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. 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 electron micrograph of a rotavirus infected enterocyte (top) compared to an uninfected cell (bottom). the bar = approx. 500 nm rotaviruses replicate mainly in the gut, and infect enterocytes of the villi of the small intestine, leading to structural and functional changes of the epithelium. 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 enterocytes. the toxic rotavirus protein nsp4 induces age- and calcium ion-dependent chloride secretion, disrupts sglt1 (sodium/glucose cotransporter 2) transporter-mediated reabsorption of water, apparently reduces activity of brush-border membrane disaccharidases, and activates the calcium ion-dependent secretory reflexes 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. 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). 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 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 interferons and other cytokines (particularly th1 and th2) which inhibit the replication of the virus and recruit macrophages and natural killer cells 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 as the cause of severe diarrhoea. most children admitted to hospital with gastroenteritis are tested for rotavirus. specific diagnosis of infection with rotavirus 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 rotavirus. other methods, such as electron microscopy and pcr (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 or nasogastric intubation, and the child's electrolytes 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, diosmectite or racecadotril." prevention main article: rotavirus vaccine 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 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 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, a type of bowel obstruction, 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 rotavirus a 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 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 2 million 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. the seasonal variation of rotavirus a infections in england: rates of infection peak during the winter months. 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 one of flewett's original electron micrographs showing a single rotavirus particle. when examined by negative stained electron microscopy, rotaviruses often resemble wheels. 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 suggested the name rotavirus after observing that, when viewed through an electron