Rotavirus vaccines against diarrhoeal disease

Rotaviruses are responsible for more diarrhoeal disease-associated mortality than any other single agent. Vaccination may therefore hold the key to combating diarrhoeal disease worldwide. Natural immunity to rotavirus infection indicates that rather than protection from reinfection such immunity gives rise to less severe and less frequent attacks of diarrhoea. Early attempts to design a rotavirus vaccine with bovine rotavirus failed because of poor efficacy in some developing countries. Research into rhesus rotavirus, particularly the high-titre rhesus rotavirus tetravalent (RRV-TV) vaccine, has given slightly better results. A stumbling block to truly effective oral vaccines seems to be immunogenicity in developing countries. If efficacy can be ensured by trials in the developing countries, money spent on rotavirus vaccines will be well spent.     

Neonatal hypocalcaemia associated with rotavirus diarrhoea

We observed an association between rotavirus diarrhoea and hypocalcaemia in several patients and therefore started a prospective evaluation with measurement of calcium levels in all patients with rotavirus infection during a period of 8 months. We report on 54 infants with rotavirus gastro-enteritis. Serum concentrations of sodium, potassium, and total and ionized calcium were measured on admission. If hypocalcaemia was detected, total and ionized calcium were measured every day until recovery. Calcium was supplemented as calcium gluconate which was added to milk. Out of 54 newborns with rotavirus gastro-enteritis, 20 developed hypocalcaemia. All these newborns had severe diarrhoea. Seven infants were admitted because of convulsions, but EEG and ultrasonographic examination of the brain revealed no abnormalities. Once the infants' clinical condition and the consistency and frequency of the stool had improved, calcium concentrations increased and remained within the reference range without supplementation. CONCLUSION: Rotavirus gastro-enteritis seems to be a cause of neonatal hypocalcaemia.     

A case control study of potential enteric pathogens for calves raised in cow-calf herds

A matched case control study was performed to describe the epidemiological features of potential enteric pathogens for calves reared in 53 cow-calf herds located in western Switzerland. A total of 106 diarrhoeic calves and 126 healthy control calves were collected, all calves were less than 4 months old. Faecal samples were analysed for presence of infectious agents related to calf diarrhoea including enterotoxigenic E. coli, Verotoxin producing E. coli (VTEC), Campylobacter sp., Yersinia sp., Salmonella sp., rotavirus, coronavirus, helminths and coccidian protozoa. Multivariate logistic models were used to analyse the relationship between presence of infection and onset of diarrhoea. The study provided evidence of significant associations between diarrhoea and infection with rotavirus, Campylobacter coli and the presence of Verotoxin in faecal samples. With the exception of Cryptosporidium parvum intestinal parasites including Strongylidae and Eimeria sp. were found to be less prevalent in cases than in controls. Control calves were significantly more frequently infected with Strongyloides papillosus than case animals.     

Electrophoretic typing of nosocomial rotavirus infection in a general paediatric unit showing the continual introduction of community strains

During 1989 stool specimens from hospitalised children with gastroenteritis at Ga-Rankuwa Hospital in South Africa were examined for the presence of rotaviruses. Overall 16% of the children were positive for rotavirus. However, 43% of the rotavirus positive patients were infected in the hospital. Further characterisation of the rotavirus strains was performed by electrophoresis of the RNA genome and hybridisation analysis of the VP7 and VP4 genes present. The strains associated with nosocomial infection were similar to those strains acquired in the community. The majority of the strains, both community- or hospital-acquired, were associated with a serotype 1 strain with a long electrophoretype and bearing the Wa-like VP4 gene. Three minor rotavirus strains with a long electrophoretype were also observed to be circulating bearing serotype 1 or 4 VP7 genes and the Wa-like VP4 gene. Interestingly, a serotype 4 strain bearing the M37-like VP4 gene was identified to occur almost exclusively in neonates although the gene was associated with diarrhoea in these cases. Two strains with differing short RNA electrophoretypes were also observed, members of which hybridised to VP7 serotype 2 and VP4 DS-1 type probes.     

