serotypes and the protease-sensitive protein VP4 defines P serotypes. Because the two genes that determine G-types and P-types can be passed on separately to progeny viruses, different combinations are found. A whole genome genotyping system has been established for ''rotavirus A'', which has been used to determine the origin of atypical strains. The prevalence of the individual G-types and P-types varies between, and within, countries and years. There are at least 36 G types and 51 P types but in infections of humans only a few combinations of G and P types predominate. They are G1P G2P G3P G4P G9P and G12P


Structure

The genome of rotaviruses consists of 11 unique double helix molecules of
RNA Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
(dsRNA) which are 18,555 nucleotides in total. Each helix, or segment, is a gene, numbered 1 to 11 by decreasing size. Each gene codes for one protein, except genes 9, which codes for two. The RNA is surrounded by a three-layered icosahedral protein capsid. Viral particles are up to 76.5nm in diameter and are not enveloped.


Proteins

There are six viral proteins (VPs) that form the virus particle ( virion). These ''structural'' proteins are called VP1, VP2, VP3, VP4, VP6 and VP7. In addition to the VPs, there are six ''nonstructural'' proteins (NSPs), that are only produced in cells infected by rotavirus. These are called NSP1, NSP2, NSP3, NSP4, NSP5 and NSP6. At least six of the twelve proteins encoded by the rotavirus genome bind
RNA Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
. The role of these proteins in rotavirus replication is not entirely understood; their functions are thought to be related to RNA synthesis and packaging in the virion, mRNA transport to the site of genome replication, and mRNA translation and regulation of gene expression.


Structural proteins

VP1 is located in the core of the virus particle and is an
RNA-dependent RNA polymerase RNA-dependent RNA polymerase (RdRp) or RNA replicase is an enzyme that catalyzes the replication of RNA from an RNA template. Specifically, it catalyzes synthesis of the RNA strand complementary to a given RNA template. This is in contrast to t ...
enzyme. In an infected cell this enzyme produces mRNA transcripts for the synthesis of viral proteins and produces copies of the rotavirus genome RNA segments for newly produced virus particles. VP2 forms the core layer of the virion and binds the RNA genome. VP3 is part of the inner core of the virion and is an enzyme called
guanylyl transferase Guanylyl transferases are enzymes that transfer a guanosine mono phosphate group, usually from GTP to another molecule, releasing pyrophosphate. Many eukaryotic guanylyl transferases are capping enzymes that catalyze the formation of the 5' cap in ...
. This is a
capping enzyme A capping enzyme (CE) is an enzyme that catalyzes the attachment of the 5' cap to messenger RNA molecules that are in the process of being synthesized in the cell nucleus during the first stages of gene expression. The addition of the cap occurs ...
that catalyses the formation of the
5' cap In molecular biology, the five-prime cap (5′ cap) is a specially altered nucleotide on the 5′ end of some primary transcripts such as precursor messenger RNA. This process, known as mRNA capping, is highly regulated and vital in the creation o ...
in the post-transcriptional modification of mRNA. The cap stabilises viral mRNA by protecting it from
nucleic acid Nucleic acids are biopolymers, macromolecules, essential to all known forms of life. They are composed of nucleotides, which are the monomers made of three components: a 5-carbon sugar, a phosphate group and a nitrogenous base. The two main cl ...
degrading enzymes called nucleases. VP4 is on the surface of the virion that protrudes as a spike. It binds to molecules on the surface of cells called receptors and drives the entry of the virus into the cell. VP4 has to be modified by the protease enzyme trypsin, which is found in the gut, into VP5* and VP8* before the virus is infectious. VP4 determines how virulent the virus is and it determines the P-type of the virus. In humans there is an association between the blood group ( Lewis antigen system, ABO blood group system and
secretor status Secretor status refers to the presence or absence of water-soluble ABO blood group antigens in a person's bodily fluids, such as saliva, tears, breast milk, urine, and semen. People who secrete these antigens in their bodily fluids are referred ...
) and susceptibility to infection. Non-secretors seem resistant to infection by types P and P indicating that blood group antigens are the receptors for these genotypes. This resistance is dependent on the rotavirus genotype. VP6 forms the bulk of the capsid. It is highly antigenic and can be used to identify rotavirus species. This protein is used in laboratory tests for rotavirus A infections. VP7 is a
glycoprotein Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycos ...
that forms the outer surface of the virion. Apart from its structural functions, it determines the G-type of the strain and, along with VP4, is involved in
immunity Immunity may refer to: Medicine * Immunity (medical), resistance of an organism to infection or disease * ''Immunity'' (journal), a scientific journal published by Cell Press Biology * Immune system Engineering * Radiofrequence immunity desc ...
to infection.


