key: cord-0008526-fi3u46t0 authors: Barnett, Bill title: Viral Gastroenteritis date: 2016-04-06 journal: Med Clin North Am DOI: 10.1016/s0025-7125(16)31165-8 sha: 679335e4dd4f4725ad646ab8fe716590bbfd0456 doc_id: 8526 cord_uid: fi3u46t0 nan agents of gastroenteritis. These viruses include adenoviruses, astroviruses, caliciviruses, coronaviruses, and a group of poorly defined agents referred to as the small, round viruses. However, at this time the Norwalk-like viruses and rotaviruses appear to be the major viral agents associated with gastroenteritis. The subject of viral gastroenteritis has been frequently reviewed. 20 , 23, 83, 159, 181, 211 Other review articles deal specifically with the Norwalklike viruses 21 and the rotaviruses. 72 , 112, 193 ROTAVIRUSES In 1969 Mebus et al. reported that a reovirus-like agent was associated with severe diarrhea in newborn calves.l 5o Numerous viral particles, 65 nm in diameter, were present in the feces; these viruses differed morphologically both from the reoviruses and orbiviruses. Procedures based on immunofluorescence were developed for diagnosis, and the virus was adapted to cell culture, 149 which later led to an oral, live-type bovine vaccine. 152 These reports received little attention outside of veterinary medicine until 1973, when a morphologically identical and serologically related virus was found in the epithelial cells of duodenal biopsy specimens from Australian children with acute nonbacterial gastroenteritis. 15 Almost simultaneously, similar reports appeared in England and Canada. 67, 153 Similar viruses have also been found to be associated with gastroenteritis in a wide range of animal species. 72 The early literature describing this group of viruses is somewhat confusing as a result of the many names used to describe them, such as reovirus-like, 71 96, 178 The International Committee on Taxonomy of Viruses has placed this group of viruses in a new genus called rotaviruses, to be included with the reoviruses in the family Reoviridae. 144 The name reovirus is an acronym for "respiratory enteric orphan" (orphan because of no apparent association with a disease). As a result of their wheel-like appearance, the term rotavirus (from the Latin rota, a wheel) was suggested for this new genus of viruses. 68 Rotaviruses have a very distinctive morphology and are easily recognized in electron micrographs (Fig. 1) . The intact rotavirus has a buoyant 1032 BILL BARNETT agents of gastroenteritis. These viruses include adenoviruses, astroviruses, caliciviruses, coronaviruses, and a group of poorly defined agents referred to as the small, round viruses. However, at this time the Norwalk-like viruses and rotaviruses appear to be the major viral agents associated with gastroenteritis. The subject of viral gastroenteritis has been frequently reviewed. 20, 23. 83,159,181,211 Other review articles deal specifically with the Norwalklike viruses21 and the rotaviruses. 72, 112, 193 ROTAVIRUSES In 1969 Mebus et al. reported that a reovirus-like agent was associated with severe diarrhea in newborn calves. 150 Numerous viral particles, 65 nm in diameter, were present in the feces; these viruses differed morphologically both from the reoviruses and orbiviruses. Procedures based on immunofluorescence were developed for diagnosis, and the virus was adapted to cell culture, 149 which later led to an oral, live-type bovine vaccine. 152 These reports received little attention outside of veterinary medicine until 1973, when a morphologically identical and serologically related virus was found in the epithelial cells of duodenal biopsy specimens from Australian children with acute nonbacterial gastroenteritis. 15 Almost simultaneously, similar reports appeared in England and Canada. 67, 153 Similar viruses have also been found to be associated with gastroenteritis in a wide range of animal species. 72 The early literature describing this group of viruses is somewhat confusing as a result of the many names used to describe them, such as reovirus-like, 71 178 The International Committee on Taxonomy of Viruses has placed this group of viruses in a new genus called rotaviruses, to be included with the reoviruses in the family Reoviridae, 144 The name reovirus is an acronym for "respiratory enteric orphan" (orphan because of no apparent association with a disease). As a result of their wheel-like appearance, the term rotavirus (from the Latin rota, a wheel) was suggested for this new genus of viruses. 68 Rotaviruses have a very distinctive morphology and are easily recognized in electron micrographs (Fig. 1) . The intact rotavirus has a buoyant Figure 1 . Viruses associated with gastroenteritis. All the electron micrographs are of viruses from diarrheic stool samples and are printed at the same magnification. A, Rotaviruses from an infant. B, Marin County Virus, a Norwalk-like virus. By immunoelectron microscopy, the fuzziness is a result 'of antibody coating the virus particles. C, Adenoviruses from an infant with gastroenteritis. The bar represents 100 nm. D, Astrovirus. This group of particles shows a typical star-shaped surface morphology and smooth outer edge. E, Coronavirus. A pleomorphic particle with pin-like surface projections around the periphery. The shafts of the "pins" are not visible, but the constant distance of the heads from the membrane confirms that they must be there. F, Calicivirus. The particles show cup-shaped, stain-filled hollows on the surface. G, Rotavirus and astrovirus. It is not uncommon to find more than one virus in a stool, and almost any combination can be found. This particular one is not uncommon, but there is no evidence to suggest that the association is anything but casual. . This group of particles shows a typical star-shaped surface morphology and smooth outer edge. E, Coronavirus. A pleomorphic particle with pin-like surface projections around the periphery. The shafts of the "pins" are not visible, but the constant distance of the heads from the membrane confirms that they must be there. F, Calicivirus. The particles show cup-shaped, stain-filled hollows on the surface. G, Rotavirus and astrovirus, It is not uncommon to find more than one virus in a stool, and almost any combination can be found. This particular one is not uncommon, but there is no evidence to suggest that the association is anything but casual. H, Rotavirus, calicivirus, and small round virus. The single rotavirus and two caliciviruses are unmistakable. The reader may decide for himself whether the other particles are (a) truly virus or (b) atypical caliciviruses or a different virus altogether. (Electron micrographs A, B, and C are courtesy of Dr. L. S. Oshiro; electron micrographs D, E, F, G, and H are courtesy of Dr. C. R. Madeley.) density in cesium chloride (CsCI) of 1.35 gm per cm3, 61 a diameter of 68 nm,166 and is infectious. These intact virions, sometimes called L virions,44 consist of two layers of polypeptides surrounding a 36-nm core that contains the viral nucleic acids. When the outer polypeptide coat is absent, the resulting particle is not infectious and is referred to as the singleshelled 97 or D-particle. D-particles are frequently seen in electron micrographs of fecal specimens, having a buoyant density of 1.38 gm per cm 3 (thus the designations D for dense and L for light). Although extracellular D-particles are not infectious, the conversion of the L-particles to D-particles after entry into the host cell appears to be an obligate step in the rotaviral replicative cycle. 43 The infectivity of rotavirus may be enhanced over lOO-fold following exposure of the virus to trypsin. 11 This phenomenon of enzyme enhancement has been used to aid in the detection 32 , 142, 156, 179, 186 and propagation 3 , 8, 42, 78,177,200 of rotavirus. The mechanism of enhancement is related to the intracellular uncoating of the L-particle to the D-particle. The trypsin cleaves an 88,000 dalton structural polypeptide of the Lparticle to yield a 67,000 dalton and a 21,000 dalton polypeptide, both of which remain attached to the virion. This cleavage then facilitates the intracellular conversion of the L-particle to the D-particle. 43 The trypsinmediated enhancement of rotavirus infectivity will also occur as the ingested rotavirus passes through the digestive tract of the host. The rotavirus genome is composed of 11 segments of linear, doublestranded RNA.l° ' 104, 161, 170, 178 All members of the family Reoviridae have segmented double-stranded RNA genomes. Special electron microscopic techniques can be used to visualize the individual RNA segments being released from disrupted rotavirus particles (Fig. 2) . Apparently each of these double-stranded RNA molecules is a monocistronic message specifying a viral polypeptide. One of these is a 38,000 dalton structural glycoprotein, which is the major outer capsid protein and which elicits neutralizing antibody. 63, 64, 143, 171 This polypeptide is probably coded by the eighth genome segment. 146 The eleven genome segments may be resolved by polyacrylamide gel electrophoresis and are referred to by numbers 1 to 11, in order of descending molecular weights. Virologists are particularly interested in the 38,000 dalton glycoprotein, which may hold the key to the antigenic diversity of rotaviruses and thus be of major importance in the design of a vaccine for immunoprophylaxis. In addition to this serotypespecific antigen, rotaviruses share a common group antigen demonstrable by complement fixation, immunofluorescence tests, and enzyme-linked immunosorbent assay (ELISA). This common antigen is associated with one of the inner capsid polypeptides. Recently a human rotavirus,162 a porcine rotavirus,26, 30 and an avian rotavirus 147 have been isolated, all lacking the common group-specific antigen. Certain strains of rotaviruses hemagglutinate human group°red blood cells. The gene that codes for the ability to hemagglutinate has recently been identified as the fourth genome segment,103 which also codes for the trypsin enhancement characteristics of rotavirus and is responsible for restricting growth in cell culture. The 88,000 dalton polypeptide cleaved by trypsin 43 is probably coded by the fourth genome segment. BILL BARNETT density in cesium chloride (CsCI) of 1.35 gm per cm 3 ,61 a diameter of 68 nm,166 and is infectious, These intact virions, sometimes called L virions,44 consist of two layers of polypeptides surrounding a 36-nm core that contains the viral nucleic acids, When the outer polypeptide coat is absent, the resulting particle is not infectious and is referred to as the singleshelled 97 or D-particle. D-particles are frequently seen in electron micrographs of fecal specimens, having a buoyant density of 1.38 gm per cm 3 (thus the designations D for dense and L for light). Although extracellular D-particles are not infectious, the conversion of the L-particles to D-particles after entry into the host cell appears to be an obligate step in the rotaviral replicative cycle. 43 The infectivity of rotavirus may be enhanced over lOO-fold following exposure of the virus to trypsin. 11 This phenomenon of enzyme enhancement has been used to aid in the detection32, 142, 156, 179, 186 and pro-pagation3, 8, 42, 78, 177, 200 of rotavirus. The mechanism of enhancement is related to the intracellular uncoating of the L-particle to the D-particle. The trypsin cleaves an 88,000 dalton structural polypeptide of the Lparticle to yield a 67,000 dalton and a 21,000 dalton polypeptide, both of which remain attached to the virion. This cleavage then facilitates the intracellular conversion of the L-particle to the D-particle. 43 The trypsinmediated enhancement of rotavirus infectivity will also occur as the ingested rotavirus passes through the digestive tract of the host. The rotavirus genome is composed of 11 segments of linear, doublestranded RNA. 10, 104, 161, 170, 178 All members of the family Reoviridae have segmented double-stranded RNA genomes. Special electron microscopic techniques can be used to visualize the individual RNA segments being released from disrupted rotavirus particles (Fig. 2) . Apparently each of these double-stranded RNA molecules is a monocistronic message specifying a viral polypeptide. One of these is a 38,000 dalton structural glycoprotein, which is the major outer capsid protein and which elicits neutralizing antibody. 63, 64, 143, 171 This polypeptide is probably coded by the eighth genome segment. 146 The eleven genome segments may be resolved by polyacrylamide gel electrophoresis and are referred to by numbers 1 to 11, in order of descending molecular weights. Virologists are particularly interested in the 38,000 dalton glycoprotein, which may hold the key to the antigenic diversity of rotaviruses and thus be of major importance in the design of a vaccine for immunoprophylaxis. In addition to this serotypespecific antigen, rotaviruses share a common group antigen demonstrable by complement fixation, immunofluorescence tests, and enzyme-linked immunosorbent assay (ELISA). This common antigen is associated with one of the inner capsid polypeptides. Recently a human rotavirus,162 a porcine rotavirus,26, 30 and an avian rotavirus l47 have been isolated, all lacking the common group-specific antigen. Certain strains of rotaviruses hemagglutinate human group 0 red blood cells. The gene that codes for the ability to hemagglutinate has recently been identified as the fourth genome segment,103 which also codes for the trypsin enhancement characteristics of rotavirus and is responsible for restricting growth in cell culture. The 88,000 dalton polypeptide cleaved by trypsin43 is probably coded by the fourth genome segment. .~~h Electron micrograph of a rotavirus that has been exposed to 4M urea, resulting in the denaturation of the capsid proteins and the release of the double-stranded RNA genome segments. The bar represents 500 nm. (Stained with uranyl acetate and shadowed with platinum.) (From Barnett Rotaviral gastroenteritis shows both a characteristic seasonal prevalence and patient-age distribution. In temperate, climates the peak period of incidence is during the winter months, with little or no· rotaviral diarrhea present during the summer months. 28, 29, 94, 101, 124, 133, 155, 172 In a study based in Washington, D.e. it was reported that rotavirus was not detected at all during the summer months, yet accounted for 80 per cent or more of the gastroenteritis during December and January.ll1 Brandt et al. reported that the highest prevalence of rotaviral gastroenteritis correlated with cold or dry weather as opposed to warm or wet weather. 28 They proposed that indoor crowding and low indoor relative humidity contributed to respiratory transmission of rotavirus. Konno et al. concluded that the high incidence of infection was related to cold weather but not to humidity. 126 In tropical climates the seasonal distribution may be less distinct but nevertheless apparent. 94 , 139, 167, 218 In a southern Indian coastal town rotaviral diarrhea accounted for nearly 100 per cent of the November to January and 40 per cent of the April to June admissions to a pediatric diarrhea ward. 167 There was an average of 210 admissions per month, with a peak in January when 520 children were admitted. The majority of rotaviral infections with clinical symptoms occur in children under five years of age. In a prospective study based in Winnipeg, VIRAL GASTROENTERITIS Figure 2 . Electron micrograph of a rotavirus that has been exposed to 4M urea, resulting in the denaturation of the capsid proteins and the release of the double-stranded RNA genome segments. The bar represents 500 nm. Rotaviral gastroenteritis shows both a characteristic seasonal prevalence and patient-age distribution. In temperate climates the peak period of incidence is during the winter months, with little or no rotaviral diarrhea present during the summer months. 28, 29, 94. 