Shigellose

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200,000 deaths per year globally, of which 65,000 are among children under the age of 5
10 to 100 bacilli are sufficient to cause the disease

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Cause

Shigellosis is caused by Shigella bacteria which are specialized clones of Escherichia coli. Four Shigella serogroups have been identified (Shigella dysenteriae, Shigella flexneri, Shigella boydii and Shigella sonnei) which include approximately fifty serotypes. The most common serogroup in France and other industrialized countries is S. sonnei. It is also emerging globally, including in developing countries, where it is replacing S. flexneri. Deadly outbreaks of Shigella dysenteriae serotype 1 (or Shiga's bacillus) have occurred in the past. However, no further strains of this serotype have been reported since 2011. Shigella induce a very rapid pathological process. These bacteria, which contain a virulence plasmid, first invade intestinal epithelial cells before subsequently attacking the tissue forming the colorectal mucosa. This process results in intense inflammation combined with severe tissue destruction.

Symptoms

The onset of the typical acute dysenteric form in adults occurs suddenly following a brief incubation period. It is characterized by abdominal pain often combined with vomiting and frequent passage of purulent stools containing bloody mucus, which can in some cases be hemorrhagic. Patients experience high fever and a decline in their general condition.

Complications may occur over the course of the disease particularly in infants and young children, causing severe forms of shigellosis that can potentially result in death. Several types of complications exist.

  • The main acute complications are:
  • hypoglycemia and gut-origin bacteremia and septicemia potentially complicated by septic shock
  • due to fever and significant fluid and electrolyte loss through diarrhea resulting in circulatory collapse and acute kidney failure
  • hemolytic uremic syndrome and complex-origin acute kidney failure which is fatal in most cases if patients cannot be treated quickly in an ICU
  • toxic megacolon and intestinal obstruction potentially complicated by perforation with peritonitis.
  • The main chronic complications are a prolonged state of malnutrition with severe failure to thrive in young children.

Transmission

Shigellosis is a classic example of a disease caused by poor hygiene. Shigella bacteria are spread by fecal-oral transmission. They are extremely infectious, with only 10 to 100 bacilli required to cause the disease. Humans are the sole reservoir and can eliminate these bacteria in their stools in the weeks following a dysenteric episode. In most cases, the disease is transmitted directly from patients to those around them. The disease is spread by fecally contaminated food and water containing Shigella bacteria and also by flies. Given the conditions in which it occurs, the disease mainly affects children living in poor and overpopulated regions of the world where health infrastructure and personal hygiene are inadequate. It can also affect soldiers on operations in these regions, humanitarian workers and tourists. In industrialized nations, small-scale outbreaks of S. sonnei may occur among groups of young children. In recent years, S. sonnei and S. flexneri have become epidemic in the male homosexual community.

Treatment and prevention

Unlike other diarrheal diseases, shigellosis cannot be treated solely by rehydration. The bacteria invade the colonic mucosa causing an inflammatory reaction that leads to destruction of infected tissue and even long-term complications. Antibiotic therapy generally results in rapid recovery without any sequelae. However, treatment has been complicated by the emergence of multidrug-resistant strains, particularly of S. sonnei and S. flexneri, which often appear resistant to all the traditional first-line antibiotics (ampicillin, tetracycline, sulfamethoxazole-trimethoprim, chloramphenicol, nalidixic acid) and therefore rarer, more expensive antibiotics are required (fluoroquinolones, third-generation cephalosporins and azithromycin). The first strains resistant to all these molecules have been observed in the UK, US, Australia and France. Given our knowledge of previous outbreaks, it is entirely reasonable to expect further shigellosis outbreaks of these highly antibiotic-resistant strains in future years.

As with all diarrheal diseases, preventive measures focus on improving hygiene: better education on personal hygiene, latrine construction, fly control, regulations on the use of human fecal matter in agriculture, clean drinking water supply. Unfortunately, such improvements do not appear a realistic prospect in many regions of the world that have seen rapid population expansion, particularly in urban areas. Vaccine development is therefore an important and urgent priority. Preventive work on this new sexually transmitted infection is necessary in the male homosexual community.

At the Institut Pasteur

The Institut Pasteur is responsible for surveillance of shigellosis cases in France (mainland France and French overseas territories) through the National Reference Center (CNR) for Escherichia coli, Shigella and Salmonella hosted by the Enteric Bacterial Pathogens Unit led by François-Xavier Weill (deputy heads: Sophie Lefèvre and Maria Pardos de la Gandara). In 2019, the CNR identified over 1,300 Shigella strains and detected eight S. sonnei outbreaks and one S. flexneri outbreak (see the CNR's annual report for 2019).

The vaccine strategy under development was initiated in the late 1990s by the Chemistry of Biomolecules Unit (UCB) led by Laurence Mulard and is now being pursued by the UCB in collaboration with the Innovation Laboratory: Vaccines (LIV) led by Armelle Phalipon. Its aim is to develop a subunit-type vaccine derived from perfectly defined sugars produced by chemical synthesis. These synthetic sugars are designed to functionally mimic major protective targets induced by natural infection, namely complex polysaccharides that are exposed on the surface of the bacterium and essential for its survival. Successful technology transfer has led to the production of a clinical batch of a monovalent vaccine candidate targeting a prevalent S. flexneri serotype. A Phase I clinical trial conducted in Israel with European funding demonstrated its excellent tolerability profile, lack of adverse effects, and induction of a very high antibody response. These data led to a Phase IIa clinical trial currently in progress in Kenya which is jointly funded by the Bill & Melinda Gates Foundation and the Wellcome Trust. The aim of this trial is to determine the tolerability of this vaccine candidate and its ability to induce an antibody response in the target population for the disease, namely very young children in endemic areas. The results will be available in 2023. A trial aimed at determining the protective capacity of this vaccine candidate in a controlled human infection model has been initiated in the US with support from the Bill & Melinda Gates Foundation.

Discovery research conducted in parallel at the UCB in collaboration with the LIV and backed by the European Union, Bill & Melinda Gates Foundation and Gates Medical Research Institute (Gates MRI) has led to the design of vaccine candidates for S. sonnei and other prevalent S. flexneri serotypes. The development of a quadrivalent vaccine targeting the predominant Shigella strains in circulation throughout the world is in progress in partnership with the Gates MRI.

In parallel to this vaccine research, collaborative work between several teams at the Institut Pasteur in Paris, Pasteur Network member institutes and the Military Health Department (SSA) has led to the development of dipstick tests enabling rapid diagnosis in just 15 minutes based on contact with a stool sample. To date, diagnostic dipstick tests for S. flexneri 2a (a prevalent endemic serotype) and S. dysenteriae 1 (the main epidemic serotype) have been developed and other dipstick tests are being developed for the main enteric pathogens.


January 2022

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