Review article: the use of biotherapeutic agents in the prevention and treatment of gastrointestinal disease

There is presently a lack of well conducted clinical trials demonstrating any significant benefits of probiotics in humans. With the exception of diarrhoea due to rotavirus infection in children there is little evidence from randomized, double-blind, placebo-controlled studies that bacterial probiotics have a significant beneficial action in preventing diarrhoea of any cause. The yeast Saccharomyces boulardii has been shown to be of benefit in the prevention of antibiotic-associated diarrhoea but not in preventing infection with Clostridium difficile. S. boulardii may also be of benefit in preventing relapse of C. difficile infection. Because of the simplicity of in vitro systems and some animal models, beneficial characteristics of probiotics such as the ability of bacteria to bind to epithelial surfaces are not always transferable to humans. Thus any postulated benefit from consumption of probiotic bacteria should only be accepted as fact after testing in clinical studies. This review outlines our present knowledge of the mode of action of probiotics and presents the data from clinical trials on their use.     

The significance of enteroaggregative Escherichia coli in the etiology of hospitalized diarrhoea in Calcutta, India and the demonstration of a new honey-combed pattern of aggregative adherence

Previous studies have identified enteroadherent Escherichia coli that exhibit localized adherence, diffuse adherence and atypical diffuse adherence as diarrhoeagenic agents associated with infantile diarrhoea in Calcutta, India. In this study, a DNA probe specific for enteroaggregative adherence was used to determine the etiological significance of enteroaggregative E. coli in the causation of diarrhoea. From a total of 330 strains of E. coli recovered from 159 cases of acute secretory diarrhoea and 174 cases of invasive diarrhoea, 20 strains hybridized with the probe, whereas of the 25 E. coli strains recovered from 25 healthy controls only 1 strain hybridized with the probe. Of the 21 probe positive strains, 19 adhered to HeLa cells in the typical stacked-brick pattern while 2 strains recovered from 2 cases of secretory diarrhoea adhered to the glass surface in a hitherto undescribed formation which we have termed, based on the appearance, as the honey-comb pattern. The enteroaggregative E. coli strains identified in this study did not produce any conventional enterotoxins and were significantly associated with patients with secretory diarrhoea (10.7%) than with invasive diarrhoea (1.7%). The results of this study indicate that enteroaggregative E. coli play a causal role in acute secretory diarrhoea in this part of the world which lends credence to the involvement of a potent toxin in the pathogenesis of EAggEC mediated infections.     

Present findings on rotaviruses with emphasis on rotaviruses in swine

A summary of thirty pages, concerning rotaviruses, i.e. RNA-viruses, the most frequent causal agents of infectious diarrhoea in children and young farm animals. Most of the chapters are generally focused on rotavirus morphology, structure and biology. Chapter No. 6 is especially detailed, trying to offer a complete summary of available diagnostic methods. The final chapters concern in greater detail the problems of rotaviruses in pigs, such as the immunity, prevention and treatment.     

Probiotics in childhood

The Probiotics (Lactic acid bacteria) represent a nutritional live microbial supplement that positively affects host by enhancing the microbial balance. A survey is made of the most relevant studies concerning the use of probiotics in the prevention and treatment of infantile acute diarrhoea (by rotavirus or other agents), pseudomembranous colitis, hospital-acquired and antibiotic-associated diarrhoeas. Although the probiotics mechanism of action is not yet completely understood, it has been hypothesized that they exert an inhibitory effect on the intestinal inflammation by immune response modulation. Due to this property, the use of probiotics has therefore been suggested in other severe diseases such as chronic inflammatory bowel diseases, rheumatoid arthritis, food allergy, atopic dermatitis and as immunoadjuvant for oral vaccines.     

Environmental conditions of the causes of noncompliance with the program of mass chest x-ray examinations and the evaluation of health status of this group of population

It is often suggested that the irritable colon syndrome is a pre-diverticular condition and that patients with diverticular disease and predominant diarrhoea are in fact suffering from the irritable colon syndrome. In this study colonic motor function in diverticular disease (7 patients with predominant diarrhoea), in the irritable colon syndrome (7 patients with predominant diarrhoea) and in 8 normal subjects were compared. Patients with diarrhoea were matched for symptom score, stool weight and transit time. Slow wave electrical activity was measured by an intraluminal suction electrode and patients with the irritable colon syndrome displayed a predominant frequency at 3 cpm. This was not found in patients with diverticular disease. No myoelectrical evidence to link the two conditions was found.     

