Few studies provide data on the global morbidity and mortality caused by infection with Shigella spp.; such estimates are needed, however, to plan strategies of prevention and treatment. Here we report the results of a review of the literature published between 1966 and 1997 on Shigella infection. The data obtained permit calculation of the number of cases of Shigella infection and the associated mortality occurring worldwide each year, by age, and (as a proxy for disease severity) by clinical category, i.e. mild cases remaining at home, moderate cases requiring outpatient care, and severe cases demanding hospitalization. A sensitivity analysis was performed to estimate the high and low range of morbid and fatal cases in each category. Finally, the frequency distribution of Shigella infection, by serogroup and serotype and by region of the world, was determined. The annual number of Shigella episodes throughout the world was estimated to be 164.7 million, of which 163.2 million were in developing countries (with 1.1 million deaths) and 1.5 million in industrialized countries. A total of 69% of all episodes and 61% of all deaths attributable to shigellosis involved children under 5 years of age. The median percentages of isolates of S. flexneri, S. sonnei, S. boydii, and S. dysenteriae were, respectively, 60%, 15%, 6%, and 6% (30% of S. dysenteriae cases were type 1) in developing countries; and 16%, 77%, 2%, and 1% in industrialized countries. In developing countries, the predominant serotype of S. flexneri is 2a, followed by 1b, 3a, 4a, and 6. In industrialized countries, most isolates are S. flexneri 2a or other unspecified type 2 strains. Shigellosis, which continues to have an important global impact, cannot be adequately controlled with the existing prevention and treatment measures. Innovative strategies, including development of vaccines against the most common serotypes, could provide substantial benefits.

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Global Burden of Shigella Infections: Implications for Vaccine Development and Implementation of Control Strategies

Cholera caused by toxigenic Vibrio cholerae is a major public health problem confronting developing countries, where outbreaks occur in a regular seasonal pattern and are particularly associated with poverty and poor sanitation. The disease is characterized by a devastating watery diarrhea which leads to rapid dehydration, and death occurs in 50 to 70% of untreated patients. Cholera is a waterborne disease, and the importance of water ecology is suggested by the close association of V. cholerae with surface water and the population interacting with the water. Cholera toxin (CT), which is responsible for the profuse diarrhea, is encoded by a lysogenic bacteriophage designated CTXΦ. Although the mechanism by which CT causes diarrhea is known, it is not clear why V. cholerae should infect and elaborate the lethal toxin in the host. Molecular epidemiological surveillance has revealed clonal diversity among toxigenic V. cholerae strains and a continual emergence of new epidemic clones. In view of lysogenic conversion by CTXΦ as a possible mechanism of origination of new toxigenic clones of V. cholerae, it appears that the continual emergence of new toxigenic strains and their selective enrichment during cholera outbreaks constitute an essential component of the natural ecosystem for the evolution of epidemic V. cholerae strains and genetic elements that mediate the transfer of virulence genes. The ecosystem comprising V. cholerae, CTXΦ, the aquatic environment, and the mammalian host offers an understanding of the complex relationship between pathogenesis and the natural selection of a pathogen.

Epidemiology, Genetics, and Ecology of Toxigenic Vibrio cholerae

The global problem of antimicrobial resistance is particularly pressing in developing countries, where the infectious disease burden is high and cost constraints prevent the widespread application of newer, more expensive agents. Gastrointestinal, respiratory, sexually transmitted, and nosocomial infections are leading causes of disease and death in the developing world, and management of all these conditions has been critically compromised by the appearance and rapid spread of resistance. In this first part of the review, we have summarised the present state of resistance in these infections from the available data. Even though surveillance of resistance in many developing countries is suboptimal, the general picture is one of accelerating rates of resistance spurred by antimicrobial misuse and shortfalls in infection control and public health. Reservoirs for resistance may be present in healthy human and animal populations. Considerable economic and health burdens emanate from bacterial resistance, and research is needed to accurately quantify the problem and propose and evaluate practicable solutions. In part II, to be published next month, we will review potential containment strategies that could address this burgeoning problem.

https://www.thelancet.com/pdfs/journals/laninf/PIIS1473-3099(05)70189-4.pdf

Antimicrobial resistance in developing countries. Part I: recent trends and current status

In developing countries, acquired bacterial resistance to antimicrobial agents is common in isolates from healthy persons and from persons with community-acquired infections. Complex socioeconomic and behavioral factors associated with antibiotic resistance, particularly regarding diarrheal and respiratory pathogens, in developing tropical countries, include misuse of antibiotics by health professionals, unskilled practitioners, and laypersons; poor drug quality; unhygienic conditions accounting for spread of resistant bacteria; and inadequate surveillance.

Socioeconomic and behavioral factors leading to acquired bacterial resistance to antibiotics in developing countries.

