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      A Multicentre Study of Shigella Diarrhoea in Six Asian Countries: Disease Burden, Clinical Manifestations, and Microbiology


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          The burden of shigellosis is greatest in resource-poor countries. Although this diarrheal disease has been thought to cause considerable morbidity and mortality in excess of 1,000,000 deaths globally per year, little recent data are available to guide intervention strategies in Asia. We conducted a prospective, population-based study in six Asian countries to gain a better understanding of the current disease burden, clinical manifestations, and microbiology of shigellosis in Asia.

          Methods and Findings

          Over 600,000 persons of all ages residing in Bangladesh, China, Pakistan, Indonesia, Vietnam, and Thailand were included in the surveillance. Shigella was isolated from 2,927 (5%) of 56,958 diarrhoea episodes detected between 2000 and 2004. The overall incidence of treated shigellosis was 2.1 episodes per 1,000 residents per year in all ages and 13.2/1,000/y in children under 60 months old. Shigellosis incidence increased after age 40 years. S. flexneri was the most frequently isolated Shigella species (1,976/2,927 [68%]) in all sites except in Thailand, where S. sonnei was most frequently detected (124/146 [85%]). S. flexneri serotypes were highly heterogeneous in their distribution from site to site, and even from year to year. PCR detected ipaH, the gene encoding invasion plasmid antigen H in 33% of a sample of culture-negative stool specimens. The majority of S. flexneri isolates in each site were resistant to amoxicillin and cotrimoxazole. Ciprofloxacin-resistant S. flexneri isolates were identified in China (18/305 [6%]), Pakistan (8/242 [3%]), and Vietnam (5/282 [2%]).


          Shigella appears to be more ubiquitous in Asian impoverished populations than previously thought, and antibiotic-resistant strains of different species and serotypes have emerged. Focusing on prevention of shigellosis could exert an immediate benefit first by substantially reducing the overall diarrhoea burden in the region and second by preventing the spread of panresistant Shigella strains. The heterogeneous distribution of Shigella species and serotypes suggest that multivalent or cross-protective Shigella vaccines will be needed to prevent shigellosis in Asia.


          A prospective, population-based study in six Asian countries showed that Shigella appears to be more ubiquitous in Asian impoverished populations than previously thought, and antibiotic-resistant strains have emerged.

          Editors' Summary


          Infections that cause diarrhea are a major public health problem in developing countries and other places where resources are scarce, particularly in young children. Although deaths from diarrhea have decreased considerably in recent decades, diarrheal illnesses continue to cause some 2.5 million deaths each year. Shigella, a group of rod-shaped bacteria closely related to those that normally live in the human intestine, is known to cause severe diarrhea in both developed and developing countries, but the global impact of Shigella infection (shigellosis) has not been well characterized. Shigella exists in more than 40 different varieties, an increasing number of cases have been found to be resistant to available antibiotics, and no vaccine is licensed except one oral vaccine in China.

          Why Was This Study Done?

          The best information available on the impact of shigellosis has been based on historical estimates, which are subject to inaccuracy. More recent studies suggest that the older reports may have underestimated the impact of shigellosis. The authors of this study wanted to obtain more accurate, current estimates of the impact of shigellosis in developing countries.

          In addition, immunity to one type of Shigella does not necessarily provide protection against other types. Therefore, in order to develop an effective vaccine, researchers would need to know which types of Shigella are causing illness in affected parts of the world. Accordingly, the authors of this study also wanted to investigate the specific types of Shigella (called “serotypes” because they can be distinguished using serum from immune individuals) involved in cases of diarrhea.

          What Did the Researchers Do and Find?

          The researchers set up surveillance projects for diarrhea in six developing countries throughout Asia: at three rural or semirural sites (in China, Vietnam, and Thailand) and three urban slum sites (in Bangladesh, Pakistan, and Indonesia). They conducted information campaigns in each area to encourage residents to visit a participating clinic if they or their children developed diarrhea. Patients presenting with diarrhea were enrolled in the study and their medical findings were documented on standardized report forms. Stool or rectal swab specimens were obtained (with patient consent) and sent to laboratories to test for Shigella. When Shigella was identified, the bacteria was serotyped and tested for resistance to antibiotics. Because standard culture methods do not always detect Shigella when it is present, as a double-check, the researchers also tested some of the specimens for a type of DNA (called the ipaH gene) that serves as a molecular “footprint” of Shigella. Patients received treatment according to national guidelines.

          The study involved approximately 600,000 participants over 1–3 years, and detected approximately 60,000 cases of diarrhea. Shigella was found in 5% of diarrhea episodes, meaning that two new cases of shigellosis occurred per 1,000 people (of all ages) per year. Rates were higher in children and in people over age 40. Among children less than 5 years old, there were 13 new cases per 1,000 children per year. Rates of shigellosis were higher in the Bangladesh site than in the China, Pakistan, and Indonesia sites, which in turn had higher rates than the Vietnam and Thailand sites.

          In contrast to prior studies, no deaths were detected following episodes of shigellosis, and less than one-third of cases of shigellosis were associated with bloody diarrhea (dysentery).

          The distribution of serotypes was found to differ from one site to another and within a given site over time. A high percentage of Shigella detected at all sites were resistant to two or more antibiotics. Testing for the ipaH gene was able to identify Shigella in half of patients with bloody diarrhea whose routine stool cultures did not reveal Shigella.

          What Do These Findings Mean?

          This study found that shigellosis occurs in these Asian sites at a rate approximately 100 times higher than in industrialized countries. The finding that shigellosis frequently occurs in the absence of bloody stool means that government data collections using dysentery as part of the case definition can be expected to miss the majority of shigellosis cases. Also, the increased rate of shigellosis above age 40 shows that older people share significantly in the burden (and most likely the transmission) of shigellosis.