Protection against rotavirus disease after natural rotavirus infection. US Rotavirus Vaccine Efficacy Group

Determination of protective efficacy after natural rotavirus infection is important as a basis for evaluating rotavirus vaccines. Therefore, placebo recipients in a large 2-year rotavirus vaccine trial conducted across the United States were followed to determine the protection afforded by natural rotavirus infection. Serotype 1 rotaviruses predominated (93% year 1, 66% year 2), but isolates of all four major human rotavirus serotypes circulated during both years. Of the 45 placebo recipients with documented rotavirus illnesses in year 1, 1 developed rotavirus disease in year 2 compared with 29 of the other 235 placebo recipients (P = .03). Serologic data were available for 171 placebo recipients, and 37 of 140 without rotavirus illnesses in year 1 had evidence of asymptomatic rotavirus infection. None of these 37 experienced rotavirus disease in year 2 compared with 22 of the remaining 103 (P < .001). Overall efficacy after natural rotavirus infection was 93% (95% confidence interval, 50%-99%).     

Persistent diarrhea

In this article the current concepts on persistent diarrhoea are reviewed. Persistent diarrhoea is important because its aetiology is unclear, is difficult to treat, affects the nutritional status and increases the risk of death. The identification of risk factors for persistent diarrhoea is important because it can obtain valuable information relative to the pathogenesis and prevention of this disease. The concepts of diarrhoea and risk factors are also reviewed. In addition we explore the methods of management and treatment of patients with persistent diarrhoea.     

Algodystrophies of the limbs

1. We studied intestinal glucose transport in pigs during the acute and convalescent phases of an invasive viral enteritis, transmissible gastroenteritis. 2. When diarhoea was severe 40 h after experimental infection, net absorption of glucose, Na+ and water, measured by marker perfusion in the jejunum, was reduced; the enhancement of Na+ and water absorption in response to increasing perfusate glucose concentrations up to 120 mmol/l was diminished compared with the response observed in control and convalescent pigs. 3. Measured in vitro, 40 h after infection, unidirectional fluxes of 3-O-methyl-D-glucose across the jejunal epithelium were reduced and net absorption of the sugar was obliterated. Phlorizin (0.05 mmol/l), which completely inhibited net 3-O-methyl-D-glucose absorption in control tissue, had no significant effect on transmissible gastroenteritis jejunum. 4. Our data suggest that in this invasive viral enteritis, which closely resembles human rotavirus enteritis, glucose absorption is impaired as a result of defects in both active and passive glucose flux. 5. Differences between the mechanisms of viral diarrhoea, demonstrated by our study and those of the enterotoxigenic diarrhoeas, should be taken into consideration in formulating active therapeutic measures for children with acute viral diarrhoea.     

Heart signal recognition by Hidden Markov Models: the ECG case

From December 1989 to May 1990, 315 faecal samples from children under 5 years old with diarrhoea (215) and without diarrhoea (100) seen at paediatric clinics were investigated for bacterial, viral and parasitic enteropathogens. Standard and recently described methods were used for the investigations, which revealed that 74.9% of children with diarrhoea were infected with enteropathogens compared with 28% of controls. In the diarrhoeal group, 59.1% had a bacterial, 26.5% a viral and 2.3% a parasitic aetiology. Rotavirus was the pathogen most frequently detected, accounting for 22.3% of positive findings in the group with diarrhoea versus 9% in the control group. Other important agents were: enterotoxigenic Escherichia coli (ETEC) (14.4 versus 6%), enteropathogenic E. coli (EPEC) (10.7 versus 5%), enteroadherent E. coli (EAEC) (9.3 versus 4%), enterohaemorrhagic E. coli (EHEC) (5.1 versus 3%) and Salmonella spp. (3.3 versus 1%). The following enteropathogens were detected exclusively in the diarrhoeal stools: Shigella spp. (5.1%), Yersinia enterocolitica (0.9%), Aeromonas hydrophila (1.4%), Entamoeba histolytica (0.5%), Giardia lamblia (0.5%), Trichomonas hominis (0.5) and Trichuris trichiura (0.9%). The detection rates of rotavirus, EPEC and EAEC were much greater in the diarrhoeal than in the control patients. No Vibrio cholerae, enteroinvasive E. coli (EIEC), Plesiomonas spp. or Cryptosporidium spp. were detected in this study. Our data suggest that both the traditional and newly recognised diarrhoeal agents are important causes of diarrhoea in the children under 5 years old in Lagos, Nigeria.     

