ABSTRACT
Despite the global economic development, diarrhoea remains an important health concern worldwide. The epidemiological importance of Shigella spp. infections is very high, being the leading cause of bacterial diarrhoea. Clinically, shigellosis can manifest as watery diarrhoea or dysentery, with bloody stool, accompanied by fever and abdominal pain. Children and the elderly are most susceptible to developing severe forms. In this review, we highlight the rise of antibiotic-resistant Shigella spp. strains and provide an overview of recent shigellosis outbreaks. Shigellosis is an infectious disease that should not be neglected, as evidenced by the many outbreaks reported throughout the world.
Keywords: diarrhoea, outbreak, Shigella, antibiotic resistance
REZUMAT
În ciuda dezvoltării economice la nivel mondial, diareea rămâne o problemă importantă de sănătate publică. Importanța epidemiologică a infecțiilor cu Shigella spp. este foarte mare, fiind principala cauză bacteriană a diareei. Din punct de vedere clinic, shigeloza se poate manifesta sub formă de diaree apoasă sau dizenterie cu scaun cu sânge, însoțită de febră și dureri abdominale. Copiii și vârstnicii sunt susceptibili de a dezvolta forme severe. În acest articol prezentăm izbucniri epidemice recente de shigeloză și atragem atenția asupra apariției tulpinilor de Shigella spp. rezistente la antibiotice. Multe izbucniri epidemice au fost raportate în întreaga lume, indicând faptul că shigeloza este o boală infecțioasă care nu trebuie neglijată.
Cuvinte-cheie: diaree, outbreak, Shigella, rezistență la antibioticei
1. INTRODUCTION
Shigella spp. include serious pathogens responsible for diarrhoea – representing important and global public health concern. In 2016, Shigella was the main bacteria to cause diarrhoea and the second leading cause of diarrhoea-related mortality [1]. Annually around 165 million cases of shigellosis are registered and up to 100,000 deaths occur from it, the highest mortality rate being in children under 5 years of age [2]. In 1892, Sir William Osler defined dysentery as "one of the four great epidemic diseases of the world" [3]. The etiological agent of dysentery, Shigella dysenteriae, was discovered 5 years later by Kiyoshi Shiga during a Japanese epidemic [4].
Shigella is a facultative anaerobic, nonmotile Gram-negative bacillus. The genus Shigella encompasses four species: S. dysenteriae, S. flexneri, S. boydii, and S. sonnei. Each species represents a different serogroup (A to D) and is comprised of many serotypes, except for S. sonnei, which has only one [5]. The two species that are now contributing to the global epidemiological burden of shigellosis are S. flexneri and S. sonnei. S. boydii infections are found mainly on the Indian subcontinent. S. dysenteriae is rarely isolated today but has been previously involved in numerous cases of fatal dysentery [6]. Approximately 80% of Shigella spp. infections in wealthy nations are caused by S. sonnei [7]. In developing countries, the main species involved is Shigella flexneri. Humans are the only natural reservoir for Shigella spp. Shigella spp. infections occur through contact with infected people, or consumption of contaminated water and food. In developed countries, the bacteria are primarily transmitted via the faecal-oral route, whereas in developing countries the main transmission pathways are faecal-oral route, water-borne, and foodborne. It should be noted that the prevalence of sexually transmitted Shigella spp. infections among men who have sex with men (MSM) is rising in developed countries [8-9].
Several risk factors for shigellosis have been identified; the most vulnerable groups are infants and the elderly. In addition, studies have shown that children and the elderly shed the highest bacterial load and therefore they play an important role in the spread of infection. More serious forms of the disease are observed in malnourished individuals. Moreover, patients with various pathologies such as cancer, diabetes, or immunosuppressive conditions are more prone to contracting the infection. Furthermore, MSM represent an important risk group, given their sexual habits [10]. As a rule, Shigella spp. produce a selflimiting disease, although it can prove fatal in infants and immunosuppressed people. The clinical picture varies with the host's immune response; watery or bloody diarrhoea, fever, and abdominal pain may occur. It must be taken into account that the infectious dose is very low, between 10 and 100 organisms. In addition, the organism can adapt to unfavourable conditions, such as the acidic pH in the stomach [5].