101, 124, 133, 155, 172 In a study based in Washington, D,e. it was reported that rotavirus was not detected at all during the summer months, yet accounted for 80 per cent or more of the gastroenteritis during December and January.lll Brandt et al. reported that the highest prevalence of rotaviral gastroenteritis correlated with cold or dry weather as opposed to warm or wet weather. 28 They proposed that indoor crowding and low indoor relative humidity contributed to respiratory transmission of rotavirus. Konno et al. concluded that the high incidence of infection was related to cold weather but not to humidity, 126 In tropical climates the seasonal distribution may be less distinct but nevertheless apparent, 94, 139, 167, 218 In a southern Indian coastal town rotaviral diarrhea accounted for nearly 100 per cent of the November to January and 40 per cent of the April to June admissions to a pediatric diarrhea ward. 167 There was an average of 210 admissions per month, with a peak in January when 520 children were admitted. The majority of rotaviral infections with clinical symptoms occur in children under five years of age. In a prospective study based in Winnipeg, Canada, Gurwith et al. found that rotaviral gastroenteritis was uncommon during the first six months of life, but that 62 per cent of the infants had at least one rotaviral infection by two years of age. 88 Several hospital-based studies indicate the same general patient-age distribution of rotaviral gastroenteritis. I , 101 An Israel-based study reported that 94 per cent of the patients with rotaviral gastroenteritis were less than 36 months of age and 35 per cent were less than six months of age. 101 In a retrospective study, Foster et al. described an epidemic of 3439 cases of rotaviral gastroenteritis in a remote Pacific island population. 74 The majority of the clinical illnesses were in the age group less than 20 years of age. The age-specific attack rates were 40 per cent in children less than one year of age, 62 per cent in the group aged one to four years, and 12 per cent in adults 20 years of age and older. Black et al. conducted a prospective study in rural Bangladesh, where the peak prevalence of rotaviral gastroenteritis was in the 6 to 11 month age group. 17 Panicker et aI., from a study at a pediatric diarrhea ward in Calicut, India, reported that from 3355 cases of acute diarrhea, rotavirus accounted for 75 per cent of the cases in children 6 to 23 months of age, 65 per cent of the cases in those 24 to 60 months of age, and 35 per cent of the cases in those less than 6 months of age. The problem of rotaviruses in neonates is somewhat cloudy. Rotavirus was found by electron microscopy in the feces of 32 per cent of the 1056 five-day-old infants in a study of newborns in English nurseries;9,41 however, the infection was usually asymptomatic. A similar study in New York reported no rotavirus in 925 stools from 286 neonates, even though rotavirus was present in both the hospital and the community. 194 Other reports have documented the association of rotavirus with symptomatic gastroenteritis in neonates. 33 , 34 Rotavirus is the major cause of "winter diarrhea" in infants and children; additionally there have been outbreaks of rotaviral gastroenteritis in isolated nonimmune communities involving patients from all age groups. 74, 134 Rotavirus has also caused outbreaks of gastroenteritis in school children aged 6 to 12 years. 92 Rotaviral infection in a long-stay geriatric ward affected 19 of 34 patients-6 had severe gastroenteritis and 2 died. 140 A similar rotavirus outbreak in an Oslo, Norway, nursing home for the elderly resulted in clinical symptoms in 92 of the 256 residents. 89 Again a number of the patients became severely ill and one died. A similar outbreak in a London geriatric ward has been reported. 47 In all of these instances involving geriatric patients, members of the staff also were reported ill with gastroenteritis. An outbreak in a cardiology ward also affecting the health care staff has been reported. 98 Rotavirus has also been implicated in travelers' diarrhea in adult students in Mexic0 27 and in soldiers in Korea. 60 Several studies document rotaviral infection in adult contacts of pediatric patients with gastroenteritis, with the infection in adults usually mild and frequently asymptomatic. HI Canada, Gurwith et al. found that rotaviral gastroenteritis was uncommon during the first six months of life, but that 62 per cent of the infants had at least one rotaviral infection by two years of age. H8 Several hospital-based studies indicate the same general patient-age distribution of rotaviral gastroenteritis. l , 101 An Israel-based study reported that 94 per cent of the patients with rotaviral gastroenteritis were less than 36 months of age and 35 per cent were less than six months of age. 101 In a retrospective study, Foster et al. described an epidemic of 3439 cases of rotaviral gastroenteritis in a remote Pacific island population. 74 The majority of the clinical illnesses were in the age group less than 20 years of age. The age-specific attack rates were 40 per cent in children less than one year of age, 62 per cent in the group aged one to four years, and 12 per cent in adults 20 years of age and older. Black et al. conducted a prospective study in rural Bangladesh, where the peak prevalence of rotaviral gastroenteritis was in the 6 to 11 month age group. 17 Panicker et al., from a study at a pediatric diarrhea ward in Calicut, India, reported that from 3355 cases of acute diarrhea, rotavirus accounted for 75 per cent of the cases in children 6 to 23 months of age, 65 per cent of the cases in those 24 to 60 months of age, and 35 per cent of the cases in those less than 6 months of age. The problem of rotaviruses in neonates is somewhat cloudy. Rotavirus was found by electron microscopy in the feces of 32 per cent of the 1056 five-day-old infants in a study of newborns in English nurseries;9,41 however, the infection was usually asymptomatic. A similar study in New York reported no rotavirus in 925 stools from 286 neonates, even though rotavirus was present in both the hospital and the communityJ94 Other reports have documented the association of rotavirus with symptomatic gastroenteritis in neonates. 33, 34 Rotavirus is the major cause of "winter diarrhea" in infants and children; additionally there have been outbreaks of rotaviral gastroenteritis in isolated nonimmune communities involving patients from all age groups. 74, 134 Rotavirus has also caused outbreaks of gastroenteritis in school children aged 6 to 12 years. 92 Rotaviral infection in a long-stay geriatric ward affected 19 of 34 patients-6 had severe gastroenteritis and 2 died,140 A similar rotavirus outbreak in an Oslo, Norway, nursing home for the elderly resulted in clinical symptoms in 92 of the 256 residents. 89 Again a number of the patients became severely ill and one died. A similar outbreak in a London geriatric ward has been reported. 47 In all of these instances involving geriatric patients, members of the staff also were reported ill with gastroenteritis. An outbreak in a cardiology ward also affecting the health care staff has been reported. 98 Rotavirus has also been implicated in travelers' diarrhea in adult students in Mexico 27 and in soldiers in Korea. 60 Several studies document rotaviral infection in adult contacts of pediatric patients with gastroenteritis, with the infection in adults usually mild and frequently asymptomatic. Ill 183 The incubation period was 48 to 72 hr, followed by the sud-den onset of diarrhea and vomiting. The vomiting preceded the diarrhea by 2 to 36 hr in 47 per cent of the patients and appeared simultaneously with the diarrhea in 43 per cent. Vomiting was not a symptom in 10 per cent of the cases, although all had diarrhea. In addition to diarrhea and vomiting, fever was present in 63 per cent of the patients. Fifty-three per cent of the patients were dehydrated, usually less than 5 per cent dehydration. The recovery period was usually 5 to 7 days, the longest being 26 days. Bloody stools were not a clinical feature of the illness, and in most studies bloody stools are not observed; however, at least one report described bloody stools as a possible clinical feature of rotaviral diarrhea.. 54 The clinical features of a large epidemic of rotaviral gastroenteritis involving 3439 cases were described by Foster et al. 74 Systemic symptoms were usually absent except in young children. Symptomatic patients passed numerous (3 to 12 per day) watery brown stools (others have described offensive yellow green stools).l83 No blood or excess mucous was observed in stools. Other symptoms included fever, vomiting, and abdominal cramps. Upper respiratory symptoms (nonproductive cough) were present in 10 per cent of the patients. In younger children dehydration was common. Dehydration was a complicating factor in all seven children who died. The illness usually lasted one to four days, and all deaths occurred within the first four days of illness. Chiba et al. described an outbreak of diarrhea in an infant home in Sapporo, Japan, wherein 42 of the 47 infants (90 per cent) were infected, and 90 per cent of those infected showed clinical symptoms. 37 Twentyseven (64 per cent) had diarrhea, 14 per cent suffered from vomiting without diarrhea, and 12 per cent had fever (2:: 38°rectal) without intestinal symptoms. The majority had diarrhea with vomiting and fever; however, in those patients under 6 months of age, vomiting was a rare symptom. The frequency of vomiting and fever increased in the older children (over 12 months of age), while diarrhea as a symptom became somewhat less common. Black et al. noted that a greater degree of dehydration was associated with rotaviral diarrhea than with diarrhea caused by enterotoxigenic Escherichia coli or Shigella .17 These authors speculated that because of the increased dehydration, rotavirus-associated diarrhea is more likely to result in death if rehydration treatment is not implemented. Carlson et al. described the clinical and pathologic features of 21 fatal cases of rotaviral gastroenteritis. All patients were between 4 and 30 months of age and resided in the Toronto area. Dehydration (10 to 20 per cent dehydration) and associated electrolyte imbalance were the major factors causing death; however, aspiration of vomit was believed to be the major factor in 3 of the 21 deaths. The authors' report on the autopsy and biochemical findings indicated marked dehydration as the most significant feature. Clinically, vomiting was the most characteristic symptom, occurring in all 21 patients, and was the initial symptom in 14 patients. Diarrhea was a symptom in 17 patients, while fever was noted in 10 patients. In all 21 cases, death occurred within 3 days of onset of symptoms. A very thorough description of the clinical features of rotaviral gastroenteritis in children ill enough to require hospitalization was presented by Rodriguez et al. 172 den onset of diarrhea and vomiting. The vomiting preceded the diarrhea by 2 to 36 hr in 47 per cent of the patients and appeared simultaneously with the diarrhea in 43 per cent. Vomiting was not a symptom in 10 per cent of the cases, although all had diarrhea. In addition to diarrhea and vomiting, fever was present in 63 per cent of the patients. Fifty-three per cent of the patients were dehydrated, usually less than 5 per cent dehydration. The recovery period was usually 5 to 7 days, the longest being 26 days. Bloody stools were not a clinical feature of the illness, and in most studies bloody stools are not observed; however, at least one report described bloody stools as a possible clinical feature of rotaviral diarrhea. , 54 The clinical features of a large epidemic of rotaviral gastroenteritis involving 3439 cases were described by Foster et al. 74 Systemic symptoms were usually absent except in young children. Symptomatic patients passed numerous (3 to 12 per day) watery brown stools (others have described offensive yellow green stools),183 No blood or excess mucous was observed in stools. Other symptoms included fever, vomiting, and abdominal cramps. Upper respiratory symptoms (nonproductive cough) were present in 10 per cent of the patients. In younger children dehydration was common. Dehydration was a complicating factor in all seven children who died. The illness usually lasted one to four days, and all deaths occurred within the first four days of illness. Chiba et al. described an outbreak of diarrhea in an infant home in Sapporo, Japan, wherein 42 of the 47 infants (90 per cent) were infected, and 90 per cent of those infected showed clinical symptoms. 37 Twentyseven (64 per cent) had diarrhea, 14 per cent suffered from vomiting without diarrhea, and 12 per cent had fever (2: 38° rectal) without intestinal symptoms. The majority had diarrhea with vomiting and fever; however, in those patients under 6 months of age, vomiting was a rare symptom. The frequency of vomiting and fever increased in the older children (over 12 months of age), while diarrhea as a symptom became somewhat less common. Black et al. noted that a greater degree of dehydration was associated with rotaviral diarrhea than with diarrhea caused by enterotoxigenic Escherichia coli or Shigella .17 These authors speculated that because of the increased dehydration, rotavirus-associated diarrhea is more likely to result in death if rehydration treatment is not implemented. Carlson et al. described the clinical and pathologic features of 21 fatal cases of rotaviral gastroenteritis. All patients were between 4 and 30 months of age and resided in the Toronto area. Dehydration (10 to 20 per cent dehydration) and associated electrolyte imbalance were the major factors causing death; however, aspiration of vomit was believed to be the major factor in 3 of the 21 deaths. The authors' report on the autopsy and biochemical findings indicated marked dehydration as the most significant feature. Clinically, vomiting was the most characteristic symptom, occurring in all 21 patients, and was the initial symptom in 14 patients. Diarrhea was a symptom in 17 patients, while fever was noted in 10 patients. In all 21 cases, death occurred within 3 days of onset of symptoms. A very thorough description of the clinical features of rotaviral gastroenteritis in children ill enough to require hospitalization was presented by Rodriguez et al. 172 Gurwith et al. published an equally thorough description of the clinical and epidemiologic features of rotaviral infections in nonhospitalized children in a prospective study. 88 A summary of these two studies is presented in Table 2 . Rotaviral particles may be present in the feces of the infected subject at levels of 10 9 or more per gm of feces. These large numbers of viral particles allow detection by several physical or immunologic techniques. The association of rotavirus with human gastroenteritis was first demonstrated by transmission electron microscopy, 15 which remains one of the better diagnostic methods. The detection limit for rotavirus in feces is about 10 7 viral particles per ml. 123 The very distinctive morphology of rotavirus adds to the reliability of electron microscopy for this particular virus. Immune electron microscopy (IEM), similar to the conventional transmission electron microscopy except that specific antiviral serum is mixed with the sample,2, HO can add about 10-fold to the sensitivity of the test and greatly aids in distinguishing between artifacts and specific viral particles. Cell culture techniques in general have not proven satisfactory for detection of rotavirus. However, rotavirus may be detected by immunofluorescence if the sample is treated with trypsin and applied to the cell culture with the use of low-speed centrifugation. 12, 24, 204 Recently the combination of trypsin treatment of samples and the use of roller tube cultures of monkey kidney cells has proven satisfactory for isolating rotavirus from diarrheic fecal specimens. l77 , 197,206 ELISA is currently the method of choice for rotaviral detection in many laboratories. This procedure offers unprecedented sensitivity, specificity, and practicality for an immunodiagnostic technique. 