Nonstructural viral proteins

NSP1, the product of gene 5, is a nonstructural RNA-binding protein. NSP1 also blocks the
interferon Interferons (IFNs, ) are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten the ...
response, the part of the
innate immune system The innate, or nonspecific, immune system is one of the two main immunity strategies (the other being the adaptive immune system) in vertebrates. The innate immune system is an older evolutionary defense strategy, relatively speaking, and is the ...
that protects cells from viral infection. NSP1 causes the proteosome to degrade key signaling components required to stimulate production of interferon in an infected cell and to respond to interferon secreted by adjacent cells. Targets for degradation include several IRF transcription factors required for interferon gene transcription. NSP2 is an RNA-binding protein that accumulates in cytoplasmic inclusions ( viroplasms) and is required for genome replication. NSP3 is bound to viral mRNAs in infected cells and it is responsible for the shutdown of cellular protein synthesis. NSP3 inactivates two translation initiation factors essential for synthesis of proteins from host mRNA. First, NSP3 ejects poly(A)-binding protein (PABP) from the translation initiation factor eIF4F. PABP is required for efficient translation of transcripts with a 3' poly(A) tail, which is found on most host cell transcripts. Second, NSP3 inactivates eIF2 by stimulating its phosphorylation. Efficient translation of rotavirus mRNA, which lacks the 3' poly(A) tail, does not require either of these factors. NSP4 is a viral
enterotoxin An enterotoxin is a protein exotoxin released by a microorganism that targets the intestines. Enterotoxins are chromosomally encoded or plasmid encoded exotoxins that are produced and secreted from several bacterial organisms. They are heat labi ...
that induces diarrhoea and was the first viral enterotoxin discovered. It is a
viroporin Viroporins are small and usually hydrophobic multifunctional viral proteins that modify cellular membranes, thereby facilitating virus release from infected cells. Viroporins are capable of assembling into oligomeric ion channels or pores in the h ...
that elevates cytosolic Ca2+ in mammalian cells. NSP5 is encoded by genome segment 11 of rotavirus A. In virus-infected cells NSP5 accumulates in the viroplasm. NSP6 is a nucleic acid binding protein and is encoded by gene 11 from an out-of-phase open reading frame. This table is based on the
simian The simians, anthropoids, or higher primates are an infraorder (Simiiformes ) of primates containing all animals traditionally called monkeys and apes. More precisely, they consist of the parvorders New World monkeys (Platyrrhini) and Catarrhi ...
rotavirus strain SA11. RNA-protein coding assignments differ in some strains.