2. RECENT OUTBREAKS OF SHIGELLA SPP.
ProMED-mail.org was used to identify several worldwide outbreaks of Shigella spp. reported in recent years [11]. European outbreaks are discussed in a separate section.
At the beginning of 2022, many cases of shigellosis were reported in Eureka, California – cases affecting both adults and children from several households. It was assumed that the infection was spread through one or more laundry machines after an infected person had contaminated the units. Dozens of cases were later confirmed and some of the infected people required hospitalization.
In 2021, in a suburb of Zimbabwe, an outbreak of shigellosis led to one death and hundreds of cases. It was hypothesized that the infection spread through contaminated water after the local authorities had implemented a 72-hour water-shedding regime. The infectious agent was identified as Shigella flexneri.
In 2021, there were six posts on ProMEDmail (ProMED) about shigellosis outbreaks in the USA – four of them talked about an epidemic involving homeless people in San Diego County. The first cases were reported on August 16, 2021, and the symptom onset for the last case was on November 27, 2021. Forty-six cases were confirmed, while five were considered probable cases. The infection source had not been identified at the time of the report. It should be mentioned that in 2020, a total of 240 cases of shigellosis were reported in San Diego County, while the previous year had the greatest number of cases since 1995 (426 cases). In 2021, another outbreak was reported at a splash park near Wichita, USA. The survey was far from simple, more than 200 people who had visited the park responded to the call. Eight people who visited the park on June 11 were diagnosed with shigellosis. The investigation showed that none of the water samples had animal-linked contamination. It was also pointed out that the visitors to the park have tested positive for the norovirus, sapovirus, and enteropathogenic Escherichia coli. The park is supplied by a water line from the City of Goddard.
At the end of 2020, several cases of shigellosis have been reported in Kerala, India. In the Kozhikode district, 26 cases of diarrhoea have been identified in recent years. Cases of shigellosis were also reported in the areas Mundikkalthazham, Kottaparambu, and Wayanad. In August 2020, hundreds of cases of Shigella spp. infections were registered in eastern China; approximately 300 people, especially children and seniors, were hospitalized as a result. Moreover, the city's water supply was interrupted. Although water supply services have improved in recent years, many Chinese still consume bottled or boiled water.
In March 2019, an outbreak of shigellosis was reported in Guam, USA. Nine of the ten reported cases were confirmed. A year ago, in the same region, 29 cases of shigellosis were reported and 23 confirmed. In February 2019, in Mongolia, authorities decided to close several fast-food restaurants after more than 200 people had presented food poisoning symptoms (diarrhoea, vomiting, and fever), many of them needing hospitalization. It was revealed that 35 restaurant employees had not been examined by a doctor to decide whether they were fit to handle food. Furthermore, the hygiene regulations were not properly followed in that restaurant. Klebsiella spp. was isolated from the water in the restaurant, Escherichia coli was detected in a soda machine, and 4 people contracted Shigella after coming in contact with restaurant staff. The investigation concluded that shigellosis might be the cause of the food poisoning symptoms.
In 2019, in the northern Negev city of Arad, Israel, a 4-year-old girl was diagnosed with dysentery caused by Shigella spp. The girl's parents reached out to other parents whose children attended the same kindergarten. As a result, they learned that numerous other children were sick, as well. It was discovered that the food served to the children was not tested daily and was not transported at an adequate temperature.
In 2018, 44 suspected cases and 22 confirmed cases of Shigella sonnei infections were reported in a retirement community in Shelburne, USA. The source of infection had not been identified. The isolated strains proved susceptible to ciprofloxacin and resistant to ampicillin and trimethoprim-sulfamethoxazole. An earlier post from 2017 draws attention to Shigella spp. antibiotic resistance. In certain regions of India, such as Telangana, many cases of shigellosis were recorded. Ciprofloxacin is an antibiotic frequently used in the treatment of Shigella spp. infections – infections with resistant strains are associated with a delay in patient recovery or a high mortality rate. Research shows that strains that harbour the quinolone-resistance gene are also resistant to other antibiotics used in the treatment of shigellosis, including azithromycin, trimethoprim-sulfamethoxazole, amoxicillinclavulanic acid, and ampicillin.