36, 114, 191, 219, 220 ELISA is more sensitive than electron microscopy, but electron microscopy offers the advantage of detecting viruses other than rotaviruses. 182 Commercially prepared conjugates 222 and complete assay kits are available for detection of rotavirus by the ELISA procedure. A very promising development is the multiple determinant ELISA,222 which, through the elimination of several washing and incubation steps, may be completed in 40 min as opposed to 4 hr for a conventional ELISA. The key to this assay is the use of solid phase antibody and enzyme-Iabeled antibody directed at different antigenic sites on the virus. Other detection procedures for rotavirus include immunoelectroosmophoresis,79 complement fixation, 108, 225 viral RNA electrophoresis, 7, 9:3 radioimmunoassay, 49, 154 and the very rapid latex agglutination technique. lib Most individuals acquire serum antibody to rotavirus by the age of 2 years,224 and rotaviral infections associated with illness become much less common after 5 years of age. Sequential rotaviral infections commonly occur in children under 5 years of age, but these illnesses are usually the result of infections with different serotypes of rotaviruses. 73, Ill, 173,224 Since most serologic techniques such as immunofluorescence and ELISA do not distinguish between serotypes of rotaviruses, caution must be exercised in interpreting the role of rotavirus-specific antibody in protecting against rotaviral infection. The majority of rotavirus strains from different species share common antigenic determinants (termed group antigens), which are 1038 BILL BAHNETT nonhospitalized children in a prospective study.sH A summary of these two studies is presented in Table 2 . Rotaviral particles may be present in the feces of the infected subject at levels of 10 9 or more per gm of feces. These large numbers of viral particles allow detection by several physical or immunologic techniques. The association of rotavirus with human gastroenteritis was first demonstrated by transmission electron microscopy,15 which remains one of the better diagnostic methods. The detection limit for rotavirus in feces is about 10 7 viral particles per ml. 123 The very distinctive morphology of rotavirus adds to the reliability of electron microscopy for this particular virus. Immune electron microscopy (IEM), similar to the conventional transmission electron microscopy except that specific antiviral serum is mixed with the sample,2, 110 can add about lO-fold to the sensitivity of the test and greatly aids in distinguishing between artifacts and specific viral particles. Cell culture techniques in general have not proven satisfactory for detection of rotavirus. However, rotavirus may be detected by immunofluorescence if the sample is treated with trypsin and applied to the cell culture with the use of low-speed centrifugation. 12, 24, 204 Recently the combination of trypsin treatment of samples and the use of roller tube cultures of monkey kidney cells has proven satisfactory for isolating rotavirus from diarrheic fecal specimens. m, 197,206 ELISA is currently the method of choice for rotaviral detection in many laboratories. This procedure offers unprecedented sensitivity, specificity, and practicality for an immunodiagnostic technique. 36, Jl4, 191,219,220 ELISA is more sensitive than electron microscopy, but electron microscopy offers the advantage of detecting viruses other than rotaviruses. 182 Commercially prepared conjugates 222 and complete assay kits are available for detection of rotavirus by the ELISA procedure. A very promising development is the multiple determinant ELISA,222 which, through the elimination of several washing and incubation steps, may be completed in 40 min as opposed to 4 hr for a conventional ELISA. The key to this assay is the use of solid phase antibody and enzyme-Iabeled antibody directed at different antigenic sites on the virus. Other detection procedures for rotavirus include immunoelectroosmophoresis,79 complement fixation, 108, 22.5 viral RNA electrophoresis, 7, 98 radioimmunoassay,49, 134 and the very rapid latex agglutination technique. 17li Most individuals acquire serum antibody to rotavirus by the age of 2 years,224 and rotaviral infections associated with illness become much less common after 5 years of age. Sequential rotaviral infections commonly occur in children under 5 years of age, but these illnesses are usually the result of infections with different serotypes of rotaviruses. 73, 111, 173, 224 Since most serologic techniques such as immunofluorescence and ELISA do not distinguish between serotypes of rotaviruses, caution must be exercised in interpreting the role of rotavirus-specific antibody in protecting against rotaviral infection. The majority of rotavirus strains from different species share common antigenic determinants (termed group antigens), which are 14, 62, 77, 80, 207 Thus, antisera directed against rotaviruses from other species show relatively poor cross-neutralization of human rotavirus. 62 , 77 There are conflicting reports on the subject of cross-protection. Wyatt et al. observed heterologous cross-protection in calves immunized in utero with bovine rotavirus and subsequently challenged as newborns with a human origin strain of rotavirus. 217 Strains of rotaviruses from hunlans can be divided into at least three serotypes. 84 , 207, 216 The serotype specificity resides in a 38,000 dalton surface glycoprotein. 105, 146 Interestingly, this particular glycoprotein exhibits a high degree of sequence heterogeneity, 64 which may in part account for the high frequency of reinfection. Even when the problem of multiple serotypes is taken into account, there is still a poor correlation between serum rotavirus-specific antibody levels and protection against rotaviral infection. Studies in adult volunteers have shown that rotavirus-specific, secretory IgA in the intestine is the prime correlate with resistance to rotaviral disease .114 This protection is very serotype specific; thus, IgA antibody to serotype 1 does not protect against infection with serotype 2. Sonya and Holmes used an ELISA procedure to measure rotavirus-specific immunoglobulins of the IgA, IgG, and IgM classes in feces from patients infected with rotavirus. 191 The time course of coproantibody response to rotaviral infection was similar for all three immunoglobulin classes, appearing one to two weeks after the onset of illness, reaching peak titers two to four weeks after infection, then dropping sharply to undetectable levels after about two months. The sharp rise in coproantibody levels Inay play a role in the acute, self-limiting nature of most rotaviral infections, and the transient nature of this local immune response may leave the patient susceptible to a subsequent rotaviral infection. Very little is known about the role of cell-mediated immunity in rotaviral infections. Virus-specific, cell-mediated immunity did not develop in neonatal mice infected with rotavirus. 184 Passive Immunity In animal studies, orally ingested antibody in colostrum, milk, or even serum has proven effective in protecting against rotaviral infection. 25, 31, 151, 188, 189, 212 These studies indicate that the antibody must be present in the gut in order to exert a protective effect. Breast feeding decreases the incidence of gastroenteritis in children and decreases the severity of the illness. 41 , 51, 91,180, 185,203,204 This has generally been attributed to anti-rotavirus secretory IgA, present in over 90 per cent of the colostral and milk samples tested. 223 The level of anti-rotavirus secretory IgA in colostrum is independent of antibody levels in the serum. 99 Additionally, others have reported the presence of non-immunoglobulin rotavirus inhibitory activity in milk and colostrum. 164, 165, 205 Secretory IgA antibody to rotavirus is readily detected in milk 6 months to 2 years post partum. 50 , 51, 223 Although many reports indicate a protective role for breast feeding, some 1040 BILL BARNETT readily detected by complement fixation, immunofluorescence, ELISA, and radioimmunoassay.,ll, 49, 80, 107 Rotavirus strains from different host species have unique virus-specified surface antigens that usually are not dif ferentiated by these procedures but that are readily distinguishable on the basis of serum neutralization assays. 14, 62, 77, 80, 207 Thus, antisera directed against rotaviruses from other species show relatively poor cross-neutralization of human rotavirus. 62 , 77 There are conflicting reports on the subject of cross-protection. Wyatt et al. observed heterologous cross-protection in calves immunized in utero with bovine rotavirus and subsequently challenged as newbofl1s with a human origin strain of rotavirus. 217 Strains of rotaviruses from humans can be divided into at least three serotypes. 84 , 207, 216 The serotype specificity resides in a 38,000 dalton surface glycoprotein. 105, 146 Interestingly, this particular glycoprotein exhibits a high degree of sequence heterogeneity, 64 which may in part account for the high frequency of reinfection. Even when the problem of multiple serotypes is taken into account, there is still a poor correlation between serum rotavirus-specific antibody levels and protection against rotaviral infection. Studies in adult volunteers have shown that rotavirus-specific, secretory IgA in the intestine is the prime correlate with resistance to rotaviral disease .114 This protection is very serotype specific; thus, IgA antibody to serotype 1 does not protect against infection with serotype 2. Sonya and Holmes used an ELISA procedure to measure rotavirus-specific immunoglobulins of the IgA, IgG, and IgM classes in feces from patients infected with rotavirus. 191 The time course of coproantibody response to rotaviral infection was similar for all three immunoglobulin classes, appearing one to two weeks after the onset of illness, reaching peak titers two to four weeks after infection, then dropping sharply to undetectable levels after about two months. The sharp rise in coproantibody levels may play a role in the acute, self-limiting nature of most rotaviral infections, and the transient nature of this local immune response may leave the patient susceptible to a subsequent rotaviral infection. Very little is known about the role of cell-mediated immunity in rotaviral infections. Virus-specific, cell-mediated immunity did not develop in neonatal mice infected with rotavirus. 184 Passive Immunity In animal studies, orally ingested antibody in colostrum, milk, or even serum has proven effective in protecting against rotaviral infection. 25, 31, ], 51, 188, 189, 212 These studies indicate that the antibody must be present in the gut in order to exert a protective effect. Breast feeding decreases the incidence of gastroenteritis in children and decreases the severity of the illness. 41 , 51, 91, 1RO, 18, 5, 203, 204 This has generally been attributed to anti-rotavirus secretory IgA, present in over 90 per cent of the colostral and milk samples tested. 223 The level of anti-rotavirus secretory IgA in colostrum is independent of antibody levels in the serum. 99 Additionally, others have reported the presence of non-immunoglobulin rotavirus inhibitory activity in milk and colostrum. 164, 165, 205 Secretory IgA antibody to rotavirus is readily detected in milk 6 months to 2 years post partum. 50, 51, 22,3 Although many reports indicate a protective role for breast feeding, some studies have shown no protective effect with respect to rotaviral infections. 88 Vaccine Sequential rotaviral infections in the same subject are usually attributable to different serotypes of rotaviruses. 73 , 173,224 These observations are encouraging for vaccine development, since there does appear to be a naturally acquired protection against subsequent reinfection with the homologous serotype of rotavirus. Presently there is no rotavirus vaccine for human use. The prospects and problems associated with developing rotavirus vaccines have recently been reviewed. 36, 114 Much of the available evidence indicates that local immunity in the gut, such as that associated with secretory IgA, is more important than serum antibody in protecting against rotaviral disease. For this reason a high priority has been placed on the development of an oral, live-type vaccine. Attempts are underway to generate cell culture-adapted, attenuated strains of rotavirus to be tested as candidate vaccines. 114 Another approach is to isolate reassortant hybrid rotaviruses from mixed cultures of human and bovine rotaviruses. Although such hybrids have been isolated,84 their pathogenicity and immunogenicity remain to be determined. An attenuated live-type rotavirus vaccine has been used in cattle for many years. 152 A new approach with the bovine vaccine has been to utilize maternal vaccination in order to take advantage of the subsequent transfer of passive immunity to the offspring. 187 There are two major epidemiologic forms of viral gastroenteritis. Rotaviruses cause sporadic, but occasionally epidemic, gastroenteritis, usually occurring during the winter months. This form primarily affects infants and young children, lasts 5 to 8 days, often leads to dehydration, and may require medical attention. The second form of gastroenteritis is more epidemic in nature, usually results in a shorter and milder illness, and occurs throughout the year in older children and adults. A group of 27-nm viruses referred to as the Norwalk-like viruses are responsible for the majority of the outbreaks of the second form. The prototype virus of this group, the Norwalk virus, was discovered in a 1968 outbreak of gastroenteritis in Norwalk, Ohio. 113 The outbreak affected 50 per cent of the students at an elementary school and 32 per cent of the family contacts. Symptoms lasted 12 to 24 hr with an apparent incubation period of 48 hr. Of the 604 subjects with symptomatic infections, 85 per cent had nausea, 85 per cent vomiting, 52 per cent abdominal cramps, 44 per cent diarrhea, and 32 per cent fever. There were no deaths, and none of the subjects were hospitalized. Other viruses morphologically similar to, but antigenically distinct from, the Norwalk virus are also etiologic agents of acute, epidemic gastroenteritis ( Vaccine Sequential rotaviral infections in the same subject are usually attributable to different serotypes of rotaviruses. 73, 173,224 These observations are encouraging for vaccine development, since there does appear to be a naturally acquired protection against subsequent reinfection with the homologous serotype of rotavirus. Presently there is no rotavirus vaccine for human use. The prospects and problems associated with developing rotavirus vaccines have recently been reviewed. 36, 114 M uch of the available evidence indicates that local immunity in the gut, such as that associated with secretory IgA, is more important than serum antibody in protecting against rotaviral disease. For this reason a high priority has been placed on the development of an oral, live-type vaccine. Attempts are underway to generate cell culture-adapted, attenuated strains of rotavirus to be tested as candidate vaccines. 1l4 Another approach is to isolate reassortant hybrid rotaviruses from mixed cultures of human and bovine rotaviruses. Although such hybrids have been isolated,84 their pathogenicity and immunogenicity remain to be determined. An attenuated live-type rotavirus vaccine has been used in cattle for many years. 152 A new approach with the bovine vaccine has been to utilize maternal vaccination in order to take advantage of the subsequent transfer of passive immunity to the offspring. 