          The generally benign clinical course of Shigella-associated diarrhea calls into question the priority that this disease should receive in global vaccine development efforts, especially given the technological challenges posed by the complex and variable distribution of serotypes. Nonetheless, the emergence of multidrug-resistant strains clearly remains a threat, and raises the perennial issue of improved sanitation, rather than new antibiotics, as a long-term solution to the plethora of water-borne illnesses that disproportionately affect developing countries.

          Additional Information

          Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030353.

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          Most cited references44

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          Interval estimation for the difference between independent proportions: comparison of eleven methods

          Several existing unconditional methods for setting confidence intervals for the difference between binomial proportions are evaluated. Computationally simpler methods are prone to a variety of aberrations and poor coverage properties. The closely interrelated methods of Mee and Miettinen and Nurminen perform well but require a computer program. Two new approaches which also avoid aberrations are developed and evaluated. A tail area profile likelihood based method produces the best coverage properties, but is difficult to calculate for large denominators. A method combining Wilson score intervals for the two proportions to be compared also performs well, and is readily implemented irrespective of sample size.
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            Global burden of Shigella infections: implications for vaccine development and implementation of control strategies.

            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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              Double-blind vaccine-controlled randomised efficacy trial of an investigational Shigella sonnei conjugate vaccine in young adults.

              The aim of this double-blind randomised vaccine-controlled trial was to assess the efficacy of a conjugate vaccine composed of Shigella sonnei O-specific polysaccharide bound to Pseudomonas aeruginosa recombinant exoprotein A (S sonnei-rEPA) and of an oral, live-attenuated Escherichia coli/S flexneri 2a (EcSf2a-2) hybrid vaccine among military recruits in Israel at high risk of exposure to Shigella spp. We report here our preliminary findings on the efficacy of S sonnei-rEPA; we have not documented sufficient cases to assess the efficacy of EcSf2a-2. Between April, 1993, and August, 1994, male Israeli Military recruits aged 18-22 years were asked to take part in our study. We enrolled 1446 soldiers from seven separate field sites (groups A-G). Soldiers were randomly allocated one injection of S sonnei-rEPA and four doses of oral placebo (n = 576), four oral doses of EcSf2a-2 and one injection of saline placebo (n = 580), or one injection of meningococcal tetravalent control vaccine and four doses of oral placebo (n = 290). Because there were no cases of S flexneri 2a, the EcSf2a-2 and meningococcal vaccines were the control group. We defined S sonnei shigellosis as diarrhoea with a positive faecal culture for S sonnei. Each group of soldiers was followed up for 2.5-7.0 months. The primary endpoint was protective efficacy of S sonnei-rEPA against S sonnei shigellosis. Cases of culture-proven S sonnei shigellosis occurred in four groups of soldiers (groups A-D), which comprised 787 volunteers (312 received S sonnei-rEPA, 316 received EcSf2a-2, and 159 received meningococcal control vaccine). In groups A-C, cases of shigellosis occurred 70-155 days after vaccination, whereas in group D cases occurred after 1-17 days. In groups A-C, the attack rate of shigellosis was 2.2% in recipients of S sonnei-rEPA compared with 8.6% in controls (protective efficacy 74% [95% CI 28-100], p = 0.006). S sonnei-rEPA also showed significant protection against shigellosis in group D (43% [4-82], p = 0.039). Prevaccination and postvaccination ELISA measurements of antibody to S sonnei lipopolysaccharide among recipients of S sonnei-rEPA showed that the vaccinees who developed S sonnei shigellosis had significantly lower serum IgG and IgA responses to the homologous lipopolysaccharide than those who did not (p = < 0.05). One injection of S sonnei-rEPA confers type-specific protection against S sonnei shigellosis. The high antibody concentration induced by the conjugate vaccine in volunteers who did not develop shigellosis suggests that there is an association between serum antibody titre and protection.

                Author and article information

                Role: Academic Editor
                PLoS Med
                PLoS Medicine
                Public Library of Science (San Francisco, USA )
                September 2006
                12 September 2006
                : 3
                : 9
                [1 ]International Vaccine Institute, Seoul, Korea
                [2 ]Fudan University, Shanghai, China
                [3 ]National Institute of Hygiene and Epidemiology, Hanoi, Vietnam
                [4 ]Faculty of Allied Health Sciences, Thammasat University, Rangsit Center, Patumthani, Thailand
                [5 ]National Institute of Health Research and Development, Jakarta Indonesia, Ministry of Health, Jakarta, Indonesia
                [6 ]Centre for Health and Population Research, Dhaka, Bangladesh
                [7 ]Department of Paediatrics, The Aga Khan University, Karachi, Pakistan
                [8 ]United States Armed Forces Research Institute for Medical Sciences, Bangkok, Thailand
                [9 ]Centers for Vaccine Development, Baltimore, Maryland, United States of America
                Institut Pasteur, France
                Author notes
                * To whom correspondence should be addressed. E-mail: lseidlein@ 123456ivi.int
                06-PLME-RA-0131R2 plme-03-09-24
                Copyright: © 2006 von Seidlein et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 14
                Research Article
                Infectious Diseases
                Epidemiology/Public Health
                Infectious Diseases
                Custom metadata
                von Seidlein L, Kim DR, Ali M, Lee H, Wang XY, et al. (2006) A multicentre study of Shigella diarrhoea in six Asian countries: Disease burden, clinical manifestations, and microbiology. PLoS Med 3(9): e353. DOI: 10.1371/journal.pmed.0030353



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