Replication

The attachment of the virus to the host cell is initiated by VP4, which attaches to molecules, called glycans, on the surface of the cell. The virus enters cells by
receptor mediated endocytosis Receptor may refer to: * Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...
and form a
vesicle Vesicle may refer to: ; In cellular biology or chemistry * Vesicle (biology and chemistry), a supramolecular assembly of lipid molecules, like a cell membrane * Synaptic vesicle ; In human embryology * Vesicle (embryology), bulge-like features o ...
known as an endosome. Proteins in the third layer (VP7 and the VP4 spike) disrupt the membrane of the endosome, creating a difference in the calcium concentration. This causes the breakdown of VP7 trimers into single protein subunits, leaving the VP2 and VP6 protein coats around the viral dsRNA, forming a double-layered particle (DLP). The eleven dsRNA strands remain within the protection of the two protein shells and the viral
RNA-dependent RNA polymerase RNA-dependent RNA polymerase (RdRp) or RNA replicase is an enzyme that catalyzes the replication of RNA from an RNA template. Specifically, it catalyzes synthesis of the RNA strand complementary to a given RNA template. This is in contrast to t ...
creates mRNA transcripts of the double-stranded viral genome. By remaining in the core, the viral RNA evades innate host immune responses including RNA interference that are triggered by the presence of double-stranded RNA. During the infection, rotaviruses produce mRNA for both
protein biosynthesis Protein biosynthesis (or protein synthesis) is a core biological process, occurring inside cells, balancing the loss of cellular proteins (via degradation or export) through the production of new proteins. Proteins perform a number of critical ...
and gene replication. Most of the rotavirus proteins accumulate in viroplasm, where the RNA is replicated and the DLPs are assembled. In the viroplasm the positive sense viral RNAs that are used as templates for the synthesis of viral genomic dsRNA are protected from siRNA-induced RNase degradation. Viroplasm is formed around the cell nucleus as early as two hours after virus infection, and consists of viral factories thought to be made by two viral nonstructural proteins: NSP5 and NSP2. Inhibition of NSP5 by RNA interference ''in vitro'' results in a sharp decrease in rotavirus replication. The DLPs migrate to the
endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ( ...
where they obtain their third, outer layer (formed by VP7 and VP4). The progeny viruses are released from the cell by
lysis Lysis ( ) is the breaking down of the membrane of a cell, often by viral, enzymic, or osmotic (that is, "lytic" ) mechanisms that compromise its integrity. A fluid containing the contents of lysed cells is called a ''lysate''. In molecular bio ...
.


Transmission

Rotaviruses are transmitted by the faecal-oral route, via contact with contaminated hands, surfaces and objects, and possibly by the respiratory route. Viral diarrhoea is highly contagious. The faeces of an infected person can contain more than 10 trillion infectious particles per gram; fewer than 100 of these are required to transmit infection to another person. Rotaviruses are stable in the environment and have been found in estuary samples at levels up to 1–5 infectious particles per USgallon. The viruses survive between 9 and 19 days. Sanitary measures adequate for eliminating bacteria and parasites seem to be ineffective in control of rotavirus, as the incidence of rotavirus infection in countries with high and low health standards is similar.


Signs and symptoms

Rotaviral enteritis is a mild to severe disease characterised by nausea, vomiting, watery diarrhoea and low-grade fever. Once a child is infected by the virus, there is an incubation period of about two days before symptoms appear. The period of illness is acute. Symptoms often start with vomiting followed by four to eight days of profuse diarrhoea. Dehydration is more common in rotavirus infection than in most of those caused by bacterial pathogens, and is the most common cause of death related to rotavirus infection. ''Rotavirus A'' infections can occur throughout life: the first usually produces symptoms, but subsequent infections are typically mild or
asymptomatic In medicine, any disease is classified asymptomatic if a patient tests as carrier for a disease or infection but experiences no symptoms. Whenever a medical condition fails to show noticeable symptoms after a diagnosis it might be considered asy ...
, as the immune system provides some protection. Consequently, symptomatic infection rates are highest in children under two years of age and decrease progressively towards 45 years of age. The most severe symptoms tend to occur in children six months to two years of age, the elderly, and those with
immunodeficiency Immunodeficiency, also known as immunocompromisation, is a state in which the immune system's ability to fight infectious diseases and cancer is compromised or entirely absent. Most cases are acquired ("secondary") due to extrinsic factors that a ...
. Due to immunity acquired in childhood, most adults are not susceptible to rotavirus; gastroenteritis in adults usually has a cause other than rotavirus, but asymptomatic infections in adults may maintain the transmission of infection in the community. There is some evidence to suggest blood group can impact on the susceptibility to infection by rotaviruses.