187 There are two major epidemiologic forms of viral gastroenteritis. Rotaviruses cause sporadic, but occasionally epidemic, gastroenteritis, usually occurring during the winter months. This form primarily affects infants and young children, lasts 5 to 8 days, often leads to dehydration, and may require medical attention. The second form of gastroenteritis is more epidemic in nature, usually results in a shorter and milder illness, and occurs throughout the year in older children and adults. A group of 27-nm viruses referred to as the Norwalk-like viruses are responsible for the majority of the outbreaks of the second form. The prototype virus of this group, the Norwalk virus, was discovered in a 1968 outbreak of gastroenteritis in Norwalk, Ohio. 1l3 The outbreak affected 50 per cent of the students at an elementary school and 32 per cent of the family contacts. Symptoms lasted 12 to 24 hr with an apparent incubation period of 48 hr. Of the 604 subjects with symptomatic infections, 85 per cent had nausea, 85 per cent vomiting, 52 per cent abdominal cramps, 44 per cent diarrhea, and 32 per cent fever. There were no deaths, and none of the subjects were hospitalized. Other viruses morphologically similar to, but antigenically distinct from, the Norwalk virus are also etiologic agents of acute, epidemic gastroenteritis ( Because the Norwalk-like viruses are present only at low concentrations in diarrheic feces and since they have not yet been cultured in vitro, the detailed characterization of this group of viruses has not been performed. As yet we know only enough about these viruses to allow for the most tentative classification. The viral particle is round, 27-nm in diameter, and nonenveloped (see Fig. 1 ). The capsomeric substructure has not been clearly visualized. In most electron micrographs the virioN substructure is quite hazy as a result of antibody coating the particles (a consequence of the IEM procedure). The Norwalk viruses remain infectious after exposure to pH 2.7 for 3 hr, 20 per cent ether for 24 hr, or heating at 60°C for 30 min. 56 The density of the virion in CsCI is 1.37 to 1.41 gm per ml. 109 These properties led to tentative classification as a parvoviruslike agent. 109 The paroviruses are single-stranded DNA viruses that multiply in the nucleus of the host cell. Included in the family Parvoviridae are the adeno-associated viruses, which replicate only in cells that are also infected with adenovirus, the Aleutian mink disease virus, and several parvoviruses that cause gastroenteritis in agriculturally important animals. Outbreaks of severe canine gastroenteritis associated with a parvovirus occurred suddenly in many parts of the world in 1978. 65 ,145 However, it is now thought that the Norwalk viruses may not be appropriately described as parvovirus-like. When the proteins of purified Norwalk virus were analyzed by polyacrylamide gel electrophoresis, only one-a 59,000 dalton protein-was detected. 81 For the Norwalk virus to be a parvovirus, three structural proteins should have been observed. However, caliciviruses 1042 BILL BARNETT viruses.·5b. 159. 16.3.21.5 A radioimmunoassay for antibody to the Norwalk virusS. 5 has been used to perform epidemiologic studies which indicate that the Norwalk virus causes about 42 per cent of the epidemics of acute gastroenteritis. llS There are no comparable assays for the other three immunologically distinct serotypes; thus, their epidemiologic significance is not well understood. The high percentage of outbreaks caused by the Norwalk virus indicates that there are probably only a few serotypes responsible for acute gastroenteritis in contrast to the more than 70 serotypes of enteroviruses and the more than 100 different serotypes of rhinoviruses. 21 In studies with volunteers inoculated with the Norwalk, Hawaii, and Montgomery County (MC) viruses,215 all of these viruses induced short-term homologous immunity, and exposure to the Norwalk virus produced partial protection against subsequent challenge with the MC virus. The Hawaii virus did not appear to be serologically related to either the Norwalk or the MC viruses. Because the Norwalk-like viruses are present only at low concentrations in diarrheic feces and since they have not yet been cultured in vitro, the detailed characterization of this group of viruses has not been performed. As yet we know only enough about these viruses to allow for the most tentative classification. The viral particle is round, 27-nm in diameter, and nonenveloped (see Fig. 1 ). The capsomeric substructure has not been clearly visualized. In most electron micrographs the virion substructure is quite hazy as a result of antibody coating the particles (a consequence of the IEM procedure). The Norwalk viruses remain infectious after exposure to pH 2.7 for 3 hr, 20 per cent ether for 24 hr, or heating at 60° C for 30 min. 56 The density of the virion in CsCI is 1.37 to 1.41 gm per ml. 109 These properties led to tentative classification as a parvoviruslike agent. lOg The paroviruses are Single-stranded DNA viruses that multiply in the nucleus of the host cell. Included in the family Parvoviridae are the adeno-associated viruses, which replicate only in cells that are also infected with adenovirus, the Aleutian mink disease virus, and several parvoviruses that cause gastroenteritis in agriculturally important animals. Outbreaks of severe canine gastroenteritis associated with a parvovirus occurred suddenly in many parts of the world in 1978. 65 145 However, it is now thought that the Norwalk viruses may not be appropriately described as parvovirus-like. When the proteins of purified Norwalk virus were analyzed by polyacrylamide gel electrophoresis, only one-a 59,000 dalton protein-was detected. 81 For the Norwalk virus to be a parvovirus, three structural proteins should have been observed. However, caliciviruses have only one structural protein of about 65,000 daltons and share a lTIOrphologic similarity to the Norwalk virus. Caliciviruses are usually somewhat larger, 35 to 40 nlTI, but the fuzziness of most electron micrographs of 'Norwalk virus could account for a mismeasurement of their diameter. Caliciviruses are known to be associated with gastroenteritis in humans. 70, 148, 192 Caliciviruses have single-stranded RNA genomes; thus although final classification of the Norwalk viruses awaits the characterization of their nucleic acids, it is thought that they may be a type of calicivirus. Norwalk viral gastroenteritis is usually milder than the illness caused by rotavirus. Many outbreaks of 24-hr influenza, intestinal influenza, and stomach influenza are actually Norwalk viral infections. In describing 38 Norwalk viral outbreaks, Kaplan et al. point out that only 3 persons required hospitalization.u 5 However, an outbreak of Norwalk viral infection in a nursing home may have been a factor in the deaths of two patients. Norwalk viral gastroenteritis may last from 2 hr to several days, but the illness usually lasts 24 to 48 hr. The incubation period is also 24 to 48 hr. The symptoms include nausea, vomiting, abdominal cramps, diarrhea, fever, headache, and myalgias. Vomiting occurs more frequently in children, and diarrhea is more common in adults. In 6 elementary school outbreaks, 75 per cent of the ill children vomited and 46 per cent passed diarrheic stools in contrast to 4 outbreaks primarily in adults in which vomiting was a symptom in 51 per cent and diarrhea in 85 per cent. U5 In several studies adult volunteers have been challenged with Norwalk-like viruses. 20, 55, 57, 58, 196, 201 Symptoms in adult volunteers who received an oral dose of a 2 per cent stool filtrate of the original Norwalk virus closely resembled those observed in outbreaks. Thirty-three of the 55 volunteers became ill. Symptoms included anorexia in 95 per cent, headache in 84 per cent, diarrhea in 84 per cent, abdominal discomfort in 72 per cent, vomiting in 63 per cent, and fever (;::: 37.4°C) in 50 per cent. 209 Bloody stools are not seen in Norwalk viral infections. Results from small bowel biopsy specin1ens are consistent with the presence or absence of clinical illness. All volunteers who became ill were found to have lesions characteristic of Norwalk viral gastroenteritis, whereas no such lesions were observed in volunteers in whom clinical symptoms developed. 168 Norwalk-associated lesions include abnormal villous absorptive cells with decreased cell height and vacuolation of the cytoplasm and an increased infiltration of the lamina propria and villous epithelium with leukocytes. The epidemiology of Norwalk-like viral infections has been extensively studied. The explosive epidemic nature of these outbreaks tends to overshadow the relatively mild nature of the illness. Outbreaks occur year round in various settings, often associated with a vehicle such as food or water, but person-to-person transmission also plays a major role. It may be that the Norwalk-like viruses are the major cause of epidemic gastroenteritis in the developed countries. Of 74 outbreaks studied by the Centers for Caliciviruses are known to be associated with gastroenteritis in humans. 70, 148, 192 Caliciviruses have single-stranded RNA genomes; thus although final classification of the Norwalk viruses awaits the characterization of their nucleic acids, it is thought that they may be a type of calicivirus. Norwalk viral gastroenteritis is usually milder than the illness caused by rotavirus. Many outbreaks of 24-hr influenza, intestinal influenza, and stomach influenza are actually Norwalk viral infections. In describing 38 Norwalk viral outbreaks, Kaplan et al. point out that only 3 persons required hospitalization. 115 However, an outbreak of Norwalk viral infection in a nursing home may have been a factor in the deaths of two patients. Norwalk viral gastroenteritis may last from 2 hr to several days, but the illness usually lasts 24 to 48 hr. The incubation period is also 24 to 48 hr. The symptoms include nausea, vomiting, abdominal cramps, diarrhea, fever, headache, and myalgias. Vomiting occurs more frequently in children, and diarrhea is more common in adults. In 6 elementary school outbreaks, 75 per cent of the ill children vomited and 46 per cent passed diarrheic stools in contrast to 4 outbreaks primarily in adults in which vomiting was a symptom in 51 per cent and diarrhea in 85 per cent. 115 In several studies adult volunteers have been challenged with Norwalk-like viruses. 2o, 55, 57. 58,196,20) Results from small bowel biopsy specimens are consistent with the presence or absence of clinical illness. All volunteers who became ill were found to have lesions characteristic of Norwalk viral gastroenteritis, whereas no such lesions were observed in volunteers in whom clinical symptoms developed. IGS Norwalk-associated lesions include abnormal villous absorptive cells with decreased cell height and vacuolation of the cytoplasm and an increased infiltration of the lamina propria and villous epithelium with leukocytes. The epidemiology of Norwalk-like viral infections has been extensively studied. The explosive epidemic nature of these outbreaks tends to overshadow the relatively mild nature of the illness. Outbreaks occur year round in various settings, often associated with a vehicle such as food or water, but person-to-person transmission also plays a major role. It may be that the Norwalk-like viruses are the major cause of epidemic gastroenteritis in the developed countries. Of 74 outbreaks studied by the Centers for Disease Control, 42 per cent were caused by Norwalk or serologically related viruses, and the remaining 58 per cent, based on clinical and epidemiologic data, probably were caused by other Norwalk-like, but antigenically distinct, viruses. 115 Many Norwalk viral outbreaks have been associated with contaminated water supplies. There are no satisfactory procedures for detecting these viruses in water; thus coliform counts are often used as indirect evidence for possible contamination with Norwalk-like viruses. Taylor et al. described an outbreak initiated by contaminated water at an elementary school. 198 Illness developed in 72 per cent of the students and teachers. The secondary attack rate was 32 per cent in families of those who had become ill after drinking water at the school. This person-to-person secondary transmission is common for Norwalk viral infections. Several other reports of culinary water-associated outbreaks detail a similar epidemiologic picture. 116, 158, 210 Norwalk viral illness has also followed swimming exposure both in pools and lakes. 13, 118, 127 Food contaminated by Norwalk virus has also served as a vehicle; an Australia-wide outbreak of Norwalk viral gastroenteritis involving several thousand people followed the consumption of contaminated raw oysters. 160 Many other outbreaks have been associated with raw seafood and salad. 5, 86, 87 In some of these outbreaks the illness was initially referred to as food poisoning, when in fact it was the result of a Norwalk viral infection. The efficient person-to-person transmission of Norwalk viral gastroenteritis leads one to suspect a respiratory route of transmission, but this has not been demonstrated and respiratory symptoms are usually not seen in Norwalk viral infections. However, Wilson et al. reported upper respiratory symptoms in 42 per cent of those ill in a Norwalk viral gastroenteritis outbreak at a Pennsylvania summer camp. 210 Outbreaks in institutional settings have been reported. Kaplan et al. described an outbreak in a nursing home in which 46 per cent of the residents and staff experienced diarrhea and vomiting of acute onset. There were no serious sequelae, und none of the subjects required hospitalization. Serologic examination revealed Norwalk or Norwalk-like virus as the etiologic agent. Norwalk virus may play a minor role in the etiology of travelers' diarrhea. A study of adult student travelers in Mexico showed that 5 to 6 per cent of them seroconverted to Norwalk virus. 120 There are no satisfactory routine diagnostic tests for the Norwalk-like viruses. Conventional transmission electron microscopy has the drawbacks of insufficient sensitivity and specificity. The viruses are shed only briefly and in relatively small numbers; thus, it is very difficult to attain the required sensitivity with electron microscopy. In addition, the morphology of the Norwalk viruses is relatively nondistinct; thus, positive identification is usually not possible. Immune electron microscopy (IEM) offers a partial solution to these problems. 58, 113 IEM is more sensitive, and the use of a Norwalk-specific serum allows for positive identification of the viruses. A radioimmunoassay (RIA) for the Norwalk virus and its antibodies has been 1044 BILL BARNETT Disease Control, 42 per cent were caused by Norwalk or serologically related viruses, and the remaining 58 per cent, based on clinical and epidemiologic data, probably were caused by other Norwalk-like, but antigenically distinct, viruses.ll.'i Many Norwalk viral outbreaks have been associated with contaminated water supplies. There are no satisfactory procedures for detecting these viruses in water; thus coliform counts are often used as indirect evidence for possible contamination with Norwalk-like viruses. Taylor et al. described an outbreak initiated by contaminated water at an elementary school. 198 Illness developed in 72 per cent of the students and teachers. The secondary attack rate was 32 per cent in families of those who had become ill after drinking water at the school. This person-to-person secondary transmission is common for Norwalk viral infections. Several other reports of culinary water-associated outbreaks detail a similar epidemiologic picture. 1l6, 158,210 Norwalk viral illness has also followed swimming exposure both in pools and lakes. 13, 118, 127 Food contaminated by Norwalk virus has also served as a vehicle; an Australia-wide outbreak of Norwalk viral gastroenteritis involving several thousand people followed the consumption of contaminated raw oysters. 160 Many other outbreaks have been associated with raw seafood and salad. 