Acute and chronic diarrhoea and abdominal colic associated with enteroaggregative Escherichia coli in young children living in western Europe

BACKGROUND: Enteroaggregative Escherichia coli (EAggEC or EAEC) can spread and cause disease in developing countries, but it is not presently known whether it spreads disease in industrialised countries. Therefore, we did a prospective study to assess the incidence and the clinical manifestations of infections due to EAEC in children in Germany. METHODS: 798 children with diarrhoea, admitted to hospital within a defined geographical area during a 24-month period, were included in the trial. EAEC were cultured from stool specimens, screened by PCR, and identified by colony hybridisation from DNA sequences found on the virulence plasmid. The findings were confirmed by aggregative adherence to HEp-2 cells. Stool samples from 580 children admitted to hospital without diarrhoea were also studied as controls. FINDINGS: EAEC were found in the stools of 16 (2%) of 798 children with diarrhoea, but in none of 580 children without diarrhoea. Only four of the EAEC-infected children had travelled to developing countries. Most EAEC infections were acquired in the summer months. Infection with EAEC was associated with acute, watery diarrhoea in 12 children, and with chronic diarrhoea of up to 5 months' duration in four. Five children had abdominal colic that lasted for 2-4 weeks as their main symptom. The incidence of EAEC infection was 7.7 patients admitted to hospital per 100,000 children in the general population aged younger than 16 years. INTERPRETATION: EAEC infection is associated with acute, watery diarrhoea and may be acquired in industrialised countries. Chronic diarrhoea or abdominal colic of unknown aetiology in young children may also be caused by EAEC infection.     

Randomised placebo-controlled trial of rhesus-human reassortant rotavirus vaccine for prevention of severe rotavirus gastroenteritis

BACKGROUND: Rotavirus is the most common cause of acute childhood gastroenteritis. Vaccination with live oral heterologous rotavirus vaccines may prevent rotavirus gastroenteritis. We assessed the efficacy of rhesus-human reassortant rotavirus tetravalent vaccine (RRV-TV) against severe rotavirus gastroenteritis in Finnish children in a randomised placebo-controlled double-blind trial. METHODS: Placebo or RRV-TV (titre 4x10(5) plaque-forming units) was given to infants at ages 2, 3, and 5 months. The children were followed up for one or two rotavirus epidemic seasons. The main outcome measure was protection against severe rotavirus gastroenteritis (score > or =11 on a 20-point severity scale). 2398 children were enrolled and received at least one dose of RRV-TV (n=1191) or placebo (n=1207). The primary efficacy analysis was based on children who received three doses of RRV-TV (n=1128) or placebo (n=1145). FINDINGS: 256 episodes of rotavirus gastroenteritis occurred at any time during the study; 65 were among 1191 RRV-TV recipients, and 191 among 1207 placebo recipients (vaccine efficacy 66% [95% CI 55-74]; intention-to-treat analysis). 226 episodes were included in the primary efficacy analysis of fully vaccinated children (54 among 1128 RRV-TV recipients, 172 among 1145 placebo recipients; vaccine efficacy 68% [57-76]). 100 episodes were severe, eight in RRV-TV recipients and 92 in placebo recipients (vaccine efficacy 91% [82-96]). INTERPRETATION: RRV-TV vaccine was highly effective against severe rotavirus gastroenteritis in young children. Incorporation of this vaccine into routine immunisation schedules of infants could reduce severe rotavirus gastroenteritis by 90% and severe gastroenteritis of all causes in young children by 60%.     

Rotavirus

Rotavirus, the most common diarrheal pathogen in children worldwide, causes approximately one third of diarrhea-associated hospitalizations and 800,000 deaths per year. Because natural infection reduces the incidence and severity of subsequent episodes, rotavirus diarrhea might be controlled through vaccination. Serotypespecific immunity may play a role in protection from disease. Tetravalent rhesus-human reassortant rotavirus vaccine (RRV-TV) (which contains a rhesus rotavirus with serotype G3 specificity and reassortant rhesus-human rotaviruses with G1, G2, and G4 specificity) provides coverage against the four common serotypes of human rotavirus. In clinical trials in industrialized countries, RRV-TV conferred 49% to 68% protection against any rotavirus diarrhea and 61% to 100% protection against severe disease. This vaccine was licensed by the U.S. Food and Drug Administration on August 31, 1998, and should be cost-effective in reducing diarrheal diseases in industrialized countries. The vaccine's efficacy and cost-effectiveness in developing countries should be evaluated.     