Disease mechanisms

Rotaviruses replicate mainly in the gut, and infect enterocytes of the villi of the
small intestine The small intestine or small bowel is an organ in the gastrointestinal tract where most of the absorption of nutrients from food takes place. It lies between the stomach and large intestine, and receives bile and pancreatic juice through the p ...
, leading to structural and functional changes of the
epithelium Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellul ...
. There is evidence in humans, and particularly in animal models of extraintestinal dissemination of infectious virus to other organs and macrophages. The diarrhoea is caused by multiple activities of the virus. Malabsorption occurs because of the destruction of gut cells called
enterocyte Enterocytes, or intestinal absorptive cells, are simple columnar epithelial cells which line the inner surface of the small and large intestines. A glycocalyx surface coat contains digestive enzymes. Microvilli on the apical surface increase its ...
s. The toxic rotavirus protein NSP4 induces age- and calcium ion-dependent chloride secretion, disrupts SGLT1 (sodium/glucose cotransporter 2)
transporter Transporter may refer to: * Transporter (vehicles), types of vehicles designed to transport items * Transporter wagon, a railway car designed to carry another railway car * Volkswagen Transporter, a model of van * Transporter bridge, a bridge wh ...
-mediated reabsorption of water, apparently reduces activity of brush-border membrane
disaccharidase Disaccharidases are glycoside hydrolases, enzymes that break down certain types of sugars called disaccharides into simpler sugars called monosaccharides. In the human body, disaccharidases are made mostly in an area of the small intestine's wall ca ...
s, and activates the calcium ion-dependent
secretory 440px Secretion is the movement of material from one point to another, such as a secreted chemical substance from a cell or gland. In contrast, excretion is the removal of certain substances or waste products from a cell or organism. The classica ...
reflex In biology, a reflex, or reflex action, is an involuntary, unplanned sequence or action and nearly instantaneous response to a stimulus. Reflexes are found with varying levels of complexity in organisms with a nervous system. A reflex occurs ...
es of the enteric nervous system. The elevated concentrations of calcium ions in the cytosol (which are required for the assembly of the progeny viruses) is achieved by NSP4 acting as a
viroporin Viroporins are small and usually hydrophobic multifunctional viral proteins that modify cellular membranes, thereby facilitating virus release from infected cells. Viroporins are capable of assembling into oligomeric ion channels or pores in the h ...
. This increase in calcium ions leads to autophagy (self destruction) of the infected enterocytes. NSP4 is also secreted. This extracellular form, which is modified by protease enzymes in the gut, is an enterotoxin which acts on uninfected cells via integrin receptors, which in turn cause and increase in intracellular calcium ion concentrations, secretory diarrhoea and autophagy. The vomiting, which is a characteristic of rotaviral enteritis, is caused by the virus infecting the enterochromaffin cells on the lining of the digestive tract. The infection stimulates the production of 5' hydroxytryptamine (
serotonin Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vas ...
). This activates vagal afferent nerves, which in turn activates the cells of the brain stem that control the vomiting reflex. Healthy enterocytes secrete lactase into the small intestine; milk intolerance due to lactase deficiency is a symptom of rotavirus infection, which can persist for weeks. A recurrence of mild diarrhoea often follows the reintroduction of milk into the child's diet, due to bacterial fermentation of the disaccharide
lactose Lactose is a disaccharide sugar synthesized by galactose and glucose subunits and has the molecular formula C12H22O11. Lactose makes up around 2–8% of milk (by mass). The name comes from ' (gen. '), the Latin word for milk, plus the suffix '' - ...
in the gut.


Immune responses


Specific responses

Rotaviruses elicit both B and T cell immune responses. Antibodies to the rotavirus VP4 and VP7 proteins neutralise viral infectivity ''in vitro'' and ''in vivo''. Specific antibodies of the classes IgM, IgA and IgG are produced, which have been shown to protect against rotavirus infection by the passive transfer of the antibodies in other animals. Maternal trans-placental IgG might play a role in the protection neonates from rotavirus infections, but on the other hand might reduce vaccine efficacy.


Innate responses

Following infection by rotaviruses there is a rapid innate immune response involving types I and III
interferon Interferons (IFNs, ) are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten the ...
s and other cytokines (particularly Th1 and Th2) which inhibit the replication of the virus and recruit
macrophage Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...
s and
natural killer cell Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system that belong to the rapidly expanding family of known innate lymphoid cells (ILC) and repres ...
s to the rotavirus infected cells. The rotavirus dsRNA activates pattern recognition receptors such toll-like receptors that stimulate the production of interferons. The rotavirus protein NSP1 counteracts the effects of type 1 interferons by suppressing the activity of the interferon regulatory proteins IRF3, IRF5 and IRF7.