5, 86, 87 In some of these outbreaks the illness was initially referred to as food poisoning, when in fact it was the result of a Norwalk viral infection. The efficient person-to-person transmission of Norwalk viral gastroenteritis leads one to suspect a respiratory route of transmission, but this has not been demonstrated and respiratory symptoms are usually not seen in Norwalk viral infections. However, Wilson et al. reported upper respiratory symptoms in 42 per cent of those ill in a Norwalk viral gastroenteritis outbreak at a Pennsylvania summer camp. 2JO Outbreaks in institutional settings have been reported. Kaplan et al. described an outbreak in a nursing home in which 46 per cent of the residents and staff experienced diarrhea and vomiting of acute onset. There were no serious sequelae, und none of the subjects required hospitalization. Serologic examination revealed Norwalk or Norwalk-like virus as the etiologic agent. Norwalk virus may play a minor role in the etiology of travelers' diarrhea. A study of adult student travelers in Mexico showed that 5 to 6 per cent of them seroconverted to Norwalk virus. 120 There are no satisfactory routine diagnostic tests for the Norwalk-like viruses. Conventional transmission electron microscopy has the drawbacks of insufficient sensitivity and specificity. The viruses are shed only briefly and in relatively small numbers; thus, it is very difficult to attain the required sensitivity with electron microscopy. In addition, the morphology of the Norwalk viruses is relatively nondistinct; thus, positive identification is usually not possible. Immune electron microscopy (lE M) offers a partial solution to these problems. 58, 113 IEM is more sensitive, and the use of a Norwalk-specific serum allows for positive identification of the viruses. A radioimmunoassay (RIA) for the Norwalk virus and its antibodies has been a powerful tool for epidemiologic studies. 22, 8, 5 IInmune electron Inicroscopy was used to detect Norwalk viruses in saInples froIn 5 of 27 outbreaks that had been confirn1ed to be caused by Norwalk virus on the basis of seroconversion as deterInined by RIA.1l5 The major problem with RIA is that only a few laboratories in the world have the required antisera and Norwalk virus antigens, which are obtained froIn volunteers who have been challenged with the Norwalk virus. Another problem with RIA is that it does not detect the morphologically similar, but antigenically distinct, Norwalklike viruses. Norwalk viral infections occur on a worldwide basis. Greenberg et al. found that 50 to 80 per cent of adults in both developed and developing countries have serum antibody to Norwalk virus. 82 The age-related distribution of serum antibody to Norwalk virus is very distinct from that for serum antibody to rotavirus. Blacklow et al. used RIA to test sera from 308 residents of Massachusetts and found Norwalk virus antibody in 20 per cent of the infants 0 to 3 months of age (presumably of maternal origin).22 In infants 6 months of age, Norwalk antibody was not detected, and the per cent of children with detectable anti-Norwalk virus antibody remained at 5 per cent through 8 years of age. A sharp rise in the prevalence of Norwalk virus antibody was observed in the adolescent and early adult years. Approximately 50 per cent of those over 20 years of age posses~ed antibody. In the developing countries antibody to the Norwalk virus is acquired much earlier in life. In a longitudinal study of young children in Bangladesh the prevalence of antibody to Norwalk virus was 7 per cent in infants younger than 6 months and increased to 80 per cent in children 2 to 5 years of age. 18 The antigenic relationships among Snow Mountain, Hawaii, and Norwalk viruses were determined by IEM using serum antibody from previously challenged volunteers. 58 Each of the three viruses showed a strong reaction with homologous antibody, but no heterologous reactions were observed. Sera positive for antibody to the Snow Mountain virus did not react with the Marin County virus 163 in the IEM procedure. 58 Previously it had been shown that the Marin County virus does not cross-react with the Norwalk or Hawaii viruses .163 Thus, the Norwalk, Marin County, Hawaii, and Snow Mountain viruses appear to represent four antigenically distinct serotypes of morphologically indistinguishable Norwalk-like viruses. There are several other viruses in this group that remain to be serotyped. In vivo cross-challenge studies in volunteers showed that the Norwalk virus and Montgomery County virus are serologically related, whereas there was no heterologous cross-protection between the Hawaii virus and the Norwalk virus. 215 The subject of clinical immunity to Norwalk viral infection is very puzzling. In about 50 per cent of the volunteers inoculated with Norwalk virus, gastroenteritis and an antibody response to the infection developed. 201 However, the susceptibility does not appear to hold to the classic picture of antibody-mediated immunity. There is a short-term immunity to Norwalk infection-when previously ill volunteers were rechallenged 4 VIRAL GASTHOENTElUTIS a powerful tool for epidemiologic studies. 22 , 8.5 Immune electron microscopy was used to detect Norwalk viruses in samples from 5 of 27 outbreaks that had been confirmed to be caused by Norwalk virus on the basis of seroconversion as determined by RIA.1l5 The major problem with RIA is that only a few laboratories in the world have the required antisera and Norwalk virus antigens, which are obtained from volunteers who have been challenged with the Norwalk virus. Another problem with RIA is that it does not detect the morphologically similar, but antigenically distinct, Norwalklike viruses. Norwalk viral infections occur on a worldwide basis. Greenberg et al. found that 50 to 80 per cent of adults in both developed and developing countries have serum antibody to Norwalk virus. 82 The age-related distribution of serum antibody to Norwalk virus is very distinct from that for serum antibody to rotavirus. Blacklow et al. used RIA to test sera from 308 residents of Massachusetts and found Norwalk virus antibody in 20 per cent of the infants 0 to 3 months of age (presumably of maternal origin). 22 In infants 6 months of age, Norwalk antibody was not detected, and the per cent of children with detectable anti-Norwalk virus antibody remained at 5 per cent through 8 years of age. A sharp rise in the prevalence of Norwalk virus antibody was observed in the adolescent and early adult years. Approximately 50 per cent of those over 20 years of age possessed antibody. In the developing countries antibody to the Norwalk virus is acquired much earlier in life. In a longitudinal study of young children in Bangladesh the prevalence of antibody to Norwalk virus was 7 per cent in infants younger than 6 months and increased to 80 per cent in children 2 to 5 years of age. IS The antigenic relationships among Snow Mountain, Hawaii, and Norwalk viruses were determined by IEM using serum antibody from previously challenged volunteers.58 Each of the three viruses showed a strong reaction with homologous antibody, but no heterologous reactions were observed. Sera positive for antibody to the Snow Mountain virus did not react with the Marin County virus l63 in the IEM procedure. 58 Previously it had been shown that the Marin County virus does not cross-react with the Norwalk or Hawaii viruses. 163 Thus, the Norwalk, Marin County, Hawaii, and Snow Mountain viruses appear to represent four antigenically distinct serotypes of morphologically indistinguishable Norwalk-like viruses. There are several other viruses in this group that remain to be serotyped. In vivo cross-challenge studies in volunteers showed that the Norwalk virus and Montgomery County virus are serologically related, whereas there was no heterologous cross-protection between the Hawaii virus and the Norwalk virus. 215 The subject of clinical immunity to Norwalk viral infection is very puzzling. In about 50 per cent of the volunteers inoculated with Norwalk virus, gastroenteritis and an antibody response to the infection developed. 20l However, the susceptibility does not appear to hold to the classic picture of antibody-mediated immunity. There is a short-term immunity to Norwalk infection-when previously ill volunteers were rechallenged 4 to 14 weeks after the initial illness, they remained well. 20, 23, 168 However, volunteers who previously became ill when inoculated with Norwalk virus again became ill when rechallenged after 27 months, even though they often possessed high serum-or duodenal fluid-antibody titers to Norwalk virus. 52, 168 The volunteers who did not become ill usually had no or a very low antibody titer to Norwalk virus both before and after challenge. On rechallenge 27 to 42 months later, the same volunteers who became ill the first time became ill again, and those in whom gastroenteritis did not develop on initial challenge again remained symptom-free. Factors other than antibody appear to be important in susceptibility to Norwalk viral infection. Antibody may play a role in short-term immunity, but long-term immunity appears to be independent of antibody. 168 In the case of either serum antibody or local jejunal antibody to Norwalk virus, those individuals with antibody are much more likely to be susceptible than those with little or no antibody. Susceptibility may be determined by factors such as the presence or absence of viral receptors, in which case antibody is just an indication of past infection and therefore indicates susceptibility. The paradoxical relationship of antibody to susceptibility and the lack of demonstrated long-term imn1unity do not forecast much hope for the development of a vaccine to prevent Norwalk viral infections. Rotaviruses and Norwalk-like viruses appear to be the major etiologic agents for the two primary epidemiologic forms of acute viral gastroenteritis. However, there are several other candidate viruses. Other than rotaviruses, adenoviruses are the most frequently observed viruses in stools from children with gastroenteritis. Many groups have observed fastidious adenoviruses on electron micrographs (see Fig. 1 ) in diarrheic fecal specimens. 66 , 76,100,155,208,221 Unlike other adenoviruses that are easy to cultivate and type, these enteric-type (ET) adenoviruses have tesisted propagation in cell culture. It was found recently that the ET adenoviruses possess a distinct set of antigenic determinants that can be detected by ELISA.lOo, 221 Furthermore, these ET adenoviruses produce a characteristic cytopathic effect in a line of human embryonic kidney cells transformed by adenovirus type 5 (293 cells), but not in nontransformed human embryonic kidney cells. 195, 221 Fecal adenoviruses that are readily cultivatable by standard techniques are found with about the same frequency in subjects with or without gastroenteritis.I°2, 221 However, the fastidious ET adenoviruses are highly associated with gastroenteritis in children. 138 , 221 Yolken et al. examined the feces of 99 infants between the ages of 4 and 25 months while they were inpatients at a Baltimore area hospital. 221 Twenty-seven had an episode of diarrhea during the study, and ET adenovirus was identified in the stools of 52 per cent of the children with diarrhea. ET adenovirus was found in only one of 72 (1.4 per cent) children without diarrhea. The ET adenovirus-associated illnesses lasted 1046 BILL BARNETT to 14 weeks after the initial illness, they remained welJ.20, 21, 16R However, volunteers who previously became ill when inoculated with Norwalk virus again became ill when rechallenged after 27 months, even though they often possessed high serum-or duodenal fluid-antibody titers to Norwalk virus,·52, 16~ The volunteers who did not become ill usually had no or a very low antibody titer to Norwalk virus both before and after challenge, On re challenge 27 to 42 months later, the same volunteers who became ill the first time became ill again, and those in whom gastroenteritis did not develop on initial challenge again remained symptom-free, Factors other than antibody appear to be important in susceptibility to Norwalk viral infection. Antibody may play a role in short-term immunity, but long-term immunity appears to be independent of antibody. 168 In the case of either serum antibody or local jejunal antibody to Norwalk virus, those individuals with antibody are much more likely to be susceptible than those with little or no antibody. Susceptibility may be determined by factors such as the presence or absence of viral receptors, in which case antibody is just an indication of past infection and therefore indicates susceptibility. The paradoxical relationship of antibody to susceptibility and the lack of demonstrated long-term immunity do not forecast much hope for the development of a vaccine to prevent Norwalk viral infections. Rotaviruses and Norwalk-like viruses appear to be the major etiologic agents for the two primary epidemiologic forms of acute viral gastroenteritis. However, there are several other candidate viruses. Other than rotaviruses, adenoviruses are the most frequently observed viruses in stools from children with gastroenteritis. Many groups have observed fastidious adenoviruses on electron micrographs (see Fig. 1 ) in diarrheic fecal specimens. 66, 76, lOO, 155, 208, 221 Unlike other adenoviruses that are easy to cultivate and type, these enteric-type (ET) adenoviruses have tesisted propagation in cell culture. It was found recently that the ET adenoviruses possess a distinct set of antigenic determinants that can be detected by ELISA.lOo, 221 Furthermore, these ET adenoviruses produce a characteristic cytopathic effect in a line of human embryonic kidney cells transformed by adenovirus type 5 (293 cells), but not in nontransformed human embryonic kidney cells. 195, 221 Fecal adenoviruses that are readily cultivatable by standard techniques are found with about the same frequency in subjects with or without gastroenteritis. 102, 221 However, the fastidious ET adenoviruses are highly associated with gastroenteritis in children.l.38, 221 Yolken et al. examined the feces of 99 infants between the ages of 4 and 25 months while they were inpatients at a Baltimore area hospital. 221 Twenty-seven had an episode of diarrhea during the study, and ET adenovirus was identified in the stools of 52 per cent of the children with diarrhea. ET adenovirus was found in only one of 72 (1.4 per cent) children without diarrhea. The ET adenovirus-associated illnesses lasted for a mean of 8.0 days, and the children passed a mean maximum of 8.5 stools per day. Other symptoms were upper respiratory (93 per cent), with. 43 per cent having signs of pneumonia, fever (93 per cent), and vomiting (79 per cent). The epidemiology of ET adenovirus-associated gastroenteritis is not well defined. It remains to be established whether the 52 per cent association with cases of infantile gastroenteritis in the reported study is indicative of the prevalence of ET adenovirus-associated gastroenteritis. 221 Astroviruses Astroviruses are 28 to 30 nm in diameter with a very characteristic 5-or 6-pointed star-shaped surface structure (see Fig. 1 ). 39 Astroviruses have not been cultivated in vitro and their nucleic acid type is unknown; they therefore have not been classified. Several outbreaks of gastroenteritis in children, infants, and adults have been associated with astroviruses. 6 , 125, 130, 136 Studies in volunteers indicate that astroviruses are transmissible but have a low pathogenicity in adults. 129 Clinical symptoms of astroviral infection in a gastroenteritis outbreak in a kindergarten in Japan (attack rate 52.3 per cent) were vomiting (64 per cent), abdominal pain (49 per cent), diarrhea (30 per cent), and fever higher than 37.5°C (30 per cent). The disease was self-limiting, the symptoms lasted an average of 12 hours, and only one of the 46 ill subjects required medical care. 125 Astroviruses are excreted in large nurnbers and are readily detected by electron microscopy. Identification is silnplified as a result of their very characteristic morphology. IEM, using paired acute and convalescent sera and feces rich in viral particles, is useful for establishing etiology.122, 125 However, the star-like morphology is obscured in IEM when the viruses are coated by specific antibody.6 Astroviral antibody may be detected using indirect fluorescence and infected primary human embryo kidney cultures. 