In November 2017, an outbreak of Shigella flexneri was reported at a school in San Pedro de Colalao in northern Argentina. At least 88 students and teachers reported vomiting, diarrhoea (in some cases with blood), abdominal pain, and high fever. In June, a dysentery outbreak was suspected at a festival in Pennsylvania. The event participants complained of feeling sick in numerous posts on social networks after the festival. In the same month, an outbreak of dysentery was reported in Vietnam, in Lai Chau provinces; as a result, one death was recorded and 60 people required hospitalization. The first cases of dysentery have been reported as early as the end of February. In April, dozens of cases were notified and Shigella flexneri was isolated from all tested patients. The outbreak was caused by people's unsanitary behaviour – only 7% of residents in that area have hygienic toilets – combined with the hot, humid weather. Table 1 summarizes the outbreaks presented in this section.
3. SHIGELLOSIS, AN IMPORTANT THREAT IN EUROPE
According to the ECDC report released in 2020, 30 countries have reported 6,425 cases of shigellosis, of which 6,337 were confirmed. The majority (61.3%) were registered in Germany, France, the Netherlands, and the UK. For 64% of the confirmed cases, a travel history was collected, and 42.9% of the cases had one, particularly in India and Morocco. The highest notification rates were from children under 5 years of age and from men between 25 and 44 years of age [8].
The United Kingdom reported an increase in extensively drug resistant (XDR) Shigella sonnei infections, primarily in MSM, in January 2022 (47 cases of XDR S. sonnei between September 1, 2021 and January 10, 2022). Over 200 cases of S. sonnei infections linked to the UK cluster, with sampling dates ranging from 2020 to 2022, have been reported in nine European countries until February 2022: Austria, Belgium, Denmark, France, Germany, Ireland, Italy, Norway, and Spain [12]. In response to these events, the WHO Regional Office for Europe issued an alert in March 2022 regarding the rapid increase in cases of gastrointestinal infections caused by XDR Shigella sonnei among MSM [13]. Moreover, England has seen an increase in sexually transmitted Shigella flexneri infections in adult males in recent years. It is worrying because of the resurgence of azithromycin-resistant S. flexneri serotype 3a, and the emergence of two novel multidrug-resistant clades of S. flexneri 2a and S. flexneri 1b [14].
In 2021, Zayet et al. drew attention to an emerging multidrug-resistant sexually transmitted pathogen, Shigella sonnei, in Franche-Comté, France. They described three cases of multidrug-resistant S. sonnei in MSM. One of the patients was HIV-positive and the other two had received pre-exposure prophylaxis against HIV. The authors proposed the parenteral administration of third-generation cephalosporins as empiric therapy for dysentery in MSM [15]. A study performed in Spain between 2015-2019 focused on the analysis of Shigella spp. Isolated from MSM (44 S. flexneri and 26 S. sonnei). In terms of antimicrobial susceptibility, 80% of the samples showed azithromycin resistance, 65.7% showed resistance to trimethoprimsulfamethoxazole, and 32.8% to ciprofloxacin. Almost a third (27.1%) of the strains were resistant to all three antimicrobials [16].
In Poland, 321 cases of shigellosis were registered between 2018 and 2019. Most of the cases were diagnosed in individuals between 25 and 44 years of age, with twenty-seven subjects requiring hospitalization. In 2018, two major outbreaks were reported. The first outbreak (77 cases, 32 laboratory-confirmed) occurred during the European Rainbow Gathering, an event in which people assemble to live in a camp. S. sonnei was isolated from a natural water source. The second outbreak was linked to tourists traveling to Albania [17].
In August 2020, an outbreak in Denmark afflicted 44 Danes, ranging in age from 0 to 75; 13 of them required hospitalization. A case was defined as "a patient with either a culture-positive sample for Shigella sonnei or people PCR-positive for the ipaH gene". The investigation revealed that the majority of them consumed fresh mint that they had purchased in and around the Copenhagen region. It was discovered that the source was a local food trade, after twelve distinct locations were examined [11].