Markers of protection

The levels of IgG and IgA in the blood and IgA in the gut correlate with protection from infection. Rotavirus specific serum IgG and IgA at high titres (e.g. >1:200) have been claimed to be protective and there is a significant correlation between IgA titres and rotavirus vaccine efficacy.


Diagnosis and detection

Diagnosis of infection with a rotavirus normally follows diagnosis of
gastroenteritis Gastroenteritis, also known as infectious diarrhea and gastro, is an inflammation of the gastrointestinal tract including the stomach and intestine. Symptoms may include diarrhea, vomiting, and abdominal pain. Fever, lack of energy, and dehydra ...
as the cause of severe diarrhoea. Most children admitted to hospital with gastroenteritis are tested for '. Specific diagnosis of infection with ' is made by finding the virus in the child's stool by enzyme immunoassay. There are several licensed test kits on the market which are sensitive, specific and detect all serotypes of '. Other methods, such as
electron microscopy An electron microscope is a microscope that uses a beam of accelerated electrons as a source of illumination. As the wavelength of an electron can be up to 100,000 times shorter than that of visible light photons, electron microscopes have a hi ...
and
PCR PCR or pcr may refer to: Science * Phosphocreatine, a phosphorylated creatine molecule * Principal component regression, a statistical technique Medicine * Polymerase chain reaction ** COVID-19 testing, often performed using the polymerase chain r ...
(polymerase chain reaction), are used in research laboratories. Reverse transcription-polymerase chain reaction ( RT-PCR) can detect and identify all species and serotypes of human rotaviruses.


Treatment and prognosis

Treatment of acute rotavirus infection is nonspecific and involves management of symptoms and, most importantly, management of dehydration. If untreated, children can die from the resulting severe dehydration. Depending on the severity of diarrhoea, treatment consists of oral rehydration therapy, during which the child is given extra water to drink that contains specific amounts of salt and sugar. In 2004, the World Health Organisation (WHO) and UNICEF recommended the use of low-osmolarity oral rehydration solution and zinc supplementation as a two-pronged treatment of acute diarrhoea. Some infections are serious enough to warrant hospitalisation where fluids are given by
intravenous therapy Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutri ...
or nasogastric intubation, and the child's
electrolyte An electrolyte is a medium containing ions that is electrically conducting through the movement of those ions, but not conducting electrons. This includes most soluble salts, acids, and bases dissolved in a polar solvent, such as water. Upon dis ...
s and blood sugar are monitored. Rotavirus infections rarely cause other complications and for a well managed child the prognosis is excellent. Probiotics have been shown to reduce the duration of rotavirus diarrhoea, and according to the European Society for Pediatric Gastroenterology "effective interventions include administration of specific probiotics such as '' Lactobacillus rhamnosus'' or ''
Saccharomyces boulardii ''Saccharomyces boulardii'' is a tropical yeast first isolated from lychee and mangosteen fruit peel in 1923 by French scientist Henri Boulard. Although early reports claimed distinct taxonomic, metabolic, and genetic properties, ''S. boulardii' ...
'',
diosmectite Diosmectite (brand names Smecta, Smecdral) is a natural silicate of aluminium and magnesium used as an intestinal adsorbent in the treatment of several gastrointestinal diseases, including infectious and non-infectious acute and chronic diarrhoea ...
or racecadotril."