Human hepatitis B virus and hepatocellular carcinoma. I. Experimental infection of tree shrews with hepatitis B virus

A cross-sectional study involving 771 children under the age of one year, was carried out in a traditional area of urban Ilorin, Nigeria, to determine how socio-economic conditions and feeding practices relate to diarrhoeal disease among infants. After adjustment has been made (through logistic regression) for covariates, five factors had significant association with diarrhoeal disease. These are the age of the child, parity, mother's education, availability of household kitchen and the feeding of semi-solid food to the infants. The lowest diarrhoeal rate occurred in infants aged 0-3 months while the highest rate occurred among infants seven to nine months old (Odds Ratio = 4.2). Children who were of the fifth or higher birth order had significantly higher risk of diarrhoea when compared with those who were of the first or second birth order (OR = 1.62; P < 0.05). Children of mothers with secondary education had significantly higher risk of diarrhoea compared with children of illiterates (OR = 1.9; P < 0.05). Households that had no kitchen had significantly higher risk of infantile diarrhoea than households with kitchen facilities (P < 0.01). Finally, infants receiving semi-solid food had higher risk of diarrhoea compared to those children not receiving semi-solid food (P < 0.05). Diarrhoeal disease awareness campaign to educate mothers on the dangers of childhood diarrhoea and how to prevent it, through proper hygiene, especially, food hygiene, is advocated.     

Infection with group C rotavirus in a suburban community in Brazil

Group C rotaviruses are associated with sporadic outbreaks of gastroenteritis worldwide. Age-specific seroprevalence of group C rotavirus antibodies was investigated in sera, randomly collected and representative of a suburban community in Brazil which had previously been screened for group A rotavirus antibodies. Antibody prevalence to group C rotavirus was low in children under 5 years and increased slowly with age to 36% seropositivity in adults, reflecting continuous exposure to primary infection in all age groups. This suggests a higher incidence of infection than disease might predict. Adult antibody prevalence was similar to that in other geographical settings. No obvious patterns of infection with group A and group C rotavirus were found within individuals, which suggests independent transmission. However, further epidemiological studies are required to understand group C rotavirus dynamics and possible interactions with group A rotavirus transmission and immunity.     

Rotavirus disease, but not infection and development of intestinal histopathological lesions, is age restricted in rabbits

The rabbit model of rotavirus infection has proved to be useful for assessing active immunity and protection after infection or vaccination with virus or virus-like particles. One limitation of the rabbit model is that after experimental infection of rabbits, clinical diarrhea is not routinely induced. Lack of diarrhea in the rabbit model has been proposed to be due to the fluid absorptive capability of the cecum or attenuation of virus strains through tissue culture adaptation. To test whether a wild-type lapine rotavirus strain BAP (BAPwt) isolated from diarrheic rabbits would cause disease on passage in rabbits, 1-, 2-, 10-, and 16-week-old rabbits were orally inoculated with BAPwt, its tissue culture-adapted counterpart strain (BAP-2), tissue culture-adapted lapine strain ALA, or PBS. Lapine rotavirus infection in 1-week-old, but not >/=2-week-old, rabbits resulted in the development of disease characterized by soft, wet, yellow-to-brownish-green partially formed-to-liquid stools observed only at the time of virus antigen shedding. The level and duration of virus shedding after infection were prolonged in 1-week-old rabbits compared with rabbits >/=2 weeks of age. Although diarrhea was not observed beyond the first 2 weeks of life, histopathological changes, including villus shortening and fusion, increased vacuolation of epithelial cells, and mononuclear infiltration of the lamina propria, were observed throughout the small intestine between 12 and 120 h after ALA infection in 1-week-old, 1- to 2-month-old, and 11-month-old rabbits. In 11-month-old rabbits, onset of intestinal damage appeared to be slightly delayed, was less severe, and was not observed in the duodenum. There were no differences in the immune responses to rotavirus infection in rabbits of different age groups (1 week to 5 years of age). All lapine rotavirus-inoculated rabbits seroconverted and were protected from virus challenge at 28 days postinoculation. Like in mice, rotavirus disease is age restricted in rabbits.