An outbreak occurred in two youth camps in Belgium in the summer of 2019. In the first camp, 47 people out of 162 complained of gastrointestinal symptoms, and Shigella sonnei was isolated in the case of 25 of them. Only a week later, more than 20 cases were reported in a camp located nearby. The next-generation sequencing investigation confirmed the clustering of isolates from the two camps. Following the collaboration with three European Public Health Institutes, it was hypothesized that the outbreak source is a person who joined the camp after returning sick from Guatemala. This outbreak shows the importance of next-generation sequencing and collaboration between institutions for the successful resolution of an outbreak [18].
Extended-spectrum-lactamase
producing Shigella spp. have become more prevalent in recent years, posing a global health threat, particularly in Asia, though certain strains are also starting to appear in Europe. The first instance of ESBL-producing Shigella sonnei infection in Italy was documented in August 2018 in a 10-year-old child who experienced abdominal pain and bloody diarrhoea. The child had previously travelled to Albania [19]. At the end of 2018, 18 cases of shigellosis were identified in a refugee centre on Samos Island, Greece; Afghans made up the majority of the infected people. Shigella flexneri 1b was isolated in 14 cases, and S. sonnei in 3 cases. The strains were multidrug resistant. S. flexneri 1b isolates had the capacity to produce ESBL. Shigella flexneri 2a was isolated in a single case and the antibiogram showed resistance to sulfamethoxazole, trimethoprim, and pefloxacin. These data suggest that certain infectious diseases such as shigellosis could come to the fore in the actual context of a mass influx of migrants [20].
In 2018, several outbreaks with Shigella sonnei were reported in England, and whole-genome sequencing revealed that the same strain was involved. According to the research, the majority of the patients had eaten at seven locations that served Indian food – coriander was the offending menu item. Following the phylogenetic analysis, it was found that the outbreak-causing strain was part of a larger multidrug-resistant clade associated with travel to Pakistan. Therefore, the resistant strain was transmitted by a food truck [21]. Table 2 summarizes the outbreaks presented in this section.
4. DISCUSSION AND CONCLUSIONS
Finally, as we have previously stated in a 2021 published article: "Infections do not respect customs" [22]. "Even though most reports come from developing countries, cases are identified everywhere in the world. In this context, the implementation of more rigorous preventive and control measures is necessary. There is a continuous need to support and develop the public health units (human resources, equipment, reagents) and for a better collaboration between public health authorities inside and outside countries. New surveillance methods should be implemented, as PulseNet network that use DNA fingerprints of bacteria from patients to find clusters of disease and prove outbreaks, all over the world" [22].
By identifying ongoing outbreaks, health officials can contain them while industry and regulatory agencies implement changes to increase the safety of the food and water supply. At same time, it is essential to raise awareness towards the spread of multiresistant Shigella strains both in Europe and worldwide – it is high time we used antibiotics judiciously. Updated surveillance measures must be designed and put into practice. Infection control relies heavily on compliance with hygiene regulations. Additionally, the formulation of a vaccine is crucial in this context. According to WHO, "Development of Shigella vaccines has been identified as priority by IVB's Product Development for Vaccines Advisory Committee and WHO Preferred Product Characteristics (PPCs) for a safe, effective and affordable vaccine to reduce mortality and morbidity due to dysentery and diarrhoea caused by Shigella in children under 5 years of age".
Conflict of Interest: The authors have no conflict of interest to disclose.
Funding: This work received no funding.
Ethical Approval: Not applicable.
Informed Consent: Not applicable.
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Abstract
Despite the global economic development, diarrhoea remains an important health concern worldwide. The epidemiological importance of Shigella spp. infections is very high, being the leading cause of bacterial diarrhoea. Clinically, shigellosis can manifest as watery diarrhoea or dysentery, with bloody stool, accompanied by fever and abdominal pain. Children and the elderly are most susceptible to developing severe forms. In this review, we highlight the rise of antibiotic-resistant Shigella spp. strains and provide an overview of recent shigellosis outbreaks. Shigellosis is an infectious disease that should not be neglected, as evidenced by the many outbreaks reported throughout the world.