128 Most children (70 per cent) acquire astroviral antibody by 5 years of age. 128 Enteroviruses do not appear to play a major epidemiologic role in gastroenteritis, but enteroviral disease is frequently severe in infants. 39, 131, 157 Meningitis, polio-like paralytic disease, and severe systemic disease are associated with enteroviral infections. 39, 119, 131, 157 These infections are more prevalent in the summer months. The incidence is 10 or more times greater in infants than it is in school-aged children, and nearly 100 times greater than in adults. 157 Coronaviruses have been detected in the feces of persons with gastroenteritis. 45 The very distinctive morphology of coronaviruses makes them easy to identify. They are enveloped, about 100 nm in diameter, and possess characteristic club-shaped projections surrounding the virus like a halo or crown, hence the name (see Fig. 1 ). Coronaviruses are found frequently in feces from asymptomatic adults; thus, their relation to gastroenteritis is uncertain. 45 These RNA-containing viruses are associated with 5 to 10 per cent of the upper and lower respiratory tract infections in man. for a mean of 8.0 days, and the children passed a mean maximum of 8 .. 5 stools per day. Other symptoms were upper respiratory (93 per cent), with 43 per cent having signs of pneumonia, fever (93 per cent), and vomiting (79 per cent). The epidemiology of ET adenovirus-associated gastroenteritis is not well defined. It remains to be established whether the 52 per cent association with cases of infantile gastroenteritis in the reported study is indicative of the prevalence of ET adenovirus-associated gastroenteritis. 221 Astroviruses Astroviruses are 28 to 30 nm in diameter with a very characteristic 5-or 6-pointed star-shaped surface structure (see Fig. 1 ). 39 Astroviruses have not been cultivated in vitro and their nucleic acid type is unknown; they therefore have not been classified. Several outbreaks of gastroenteritis in children, infants, and adults have been associated with astroviruses. 6 . 125. 130. 136 Studies in volunteers indicate that astroviruses are transmissible but have a low pathogenicity in adults. 129 Clinical symptoms of astroviral infection in a gastroenteritis outbreak in a kindergarten in Japan (attack rate 52.3 per cent) were vomiting (64 per cent), abdominal pain (49 per cent), diarrhea (30 per cent), and fever higher than 37.5° C (30 per cent). The disease was self-limiting, the symptoms lasted an average of 12 hours, and only one of the 46 ill subjects required medical care. 125 Astroviruses are excreted in large numbers and are readily detected by electron microscopy. Identification is simplified as a result of their very characteristic morphology. IEM, using paired acute and convalescent sera and feces rich in viral particles, is useful for establishing etiology.122, 125 However, the star-like morphology is obscured in IEM when the viruses arc coated by specific antibody. (i Astroviral antibody may be detected using indirect fluorescence and infected primary human embryo kidney cultures. 128 Most children (70 per cent) acquire astroviral antibody by 5 years of age. 128 Enteroviruses do not appear to play a major epidemiologic role in gastroenteritis, but enteroviral disease is frequently severe in infants. 39, 13L 157 YIeningitis, polio-like paralytic disease, and severe systemic disease are associated with enteroviral infections. 39, 119, 131, 157 These infections are more prevalent in the summer months. The incidence is 10 or more times greater in infants than it is in school-aged children, and nearly 100 times greater than in adults. 157 Coronaviruses have been detected in the feces of persons with gastroenteritis. 45 The very distinctive morphology of coronaviruses makes them easy to identify. They are enveloped, about 100 nm in diameter, and possess characteristic club-shaped projections surrounding the virus like a halo or crown, hence the name (see Fig, 1 ). Coronaviruses are found frequently in feces from asymptomatic adults; thus, their relation to gastroenteritis is uncertain. 45 These RNA-containing viruses are associated with 5 to 10 per cent of the upper and lower respiratory tract infections in man. Caliciviruses are recognizable by the characteristic cup-like depressions on their surface that give the impression of a 6-or 10-pointed star 135 and because of their size (31 nm to 40 nIn in diameter) (see Fig. 1 ). Caliciviruses have been associated with several well-defined outbreaks of gastroenteritis primarily in infants and children. 38, 48, 69, 137, 148, 192 The symptoms associated with the reported outbreaks were nausea, vomiting, and diarrhea, Rising antibody titers were measured by IEM . 148 Most cases of viral gastroenteritis are self-limiting and only rarely require medical attention. However, in severe cases, especially in the very young or the debilitated, prompt therapy is necessary. In an analysis of 21 fatal cases of rotaviral gastroenteritis, the primary characteristic was profound dehydration. These children were 10 to 20 per cent dehydrated at the time of death. 35 Some of these children were examined for signs of dehydration in the morning, but rapidly dehydrated through the day and succumbed by evening. Thus, the primary therapy is to maintain the proper state of hydration. Acute diarrhea may be caused by any of several bacterial, protozoan, or viral agents, yet the physiologic effects are quite similar. These include (1) dehydration, electrolyte deficiency, and acidosis; and (2) anorexia and possibly vomiting, which reduces nutrient intake. 175 Acute viral diarrhea is self-limiting and c~n be effectively treated by rehydration therapy. In the majority of cases, oral rehydration therapy is quite satisfactory and has several advantages over intravenous rehydration therapy. Black has recently examined the subject of rehydration therapy and included a list of criteria for assessing the level of dehydration as well as listing accompanying recommendations for therapy. 16 The World Health Organization (WHO) is promoting the widespread use of oral rehydration therapy as a part of their commitment to primary health care. 214 The oral rehydration solution recommended by the WHO can be prepared by adding the following to one liter of water: sodium chloride, 3.5 gm; sodium bicarbonate, 2.5 gm; potassium chloride, 1.5 gm; and. glucose, 20 gm. 213 This solution has been used extensively for treatment of enterotoxin-mediated diarrhea and rotaviral diarrhea. 199 Black has discussed this formulation and recommendations for its use. 16 The WHO formulation calls for glucose, but some studies have compared glucose to sucrose as the carbohydrate source. The advantage of sucrose is its lower cost and greater availability. Several groups have reported comparable clinical results when comparing sucrose-containing solutions to glucose-containing solutions. 175 Glucose was slightly superior to sucrose in 1048 BILL BAHNETT Caliciviruses Caliciviruses are recognizable by the characteristic cup-like depressions on their surface that give the impression of a 6or IO-pointed star135 and because of their size (31 nm to 40 nm in diameter) (see Fig. 1 ). Caliciviruses have been associated with several well-defined outbreaks of gastroenteritis primarily in infants and children. 38 48.69. l.37, 148. 192 The symptoms associated with the reported outbreaks were nausea, vomiting, and diarrhea. Rising antibody titers were measured by IEM .148 Caliciviruses spread readily, and nosocomial outbreaks have been reported. 192 The roles of several other ill-defined fastidious viral agents such as the minirotavirus,192 minireoviruses,155 and the Otofuke agentl 96 remain speculative. Most cases of viral gastroenteritis are self-limiting and only rarely require medical attention. However, in severe cases, especially in the very young or the debilitated, prompt therapy is necessary. In an analysis of 21 fatal cases of rotaviral gastroenteritis, the primary characteristic was profound dehydration. These children were 10 to 20 per cent dehydrated at the time of death. 35 Some of these children were examined for signs of dehydration in the morning, but rapidly dehydrated through the day and succumbed by evening. Thus, the primary therapy is to maintain the proper state of hydration. Acute diarrhea may be caused by any of several bacterial, protozoan, or viral agents, yet the physiologic effects are quite similar. These include (1) dehydration, electrolyte deficiency, and acidosis; and (2) anorexia and possibly vomiting, which reduces nutrient intake. l75 Acute viral diarrhea is self-limiting and can be effectively treated by rehydration therapy. In the majority of cases, oral rehydration therapy is quite satisfactory and has several advantages over intravenous rehydration therapy. Black has recently examined the subject of rehydration therapy and included a list of criteria for assessing the level of dehydration as well as listing accompanying recommendations for therapy. 16 The World Health Organization (WHO) is promoting the widespread use of oral rehydration therapy as a part of their commitment to primary health care. 214 The oral rehydration solution recommended by the WHO can be prepared by adding the following to one liter of water: sodium chloride, 3.5 gm; sodium bicarbonate, 2.5 gm; potassium chloride, 1.5 gm; and glucose, 20 gm. 213 This solution has been used extensively for treatment of enterotoxin-mediated diarrhea and rotaviral diarrhea. 199 Black has discussed this formulation and recommendations for its use. 16 The WHO formulation calls for glucose, but some studies have compared glucose to sucrose as the carbohydrate source. The advantage of sucrose is its lower cost and greater availability. Several groups have reported comparable clinical results when comparing sucrose-containing solutions to glucose-containing solutions. 175 Glucose was slightly superior to sucrose in a double-blind trial with rotavirus-associated diarrhea in children. 19 Oral rehydration solutions utilizing inexpensive, commonly available ingredients have been described. 75, 132 Antidiarrheal agents including kaolin-containing adsorbent preparations, pectin suspensions, and intestinal paralytic drugs were of little value in treating acute diarrhea in children. 16, 169 Bismuth subsalicylate (Pepto-Bismol) is somewhat effective in treating travelers' diarrhea. 59 Rotaviruses and Norwalk-like viruses are the two major groups of viruses associated with gastroenteritis. Rotaviral infections are seasonal, occurring mainly in the winter months, and are the major cause of viral gastroenteritis in infants and children. Rotaviral gastroenteritis may lead to severe dehydration. Norwalk-like viruses are a major cause of explosive outbreaks of acute gastroenteritis in older children and adults. These outbreaks are frequently associated with a vehicle such as culinary water, raw vegetables, or raw seafood. Long-term resistance to Norwalk-like viral infections appears to be mediated by non-antibody factors. Several other viral agents have been associated with acute gastroenteritis. The enterictype adenoviruses may prove to be a third major group of gastroenteritis viruses. The gastroenteritis viruses are generally fastidious, and thus traditional cell culture isolation and detection procedures are not applicable. Electron microscopy and immune electron microscopy remain among the most powerful techniques for studying these viruses. As viral antigens and antisera become more readily available, more suitable techniques such as ELISA and RIA will be widely available for specific diagnoses of viral gastroenteritis. The in vitro cultivation of these viral agents will facilitate the development of diagnostic reagents and the development and evaluation of vaccines. The author wishes to thank Dr. Lyndon S. Oshiro, California State Health Laboratory, Berkeley, California, and Dr. C. R. Madeley, University of Newcastle-Upon-Tyne, United Kingdom, for contributing the electron micrographs used in Figure 1 and for their helpful comments concerning the use of electron microscopy. a double-blind trial with rotavirus-associated diarrhea in children. 19 Oral rehydration solutions utilizing inexpensive, commonly available ingredients have been described. i5, 132 Antidiarrheal agents including kaolin-containing adsorbent preparations, pectin suspensions, and intestinal paralytic drugs were of little value in treating acute diarrhea in children. 16, 169 Bismuth subsalicylate (Pepto-Bismol) is somewhat effective in treating travelers' diarrhea. 59 Rotaviruses and Norwalk-like viruses are the two major groups of viruses associated with gastroenteritis. Rotaviral infections are seasonal, occurring mainly in the winter months, and are the major cause of viral gastroenteritis in infants and children. Rotaviral gastroenteritis may lead to severe dehydration. Norwalk-like viruses are a major cause of explosive outbreaks of acute gastroenteritis in older children and adults. These outbreaks are frequently associated with a vehicle such as culinary water, raw vegetables, or raw seafood. Long-term resistance to Norwalk-like viral infections appears to be mediated by non-antibody factors. Several other viral agents have been associated with acute gastroenteritis. The enterictype adenoviruses may prove to be a third major group of gastroenteritis viruses. The gastroenteritis viruses are generally fastidious, and thus traditional cell culture isolation and detection procedures are not applicable. Electron microscopy and immune electron microscopy remain among the most powerful techniques for studying these viruses. As viral antigens and antisera become more readily available, more suitable techniques such as ELISA and RIA will be widely available for specific diagnoses of viral gastroenteritis. The in vitro cultivation of these viral agents will facilitate the development of diagnostic reagents and the development and evaluation of vaccines. The author wishes to thank Dr. Lyndon S. Oshiro, California State Health Laboratory, Berkcley, California, and Dr. C. R. Madeley, University of Newcastle-Upon-Tyne, United Kingdom, for contributing the electron micrographs used in Figure 1 and for their helpful comments concerning the use of electron microscopy. Rotaviruses and acute gastroenteritis of infants and children The morphology of virus antibody interaction Rotaviruses and acute gastroenteritis of infants and children The morphology of virus antibody interaction The effect of trypsin on the growth of rotavirus Virus-like particles in winter vomiting disease A possible virus aetiology in outbreaks of food-poisoning from cockles Astrovirus-associated gastroenteritis in children Rotavirus viral RNA electrophoresis in hospitalized infants with diarrhea in Rotavirus isolation and cultivation in the presence of trypsin Rotaviral infections in human neonates Characteristics of neonatal calf diarrhea virus ribonucleic acid Effects of enzymes on rotavirus infectivity Immunofluorescent cell assay of neonatal calf diarrhea virus Norwalk gastrointestinal illness: An outbreak associated with swimming in a recreational lake and secondary personto-person transmission Rotavirus serotypes by serum neutralization Virus particles in epithelial cells of duodenal mucosa from children with acute non-bacterial gastroenteritis The prophylaxis and therapy of secretory diarrhea Longitudinal studies of infectious diseases and physical growth of children in rural Bangladesh. 