The bacterial species Vibrio cholerae includes harmless aquatic strains as well as strains capable of causing epidemics and global pandemics of cholera. While investigating the relationship between pathogenic and nonpathogenic strains, we identified a chromosomal pathogenicity island (PAI) that is present in epidemic and pandemic strains but absent from nonpathogenic strains. Initially, two ToxR-regulated genes (aldA and tagA) were studied and were found to be associated with epidemic and pandemic strains but absent in nontoxigenic strains. The region containing aldA and tagA comprises 13 kb of previously unidentified DNA and is part of a PAI that contains a regulator of virulence genes (ToxT) and a gene cluster encoding an essential colonization factor and the cholera toxin phage receptor (toxin-coregulated pilus; TCP). The PAI is 39.5 kb in size, has low %G+C (35%), contains putative integrase and transposase genes, is flanked by att sites, and inserts near a 10Sa RNA gene (ssrA), suggesting it may be of bacteriophage origin. We found this PAI in two clinical non-O1/non-O139 cholera toxin-positive strains, suggesting that it can be transferred within V. cholerae. The sequence within this PAI includes an ORF with homology to a gene associated with the type IV pilus gene cluster of enteropathogenic Escherichia coli, a transposase from Vibrio anguillarum, and several ORFs with no known homology. As the PAI contains the CTXΦ receptor, it may represent the initial genetic factor required for the emergence of epidemic and pandemic cholera. We propose to call this island VPI (V. cholerae pathogenicity island).

https://www.pnas.org/content/pnas/95/6/3134.full.pdf

A Vibrio cholerae pathogenicity island associated with epidemic and pandemic strains

Large outbreak of clinical cholera due to Vibrio cholerae non-01 in Bangladesh

Antimicrobial resistance is becoming increasingly important in the treatment of enteric infections, particularly those due to Shigella, Vibrio cholerae, enterotoxigenic Escherichia coli (associated with traveler's diarrhea), and Salmonella typhi. The rate of antimicrobial resistance is highest in the developing world, where the use of antimicrobial drugs is relatively unrestricted. Of greatest immediate concern is the need for an effective, inexpensive antimicrobial that can be used safely as treatment for small children with dysentery due to Shigella, primarily Shigella dysenteriae type 1.

Antimicrobial Resistance in Organisms Causing Diarrheal Disease

There is a growing body of literature indicating an association between stunting and environmental enteropathy (EE), a disorder thought to be caused by repeated exposures to enteric pathogens. To investigate the relationship between exposure to enteric pathogens through geophagy, consumption of soil, EE, and stunting, we conducted a prospective cohort study of 216 children under 5 years of age in rural Bangladesh. Geophagy was assessed at baseline using 5 hour structured observation and caregiver reports. Stool was analyzed for fecal markers of intestinal inflammation: alpha-1-antitrypsin, myeloperoxidase, neopterin (all three combined to form an EE disease activity score), and calprotectin. Eighteen percent of children had observed geophagy events by structured observation and 28% had caregiver reported events in the past week. Nearly all households had Escherichia coli (97%) in soil, and 14% had diarrheagenic E. coli. Children with caregiver-reported geophagy had significantly higher EE scores (0.72 point difference, 95% confidence interval [CI]: 0.01, 1.42) and calprotectin concentrations (237.38 μg/g, 95% CI: 12.77, 462.00). Furthermore, at the 9-month follow-up the odds of being stunted (height-for-age z-score < -2) was double for children with caregiver-reported geophagy (odds ratio [OR]: 2.27, 95% CI: 1.14, 4.51). These findings suggest that geophagy in young children may be an important unrecognized risk factor for EE and stunting.

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Geophagy is associated with environmental enteropathy and stunting in children in rural Bangladesh.

Lack of Cross-Protection against Diarrhea Due to Vibrio cholerae O139 (Bengal Strain) after Oral Immunization of Rabbits with V. cholerae O1 Vaccine Strain CVD103-HgR

Immune responses against enterotoxigenic Escherichia coli (ETEC) were examined in Bangladeshi adults with naturally acquired disease and compared to responses in age-matched Bangladeshi volunteers who had been orally immunized with a vaccine consisting of inactivated ETEC bacteria expressing different colonization factor antigens (CFs) and the B subunit of cholera toxin. B-cell responses in duodenal biopsy samples, feces, intestinal washings, and blood were determined. Because most of the patients included in the study were infected with ETEC expressing CS5, immune responses to this CF were studied most extensively. Vaccinees and patients had comparable B-cell responses against this antigen in the duodenum: the median numbers of antibody-secreting cells (ASC) were 3,300 immunoglobulin A (IgA) ASC/10(7) mononuclear cells (MNC) in the patient group (n = 8) and 1,200 IgA ASC/10(7) MNC in the vaccinees (n = 13) (not a significant difference). Similarly, no statistically significant differences were seen in the levels of duodenal B cells directed against enterotoxin among vaccinees and patients. A comparison of the capacities of the various methods used to assess mucosal immune responses revealed a correlation between numbers of circulating B cells and antibody levels in saponin extracts of duodenal biopsy samples (r = 0.58; n = 13; P = 0.04) after vaccination. However, no correlation was seen between blood IgA ASC and duodenal IgA ASC after two doses of vaccine. Still, a correlation between numbers of CF-specific B cells in blood sampled from patients early during infection and numbers of duodenal B cells collected 1 week later was apparent (r = 0.70; n = 10; P = 0.03).

R. Bradley Sack

Papers

Large outbreak of clinical cholera due to Vibrio cholerae non-01 in Bangladesh

Antimicrobial Resistance in Organisms Causing Diarrheal Disease

Geophagy is associated with environmental enteropathy and stunting in children in rural Bangladesh.

Lack of Cross-Protection against Diarrhea Due to Vibrio cholerae O139 (Bengal Strain) after Oral Immunization of Rabbits with V. cholerae O1 Vaccine Strain CVD103-HgR

Intestinal Immune Responses in Patients Infected with Enterotoxigenic Escherichia coli and in Vaccinees