Prevention

Rotaviruses are highly contagious and cannot be treated with antibiotics or other drugs. Because improved sanitation does not decrease the prevalence of rotaviral disease, and the rate of hospitalisations remains high despite the use of oral rehydrating medicines, the primary public health intervention is vaccination. In 1998, a rotavirus vaccine was licensed for use in the United States.
Clinical trials Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...
in the United States, Finland, and Venezuela had found it to be 80 to 100% effective at preventing severe diarrhoea caused by ''rotavirus A'', and researchers had detected no
statistically significant In statistical hypothesis testing, a result has statistical significance when it is very unlikely to have occurred given the null hypothesis (simply by chance alone). More precisely, a study's defined significance level, denoted by \alpha, is the p ...
serious adverse effects. The manufacturer, however, withdrew it from the market in 1999, after it was discovered that the vaccine may have contributed to an increased risk for
intussusception Intussusception may refer to: * Intussusception (medical disorder) Intussusception is a medical condition in which a part of the intestine folds into the section immediately ahead of it. It typically involves the small bowel and less commonly t ...
, a type of
bowel obstruction Bowel obstruction, also known as intestinal obstruction, is a mechanical or Ileus, functional obstruction of the Gastrointestinal tract#Lower gastrointestinal tract, intestines which prevents the normal movement of the products of digestion. Eith ...
, in one of every 12,000 vaccinated infants. The experience provoked intense debate about the relative risks and benefits of a rotavirus vaccine. In 2006, two new vaccines against ' infection were shown to be safe and effective in children, and in 2009, the WHO recommended that rotavirus vaccine be included in all national immunisation programmes. The incidence and severity of rotavirus infections has declined significantly in countries that have acted on this recommendation. A 2014 review of available clinical trial data from countries routinely using rotavirus vaccines in their national immunisation programs found that rotavirus vaccines have reduced rotavirus hospitalisations by 49–92 percent and all cause diarrhoea hospitalisations by 17–55 percent. In Mexico, which in 2006 was among the first countries in the world to introduce rotavirus vaccine, diarrhoeal disease death rates dropped during the 2009 rotavirus season by more than 65 percent among children age two and under. In Nicaragua, which in 2006 became the first developing country to introduce a rotavirus vaccine, severe rotavirus infections were reduced by 40 percent and emergency room visits by a half. In the United States, rotavirus vaccination since 2006 has led to drops in rotavirus-related hospitalisations by as much as 86 percent. The vaccines may also have prevented illness in non-vaccinated children by limiting the number of circulating infections. In developing countries in Africa and Asia, where the majority of rotavirus deaths occur, a large number of safety and efficacy trials as well as recent post-introduction impact and effectiveness studies of Rotarix and RotaTeq have found that vaccines dramatically reduced severe disease among infants. In September 2013, the vaccine was offered to all children in the UK, aged between two and three months, and it is expected to halve the cases of severe infection and reduce the number of children admitted to hospital because of the infection by 70 percent. In Europe, hospitalisation rates following infection by rotaviruses have decreased by 65% to 84% following the introduction of the vaccine. Globally, vaccination has reduced hospital admissions and emergency department visits by a median of 67%. Rotavirus vaccines are licensed in over 100 countries, and more than 80 countries have introduced routine rotavirus vaccination, almost half with the support of the
GAVI GAVI, officially Gavi, the Vaccine Alliance (previously the GAVI Alliance, and before that the Global Alliance for Vaccines and Immunization) is a public–private global health partnership with the goal of increasing access to immunization ...
vaccine alliance. To make rotavirus vaccines available, accessible, and affordable in all countries—particularly low- and middle-income countries in Africa and Asia where the majority of rotavirus deaths occur, PATH (formerly Program for Appropriate Technology in Health), the WHO, the U.S. Centers for Disease Control and Prevention, and GAVI have partnered with research institutions and governments to generate and disseminate evidence, lower prices, and accelerate introduction. The vaccine may prevent type 1 diabetes.