11. Incidence of diarrhea and association with known pathogens Acquisition of serUln antibody to Norwalk virus and rotavirus and relation to diarrhea in a longitudinal study of young children in rural Bangladesh Glucose vs. sucrose in oral rehydration solutions for infants' and young children with rotavirus-associated diarrhea Viral gastroenteritis Norwalk virus: A major cause of epidenlic gastroenteritis Inlmune response and prevalence of antibody to Norwalk enteritis virus as determined by radioimmunoassay Acute infectious gastroenteritis: Etiology and pathogenesis Serological studies with reoviruslike enteritis agent Rotavirus as a cause of diarrhea in pigs Porcinepararotavirus: Detection, differentiation from rotavirus, and pathogenesis in gnotobiotic pigs Rotavirus in travelers' diarrhea: Study of an adult student population in Mexico Rotavirus gastroenteritis and weather Comparative epidemiology of two rotavirus serotypes and other viral agents associated with pediatric gastroenteritis The effect of trypsin on the growth of rotavirus Virus-like particles in winter vomiting disease A possible virus aetiology in outbreaks offood-poisoning from cockles Astrovirus-associated gastroenteritis in children Rotavirus viral RNA electrophoresis in hospitalized infants with diarrhea in Rotavirus isolation and cultivation in the presence of trypsin Rotaviral infections in human neonates Characteristics of neonatal calf diarrhea virus ribonucleic acid Effects of enzymes on rotavirus infectivity Immunofluorescent cell assay of neonatal calf diarrhea virus Norwalk gastrointestinal illness: An outbreak associated with swimming in a recreational lake and secondary personto-person transmission Rotavirus serotypes by serum neutralization Virus particles in epithelial cells of duodenal mucosa from children with acute non-bacterial gastroenteritis The prophylaxis and therapy of secretory diarrhea Longitudinal studies of infectious diseases and physical growth of children in rural Bangladesh. 11. Incidence of diarrhea and association with known pathogens Acquisition of serum antibody to N orwalk virus and rotavirus and relation to diarrhea in a longitudinal study of young children in rural Bangladesh Glucose vs. sucrose in oral rehydration solutions for infants and young children with rotavirus-associated diarrhea Viral gastroenteritis Norwalk virus: A major cause of epidemic gastroenteritis Immune response and prevalence of antibody to Norwalk enteritis virus as determined by radioimmunoassay Acute infectious gastroenteritis: Etiology and pathogenesis Serological studies with reoviruslike enteritis agent Rotavirus as a cause of diarrhea in pigs Porcine pararotavirus: Detection, differentiation from rotavirus, and pathogenesis in gnotobiotic pigs Rotavirus in travelers' diarrhea: Study of an adult student population in Mexico Rotavirus gastroenteritis and wE'athE'r Comparative epidemiology of two rotavirus serotypes and other viral agents associated with pediatric gastroenteritis Characterization of an antigenically distinct porcine rotavirus Neonatal calf diarrhoea: Identification of a reoviruslike (rotavirus) agent in faeces by immunofluorescence and immune electron microscopy Diagnosis of rotavirus infection by cell culture New virus associated with diarrhoea in neonates Noncultivatable viruses and neonatal diarrhea: Fifteen-month survey in a newborn special care nursery Fatal rotavirus gastroenteritis: An analysis of 21 cases Immunization of infants and young children against rotaviral gastroenteritis-prospects and problems An outbreak of acute gastroenteritis due to rotavirus in an infant home Fecal shedding of virus in relation to the days of illness in infantile gastroenteritis due to calicivirus Enterovirus 71 infection: Report of an outbreak with two cases of paralysis and a review of the literature Parvovirus gastroenteritis-A new entity for Australia Asymptomatic endemic rotavirus infections in the newborn Production of high-titer bovine rotavirus with trypsin Trypsin enhancement of rotavirus infectivity: Mechanism of enhancement Role of two particle types in bovine rotavirus morphogenesis The human enteric coronaviruses A virus from epidemic vomiting disease An outbreak of rotavirus infection in a long-stay ward of a geriatric hospital Winter vomiting disease caused by calicivirus Simplified radioimmunoassay for detection of human rotavirus in stools Secretory IgA antibody to rotavirus in human milk 6--9 months postpartum Persistence of antibodies to rotavirus in human nlilk Immunoglobulin M response to the Norwalk virus of gastroenteritis Importance of a new virus in acute sporadic enteritis in children A clinical study of rotavirus gastroenteritis Transmission of acute infectious nonbacterial gastroenteritis to volunteers by oral adlninistration of stool infiltrate Biological properties of Norwalk agent of acute infectious nonbacterial gastroenteritis Characterization of an antigenically distinct porcine rotavirus Neonatal calf diarrhoea: Identification of a reoviruslike (rotavirus) agent in faeces by immunofluorescence and immune electron microscopy Diagnosis of rotavirus infection by cell culture New virus associated with diarrhoea in neonates Noncultivatable viruses and neonatal diarrhea: Fifteen-month survey in a newborn special care nursery Fatal rotavirus gastroenteritis: An analysis of 21 cases Immunization of infants and young children against rotaviral gastroenteritis-prospects and problems An outbreak of acute gastroenteritis due to rotavirus in an infant home Fecal shedding of virus in relation to the days of illness in infantile gastroenteritis due to calicivirus Enterovirus 71 infection: Report of an outbreak with two cases of paralysis and a review of the literature Parvovirus gastroenteritis-A new entity for Australia Asymptomatic endemic rotavirus infections in the newborn Production of high-titer bovine rotavirus with trypsin Trypsin enhancement of rota virus infectivity: Mechanism of enhancement Role of two particle types in bovine rotavirus morphogenesis The human enteric coronaviruses A virus from epidemic vomiting disease An outbreak of rotavirus infection in a long-stay ward of a geriatric hospital Winter vomiting disease caused by calicivirus Simplified radioimmunoassay for detection of human rotavirus in stools Secretory IgA antibody to rotavirus in human milk 6-9 months postpartum Persistence of antibodies to rotavirus in human milk Immunoglobulin M response to the Norwalk virus of gastroenteritis Importance of a new virus in acute sporadic enteritis in children A clinical study of rotavirus gastroenteritis Transmission of acute infectious nonbacterial gastroenteritis to volunteers by oral administration of stool infiltrate Viral gastroenteritis induced by the Hawaii agent Detection by in1lnune electron microscopy of the Snow Mountain agent of acute viral gastroenteritis Syn1ptomatic treatn1ent of diarrhea with bismuth subsalicylate among students attending a Mexican university Travelers' diarrhea among D.S. Army troops in South Korea Separation and infectivity of two particle types of human rotavirus Identification of rotaviruses of different origins by the plaque-reduction test Proteolytic enhancen1ent of rotavirus infectivity: Molecular mechanisms Heterogeneity in the structural glycoprotein (VP7) of simian rotavirus SAIL Virology Parvovirus infection in dogs Diagnosis of enteritis virus Virus particles in gastroenteritis. Lancet Viruses from acute gastroenteritis of children and newborn calves Calicivirus in man. Lancet, 1 :197 Calicivirus in man Diagnostic electron microscopy of faeces. 11. Acute gastroenteritis associated with reovirus-like particles The rotaviruses Recurrent rotavirus gastroenteritis. Lancet Gastroenteritis due to rotavirus in an isolated Pacific island group: An epidemic of 3,439 cases Recent developments in diarrheal diseases Characteristics of n0ncultivatable adenoviruses associated with diarrhea in infants: A new subgroup of human adenoviruses Antigenic relationships among some anin1al rotaviruses: Virus neutralization in vitro and cross-protection in piglets Proteolytic enhancement of rotavirus infectivity: Biological mechanisms Rapid diagnosis of rotavirus infections: Comparison of electron microscopy and immunoelectro-osmophoresis for the detection of rotavirus in human infantile gastroenteritis Serological analysis of the subgroup protein of rotavirus, using monoclonal antibodies Proteins of Norwalk virus Prevalence of antibody to the Norwalk virus in various countries New insights in viral gastroenteritis Rescue and serotypic characterization of noncultivatable human rotavirus by gene reassortment Viral gastroenteritis induced by the Hawaii agent Detection lJY immune electron microscopy of the Snow Mountain agent of acute viral gastroenteritis Symptomatic treatment of diarrhea with bismuth sub salicylate among students attending a Mexican university Travelers' diarrhea among V.S. Army troops in South Korea Separation and infectivity of two particle types of human rotavirus Identification of rotaviruses of different origins by the plaque-reduction test Proteolytic enhancement of rotavirus infectivity: Molecular mechanisms Heterogeneity in the structural glycoprotein (VP7) of simian rotavirus SAIl. Virology Parvovirus infection in dogs Diagnosis of enteritis virus Virus particles in gastroenteritis. Lancet Viruses from acute gastroenteritis of children and newborn calves Calicivirus in man. Lancet, 1:197 Calicivirus in man Diagnostic electron microscopy of faeces. n. Acute gastroenteritis associated with reovirus-like particles The rotaviruses Recurrent rotavirus gastroenteritis. Lancet, 1 :983 Gastroenteritis due to rotavirus in an isolated Pacific island group: An epidemic 01'3,439 cases Recent developments in diarrheal diseases Characteristics of noncultivatable adenoviruses associated with diarrhea in infants: A new subgroup of human adenoviruses Antigenic relationships among some animal rotaviruses: Virus neutralization in vitro and cross-protection in piglets Proteolytic enhancement of rotavirus infectivity: Biological mechanisms Rapid diagnosis of rota virus infections: Comparison of electron microscopy and immunoelectro-osmophoresis for the detection of rotavirus in human infantile gastroenteritis Serological analysis of the subgroup protein of rotavirus, using monoclonal antibodies Proteins of Norwalk virus Prevalence of antibody to the Norwalk virus in various countries New in sights in viral gastroenteritis Hescue and serotypic characterization of non cultivatable human rotavirus by gene reassortment Solid phase microtiter radioilll-111unoassay for detection of the Norwalk strain of acute nonbacterial epidemic gastroenteritis virus and its antibodies Norwalk virus gastroenteritis following raw oyster consun1ption A prospective study of rotavirus infection in infants and young children An epidemic of rotavirus-associated gastroenteritis in a nursing home for the elderly. Scand Recent developments in viral gastroenteritis Breast milk and defense against infection in the newborn Acute gastroenteritis among schoolchildren associated with reovirus-like agent Rapid diagnosis of rotavirus infection by direct detection of viral nucleic acid in silver-stained polyacrylamide gels Comparison of human rotavirus disease in tropical and temperate settings Is lactase the receptor and uncoating enzyme for infantile enteritis (rota) viruses? Infantile enteritis viruses: Morphogenesis and morphology An outbreak of rotavirus infection among adults in a cardiology ward Anti-rotavirus antibody in human colostrum Direct identification of enteric adenovirus, a candidate new serotype, associated with infantile gastroenteritis Etiology of acute gastroenteritis in children in Israel: Role of human reoviruslike agent and bacterial pathogens Diarrhea and vomiting in infancy and childhood Identification of the rotaviral gene that codes for hemagglutination and protease-enhanced plaque formation Differentiation of human and calf reovirus-like agents associated with diarrhea using polyacrylamide gel electrophoresis of RNA Genes of human (strain Wa) and bovine (strain UK) rotaviruses that code for neutralization and subgroup antigens A microtiter solid phase radioimmunoassay for detection of the human reovirus-like agent in stools Antigenic relationships among five reovirus-like (RVL) agents by complement fixation (CF) and development of new substitute CF antigens for the human RVL agent of infantile gastroenteritis (39434) New complement-fixation test for the human reovirus-like virus agent of infantile gastroenteritis. Nebraska calf diarrhea virus used as antigen Density in CsCl of the 27-nm "8FIIa" particle associated with acute infectious nonbacterial gastroenteritis: Determination by VIRAL GASTROENTElUTIS 1053 Solid phase microtiter radioimmunoassay for detection of the Norwalk strain of acute nonhacterial epidemic gastroenteritis virus and its antibodies Foodborne Norwalkvirus Norwalk virus gastroenteritis following raw oyster consumption A prospective study of rotavirus infection in infants and young children An epidemic of rotavirus-associated gastroenteritis in a nursing home for the elderly. Scand Recent developments in viral gastroenteritis Breast milk and defense against infection in the newborn Acute gastroenteritis among schoolchildren associated with reovirus-like agent Rapid diagnosis of rotavirus infection by direct detection of viral nucleic acid in silver-stained polyacrylamide gels Comparison of human rotavirus disease in tropical and temperate settings Is lactase the receptor and uncoating enzyme for infantile enteritis (rota) viruses? Infantile enteritis viruses: Morphogenesis and morphology An outbreak of rotavirus infection among adults in a cardiology ward Anti-rotavirus antibody in human colostrum Direct identification of enteric adenovirus, a candidate new serotype, associated with infantile gastroenteritis Etiology of acute gastroenteritis in children in Israel: Role of human reoviruslike agent and bacterial pathogens Diarrhea and vomiting in infancy and childhood Identification of the rotaviral gene that codes for hemagglutination and protease-enhanced plaque formation Differentiation of human and calf reovirus-like agents associated with diarrhea using polyacrylamide gel electrophoresis of RNA Genes of human (strain Wa) and bovine (strain UK) rotaviruses that code for neutralization and subgroup antigens A microtiter solid phase radioimmunoassay for detection of the human reovirus-like agent in stools Antigenic relationships among five reovirus-like (RVL) agents by complement fixation (CF) and development of new substitute CF antigens for the human RVL agent of infantile gastroenteritis (39434) New complement-fixation test for the human reovirus-like virus agent of infantile gastroenteritis. Nebraska calf diarrhea virus used as antigen Density in CsCI of the 27-nm "SFIIa" particle associated with acute infectious nonbacterial gastroenteritis: Determination by ultracentrifugation and immune electron microscopy Reovirus-like agent in stools: Association with infantile diarrhea and development of serological tests Human reovirus-like agent as the major pathogen associated with "winter" gastroenteritis in hospitalized infants and young children Rotavirus and other viral diarrhoeas Visualization by immune electron microscopy of a 27-nm particle associated with acute infectious nonbacterial gastroenteritis Approaches to immunization of infants and young children against gastroenteritis due to rotavirus Epidemiology of Norwalk gastroenteritis and the role of Norwalk virus in the outbreaks of acute nonbacterial gastroenteritis Gastroenteritis due to Norwalk virus: An outbreak associated with a municipal water system An outbreak of acute gastroenteritis in a nursing home An outbreak of Norwalk gastroenteritis associated with swimming in a pool and secondary person-ta-person translnission Enterovirus type 71 infection in Melbourne Norwalk virus and rotavirus in travellers' diarrhoea in Mexico Human reovirus-like agent infection: Occurrence in adult contacts of pediatric patients with gastroenteritis Small spherical viruses in faeces from gastroenteritis patients Application of electron microscopy in viral diagnosis A long-term survey of rotavirus infection in Japanese children with acute gastroenteritis Astrovirus-associated epidemic gastroenteritis in Japan Influence of temperature and relative humidity on human rotavirus infection in Japan Norwalk virus enteric illness acquired by swimming exposure. An1 Astrovirus gastroenteritis age distribution of antibody Astrovirus infection in volunteers Astrovirus associated