Epidemiology

''Rotavirus A'', which accounts for more than 90% of rotavirus gastroenteritis in humans, is endemic worldwide. Each year rotaviruses cause millions of cases of diarrhoea in developing countries, almost 2million of which result in hospitalisation. In 2019, an estimated 151,714 children younger than five died from rotavirus infections, 90 percent of whom were in developing countries. Almost every child has been infected with rotaviruses by age five. Rotaviruses are the leading single cause of severe diarrhoea among infants and children, is responsible for about a third of the cases requiring hospitalisation, and causes 37% of deaths attributable to diarrhoea and 5% of all deaths in children younger than five. Boys are twice as likely as girls to be admitted to hospital for rotavirus infections. In the pre-vaccination era, rotavirus infections occurred primarily during cool, dry seasons. The number attributable to food contamination is unknown. Outbreaks of ''rotavirus A'' diarrhoea are common among hospitalised infants, young children attending day care centres, and elderly people in nursing homes. An outbreak caused by contaminated municipal water occurred in Colorado in 1981. During 2005, the largest recorded epidemic of diarrhoea occurred in Nicaragua. This unusually large and severe outbreak was associated with mutations in the ''rotavirus A'' genome, possibly helping the virus escape the prevalent immunity in the population. A similar large outbreak occurred in Brazil in 1977. ''Rotavirus B'', also called adult diarrhoea rotavirus or ADRV, has caused major epidemics of severe diarrhoea affecting thousands of people of all ages in China. These epidemics occurred as a result of sewage contamination of drinking water. ''Rotavirus B'' infections also occurred in India in 1998; the causative strain was named CAL. Unlike ADRV, the CAL strain is endemic. To date, epidemics caused by ''rotavirus B'' have been confined to mainland China, and surveys indicate a lack of immunity to this species in the United States. ''Rotavirus C'' has been associated with rare and sporadic cases of diarrhoea in children, and small outbreaks have occurred in families. File:Rotavirus seasonal distribution.png, The seasonal variation of ''rotavirus A'' infections in England: rates of infection peak during the winter months. File:Avertable-deaths-from-rotavirus-with-full-vaccine-coverage.png, Preventable child deaths from rotavirus vaccination, 2016. Annual number of preventable deaths in children under five years old from rotavirus if full coverage of the rotavirus vaccine was achieved.


Other animals

Rotaviruses infect the young of many species of animals and they are a major cause of diarrhoea in wild and reared animals worldwide. As a pathogen of livestock, notably in young calves and piglets, rotaviruses cause economic loss to farmers because of costs of treatment associated with high morbidity and mortality rates. These rotaviruses are a potential reservoir for genetic exchange with human rotaviruses. There is evidence that animal rotaviruses can infect humans, either by direct transmission of the virus or by contributing one or several RNA segments to reassortants with human strains.


History

In 1943, Jacob Light and Horace Hodes proved that a filterable agent in the faeces of children with infectious diarrhoea also caused scours (livestock diarrhoea) in cattle. Three decades later, preserved samples of the agent were shown to be rotavirus. In the intervening years, a virus in mice was shown to be related to the virus causing scours. In 1973, Ruth Bishop and colleagues described related viruses found in children with gastroenteritis. In 1974,
Thomas Henry Flewett Thomas Henry Flewett, MD, FRCPath, FRCP (29 June 1922 – 12 December 2006) was a founder member (and subsequently Fellow) of the Royal College of Pathologists and was elected (by distinction) a Fellow of the Royal College of Physicians of Lo ...
suggested the name ''rotavirus'' after observing that, when viewed through an electron microscope, a rotavirus particle looks like a wheel ( in Latin) the name was officially recognised by the International Committee on Taxonomy of Viruses four years later. In 1976, related viruses were described in several other species of animals. These viruses, all causing acute gastroenteritis, were recognised as a collective pathogen affecting humans and other animals worldwide. Rotavirus serotypes were first described in 1980, and in the following year, rotaviruses from humans were first grown in
cell culture Cell culture or tissue culture is the process by which cells are grown under controlled conditions, generally outside of their natural environment. The term "tissue culture" was coined by American pathologist Montrose Thomas Burrows. This te ...
s derived from monkey kidneys, by adding trypsin (an enzyme found in the
duodenum The duodenum is the first section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear, and the terms anterior intestine or proximal intestine m ...
of mammals and now known to be essential for rotavirus to replicate) to the culture medium. The ability to grow rotaviruses in culture accelerated the pace of research, and by the mid-1980s the first candidate vaccines were being evaluated.


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* * * {{Taxonbar, from=Q164778 Gastroenterology Pediatrics Virus genera