gastroenteritis in a children's ward Enterovirus infections in neonates International conference on the diarrhea of travelers-New directions in research: A summary A year's experience of the rotavirus syndrome and its association with respiratory illness An outbreak of rotavirus diarrhea ultracentrifugation and immune electron microscopy Reovirus-like agent in stools: Association with infantile diarrhea and development of serological tests Human reovirus-like agent as the major pathogen associated with "winter" gastroenteritis in hospitalized infants and young children Rotavirus and other viral diarrhoeas Visualization by immune electron microscopy of a 27 -nm particle associated with acute infectious nonbacterial gastroenteritis Approaches to immunization of infants and young children against gastroenteritis due to rotavirus Epidemiology of Norwalk gastroenteritis and the role of Norwalk virus in the outbreaks of acute non bacterial gastroenteritis Gastroenteritis due to Norwalk virus: An outbreak associated with a municipal water system An outbreak of acute gastroenteritis in a nursing home An outbreak of Norwalk gastroenteritis associated with swimming in a pool and secondary person-to-person transmission Enterovirus type 71 infection in Melbourne Norwalk virus and rotavirus in travellers' diarrhoea in Mexico Human reovirus-like agent infection: Occurrence in adult contacts of pediatric patients with gastroenteritis Small spherical viruses in faeces from gastroenteritis patients Application of electron microscopy in viral diagnosis A long-term survey of rotavirus infection in Japanese children with acute gastroenteritis Astrovirus-associated epidemic gastroenteritis in Japan Influence of temperature and relative humidity on human rotavirus infection in Japan Norwalk virus enteric illness acquired by swimming exposure Astrovirus gastroenteritis age distribution of antibody Astmvirus infection in volunteers Astrovirus associated gastroenteritis in a children's ward Enterovirus infections in neonates International conference on the diarrhea of travelers-New directions in research: A summary A year's experience of the rotavirus syndrome and its association with respiratory illness An outbreak of rotavirus diarrhea among a nonimmune, isolated South American Indian community Comparison of the features of astroviruses and caliciviruses seen in samples of feces by electron microscopy Viruses in infantile gastroenteritis. Lancet Stool viruses in babies in Glasgow Aetiology of acute gastroenteritis in infancy and early childhood in Southern India Rotavirus infection in a geriatric population Ultra structure of infantile gastroenteritis virus Plaque assay of neonatal calf diarrhea virus and the neutralizing antibody in human sera Polypeptides of bovine rotavirus International committee on taxonomy of viruses classification and nomenclature of viruses Experimental infection of conventional dogs with canine parvovirus The molecular biology of rotaviruses. 11. Identification of the protein-coding assignments of calf rotavirus genome RNA species Isolation from chickens of a rotavirus lacking the rotavirus group antigen Calicivirus associated with winter vomiting disease Cell culture propagation of neonata1 calf diarrhea (scours) virus Calfdiarrhea(scours); reproduced with a virus froIn a field outbreak Immunity to calf diarrhea virus Results of a field trial using a reo-like virus vaccine Orbivirus acute gastroenteritis of infancy Solid phase radioimmunoassay for the detection of rotavirus Viruses associated with acute gastroenteritis in young children A simple immunofluorescent technique for the detection of human rotavirus Enteroviral disease in early infancy A waterborne outbreak of gastroenteritis with secondary person-to-person spread: Association with a viral agent Aetiology of viral gastroenteritis An Australia-wide outbreak of gastroenteritis fron1 oysters caused by Norwalk virus Characterization of a rotavirus Isolation of a human pararotavirus A 27-nm virus isolated during an VIRAL GASTROENTERITIS 1055 Comparison of the features of astroviruses and caliciviruses seen in samples offeces by electron microscopy Viruses in infantile gastroenteritis. Lancet Stool viruses in babies in Glasgow Aetiology of acute gastroenteritis in infancy and early childhood in Southern India Rotavirus infection in a geriatric population Ultra structure of infantile gastroenteritis virus Plaque assay of neonatal calf diarrhea virus and the neutralizing antibody in human sera Polypeptides of bovine rotavirus International committee on taxonomy of viruses classification and nomenclature of viruses Experimental infection of conventional dogs with canine parvovirus The molecular biology of rotaviruses. II. Identification of the protein-coding assignments of calf rotavirus genome RNA species Isolation from chickens of a rotavirus lacking the rotavirus group antigen Calicivirus associated with winter vomiting disease Cell culture propagation of ne onata I calf diarrhea (scours) virus Calf diarrhea (scours); reproduced with a virus from a field outbreak Immunity to calf diarrhea virus Results of a field trial using a reo-like virus vaccine Orbivirus acute gastroenteritis of inhmcv Solid phase radioimmunoassay for the detection of rotavirus Viruses associated with acute gastroenteritis in young children A simple immunoiluorescent technique for the detection of human rotavirus Enteroviral disease in early infancy A waterborne outbreak of gastroenteritis with secondary person-to-person spread: Association with a viral agent An Australia-wide outbreak of gastroenteritis from oysters caused by Norwalk virus Characterization of a rotavirus Isolation of a human pararotavirus A 27-nrn virus isolated during an outbreak of acute infectious nonbacterial gastroenteritis in a convalescent hospital: A possible new serotype The effect of hUlnan milk fractions on rotavirus in relation to the secretory IgA content Effect of fractions of Ethiopian and Norwegian colostrum on rotavirus and Escherichia coli heat-labile enterotoxin Morphology and stability of infantile gastroenteritis virus: Comparison with reovirus and blue tongue virus Rotavirus acute diarrhoeal disease in children in a southern Indian coastal town Clinical immunity in acute gastroenteritis caused by the Norwalk agent Antidiarrheal agents in the treatment of acute diarrhea in children Biochemical and biophysical characteristics of diarrhea viruses of human and calf origin Further biochemical characterization, including the detection of surface glycoproteins of human calf and Simian rotavirus Clinical features of acute gastroenteritis associated with human reovirus-like agent in infants and young children Sequential enteric illness associated with different rotavirus serotypes Common exposure outhreak of gastroenteritis due to type 2 rotavirus with high secondary attack rate within fan1ilies The current status of oral therapy in the treatment of acute diarrheal illness Detection of rotavirus in faeces by latex agglutination Isolation of human rotavirus in cell cultures Characteristics of the genome of human infantile enteritis virus (rotavirus) Enhancement of antigen incorporation and infectivity of cell cultures by human rotavirus The role of breast-feeding in the prevention of rotavirus infection Recent advances in viral gastroenteritis. Gastroenterology Infantile gastroenteritis caused by rotavirus: COlnparison of enzyme-linked immunosorbent assay and electron microscopy for rapid diagnosis Infantile gastroenteritis: A clinical study of reovirus-like agent infection Virus-specific immunity in neonatal and adult mouse rotavirus infection S-IgA cholera toxin and rotavirus antibody in human colostrum A plaque assay for the simian rotavirus SA 11 Passive immunity in calf rotavirus infections: Maternal vaccination increases and prolongs immunoglobulin Cl antibody secretion in milk Rotavirus infection in lambs: Studies on passive protection BILL BARNETT outhreak of acute infectious non bacterial gastroenteritis in a convalescent hospital: A possible new serotype The effect of human milk fractions on rotavirus in relation to the secretory IgA content Efl'ect of fractions of Ethiopian and Norwegian colostrum on rotavirus and Escherichia coli heat-labile enterotoxin \lorphology and stability of infantile gastroenteritis virus: Comparison with reovirns and blue tongue virus Rotavirus acute diarrhoeal disease in children in a southern Indian coastal town Clinical immunity in acute gastroenteritis caused by the Norwalk agent. l\:. Engl Antidiarrheal agents in the treatment of acute diarrhea in children Biochemical and biophysical characteristics of diarrhea viruses of human and calf origin Further biochemical characterization, including the detection of surface glycoproteins of human calf and Simian rotavirus Clinical features of acute gastroenteritis associated with human reovirus-like agent in infants and young children Sequential enteric illness assoeiated with different rotavirus serotypes Common exposure outhreak of gastroenteritis due to type 2 rotavirus with high secondary attack rate within hm1ilies The current status of oral therapy in the treatment of acute diarrheal illness Detection of rotavirus in faeces by latex agglutination Isolation of human rotavirus in cell cultures Characteristics of the genome of human infantile enteritis virus (rotavirus) Enhaneement ofimtigen incorporation and infectivity of cell cultures by human rotavirus The role of breast-feeding in the prevention of rotavirus infection Recent advances in viral gastroenteritis. Gastroenterology Infantile gastroenteritis caused by rotavirus: Comparison of enzyme-linked immunosorbent assay and electron microscopy for rapid diagnosis Infantile gastroenteritis: A clinical study of reovirus-like agent infection Virus-specific immunity in neonatal and adult mouse rotavirus infection S-IgA cholera toxin and rotavirus antibody in human colostrum A plaque assay for the simian rotavirus SA 11 Passive immunity in calfrotavirus infections: Maternal vaccination increases and prolongs immunoglobulin Cl antibody secretion in milk Rotavirus infection in lambs: Studies on passive protection The imlllunoprophylaxis of rotavirus infections in lalnbs The Illagnitude of the global problem of acute diarrhoeal disease: A review of active surveillance data Coproantibody response to rotavirus infection Nosocomial infantile gastroenteritis associated with Illinirotavirus and calicivirus Rotavirus: The first five years Rotavirus infection in neonates Propagation and in vitro studies of previously non-cultivatable enteral adenoviruses in 293 cells Virus-like particle, 35 to 40 nnl, associated with an institutional outbreak of acute gastroenteritis in adults Electrophoretic analysis of RNA segments of human rotaviruses cultivated in cell culture Norwalk-related viral gastroenteritis due to contanlinated drinking water Oral rehydration therapy for treatment of rotavirus diarrhoea in a rural treatment centre in Bangladesh Cell culture propagation of porcine rotavirus (reovirus-like agent) Pattern of shedding of the Norwalk particle in stools during experinlentally induced gastroenteritis in volunteers as determined by immune electron microscopy Detection by immune electron microscopy of 26-27 nm virus-like particles associated with two family outbreaks of gastroenteritis Rotavirus neutralization by hunlan milk Rotavirus infections in a Inaternity unit Cord blood and breastmilk antibodies in neonatal rotavirus infection Sequential passages of human rotavirus in Ma-104 cells Three human rotavirus serotypes demonstrated by plaque neutralization of isolated strains Electron microscopy' of fatal adenovirus gastroenteritis WHO Scientific Working Group: Rotavirus and other viral diarrhoeas Waterborne gastroenteritis due to the Norwalk agent: Clinical and epidemiologic investigation Viral gastroenteritis Levels of colostral antibodies against neonatal calf diarrhoea virus World Health Organization: A Manual for the Treatment of Acute Diarrhoea. Unpublished document, WHO/CDD/SERl80 World Health Organization: Control of diarrhoeal diseases Comparison of three agents of acute infectious nonbacterial gastroenteritis by cross-challenge in volunteers Definition of human rotavirus serotypes by plaque reduction assay Rotaviral immunity in gnotobiotic VIRAL GASTROENTERITIS The immunoprophylaxis of rotavirus infections in lambs The magnitude of the global problem of acute diarrhoeal disease: A review of active surveillance data Coproantibody response to rotavirus infection Nosocomial inEmtile gastroenteritis associated with minirotavirus and calicivirus Hotavirus: The first five years Hotavirus infection in neonates Propagation and in vitro studies of previously non-cultivatable enteral adenoviruses in 293 cells Virus-like particle, 35 to 40 nm, associated with an institutional outbreak of acute gastroenteritis in adults Electrophoretic analysis of RNA segments of human rotaviruses cultivated in cell culture Norwalk-related viral gastroenteritis due to contaminated drinking water Oral rehydration therapy for treatment of rotavirus diarrhoea in a rural treatment centre in Bangladesh Cell culture propagation of porcine rotavirus (reovirus-like agent) Pattern of shedding of the Norwalk particle in stools during experimentally induced gastroenteritis in volunteers as determined by immune electron microscopy Detection by immune electron microscopy of 26-27 mn virus-like particles associated with two family outbreaks of gastroenteritis Hotavirus neutralization by human milk Hotavirus infections in a maternity unit Cord blood and breastmilk antibodies in neonatal rotavirus infection Sequential passages of human rotavirus in 1\la-104 cells Three human rotavirus serotypes demonstrated by plaque neutralization of isolated strains Electron microscopy of fatal adenovirus gastroenteritis WHO Scientific Working Group: Rotavirus and other viral diarrhoeas Waterborne gastroenteritis due to the Norwalk agent: Clinical and epidemiologic investigation Viral gastroenteritis Levels of colostral antibodies against neonatal calf diarrhoea virus World Health Organization: A Manual for the Treatment of Acute Diarrhoea. Unpublished document, WHOICDD/SERl80 World Health Organization: Control of diarrhoeal diseases Comparison of three agents of acute infectious nonbacterial gastroenteritis by cross-challenge in volunteers Definition of human rotavirus serotypes by plaque reduction assay Hotaviral immunity in gnotobiotic calves: Heterologous resistance to human virus induced by bovine virus Diarrhea associated with rotavirus in rural Guatemala: A longitudinal study of 24 infants and young children Immune response to rotaviral infection-Measurement by enzyme immunoassay Enzyme-linked immunosorbent assay (ELISA) for detection of human reovirus-like agent of infantile gastroenteritis Gastroenteritis associated with enteric type adenovirus in hospitalized infants Rapid multiple-determinant enzyme immunoassay for the detection of human rotavirus Secretory antibody directed against rotavirus in human milk-Measurement by means of enzyme-linked immunosorbent assay Epidemiology of human rotavirus types 1 and 2 as studied by enzyme-linked immunosorbent assay Routine diagnosis of human rotaviruses in stools Utah 84322 calves: Heterologous resistance to human virus induced by bovine virus Diarrhea associated with rotavirus in rural Guatemala: A longitudinal study of 24 infants and young children Immune response to rotaviral infection-Measurement by enzyme immunoassay Enzyme-linked immunosorbent assay (ELISA) for detection of human reovirus-like agent of infantile gastroenteritis Gastroenteritis associated with enteric type adenovirus in hospitalized infants Rapid multiple-determinant enzyme immunoassay for the detection of' human rotavirus Secretory antibody directed against rotavirus in human milk-Measurement by means of enzyme-linked immunosorbent assay Epidemiology of human rotavirus types 1 and 2 as studied by enzyme-linked immunosorbent assay Routine diagnosis of human rotaviruses in stools