Shigella infection in children and adults: a formidable foe
Authors: Karen L Kotloff
Journal: The Lancet Global Health (2017)

Mortality from diarrhoeal diseases overall and from Shigella-associated diarrhoeal diseases specifically have declined substantially during the past 30 years. Global reductions in malnutrition and measles incidence, and increased access to oral rehydration, antibiotics, and micronutrients undoubtedly have contributed to these trends. The near disappearance of Shigella dysenteriae type 1 infections since the late 1990s is another important factor. Although this strain contributes minimally to endemic shigellosis, it is capable of causing large devastating epidemics and pandemics—particularly in conditions of extreme overcrowding, poor sanitation and hygiene, and high density of houseflies (Musca domestica)—that are often triggered by social upheaval or natural disaster. Four S dysenteriae type 1 pandemics have emerged during the last century: in Central America (1968–72), south Asia (1980s), central Africa (1980s), and east Africa (1990s). The pandemic strains have been resistant to multiple antibiotics and were associated with high attack rates (more than 30% of some populations developed illness) and case-fatality, affecting nearly all age groups.1Gangarosa EJ Perera DR Mata LJ Mendizabal-Morris C Guzman G Reller LB Epidemic Shiga bacillus dysentery in Central America. II. Epidemiologic studies in 1969.J Infect Dis. 1970; 122: 181-190Crossref PubMed Scopus (77) Google Scholar, 2Public health impact of Rwandan refugee crisis: what happened in Goma, Zaire, in July, 1994? Goma Epidemiology Group.Lancet. 1995; 345: 339-344Summary Full Text PDF PubMed Scopus (300) Google Scholar, 3Rahaman MM Khan MM Aziz KMS Islam MS Kibriya AK An outbreak of dysentery caused by Shigella dysenteriae type 1 on a Coral Island in the Bay of Bengal.J Infect Dis. 1975; 132: 15-19Crossref PubMed Scopus (72) Google Scholar Even in the face of reduced mortality, the burden of Shigella infection remains unacceptably high. The Global Burden of Disease Consortium ranked Shigella as the second leading cause of diarrhoeal deaths in the world in 2015 and the third leading cause of diarrhoeal deaths in children younger than 5 years.4GBD Diarrhoeal Diseases CollaboratorsEstimates of global, regional, and national morbidity, mortality, and aetiologies of diarrhoeal diseases: a systematic analysis for the Global Burden of Disease Study 2015.Lancet Infect Dis. 2017; 17: 909-948Summary Full Text Full Text PDF PubMed Scopus (663) Google Scholar Recent large epidemiological studies5Kotloff KL Nataro JP Blackwelder WC et al.Burden and aetiology of diarrhoeal disease in infants and young children in developing countries (the Global Enteric Multicenter Study, GEMS): a prospective, case-control study.Lancet. 2013; 382: 209-222Summary Full Text Full Text PDF PubMed Scopus (2261) Google Scholar, 6Liu J Platts-Mills JA Juma J et al.Use of quantitative molecular diagnostic methods to identify causes of diarrhoea in children: a reanalysis of the GEMS case-control study.Lancet. 2016; 388: 1291-1301Summary Full Text Full Text PDF PubMed Scopus (467) Google Scholar from low-income countries have confirmed the importance of Shigella as a cause of diarrhoeal morbidity among infants and young children. The ongoing burden shown in these studies raises a key question: how does this bacterium continue to elude control efforts and cause high rates of morbidity and mortality? One explanation is that Shigella has the ability to cause disease with a small inoculum, facilitating spread from person to person in settings where sanitation and hygiene are compromised.7DuPont HL Levine MM Hornick RB Formal SB Inoculum size in shigellosis and implications for expected mode of transmission.J Infect Dis. 1989; 159: 1126-1128Crossref PubMed Scopus (424) Google Scholar Additionally, it has the capacity to produce enduring intestinal injury with mucosal destruction and intense inflammation, while subverting the host immune system to its survival advantage. The ease with which Shigella acquires antibiotic resistance from mobile genetic elements also plays a part: high levels of resistance to previous first-line agents have left azithromycin, ciprofloxacin, and ceftriaxone as the drugs of choice for empiric therapy. However, resistance is now emerging to these agents and spreading globally. As a result, international disease control programmes have declared antibiotic-resistant Shigella as a serious threat requiring new interventions, which include vaccine development. Finally, the impact of malnutrition and immunodeficiency related to the HIV epidemic on susceptibility and severity of the disease must be considered. The ongoing challenges that Shigella presents require continuing vigilance to identify gaps in understanding of disease epidemiology that might lead to improved control efforts. In this issue of The Lancet Global Health, Kirkby Tickell and colleagues8Tickell KD Brander RL Atlas HE Pernica JM Walson JL Pavlinac PB Identification and management of Shigella infection in children with diarrhoea: a systematic review and meta-analysis.Lancet Glob Health. 2017; 5: e1235-e1248Summary Full Text Full Text PDF PubMed Scopus (40) Google Scholar did three systematic reviews (for mortality, diagnostic value, and antibiotic treatment of Shigella and dysentery) and meta-analyses, where appropriate, of studies in resource-limited settings to examine factors that might contribute to the persistent disease burden. They examined studies of patients (mostly infants and young children) admitted to hospital with diarrhoea, and showed that Shigella infection is associated with mortality (pooled odds ratio 2·8, 95% CI 1·6–4·8; p=0·000), whereas dysentery was not (1·3, 0·7–2·3; p=0·37). Malnutrition and often persistent diarrhoea were independent risk factors for death in patients infected with Shigella. These findings reflect a well known cycle, in which malnourished children have longer durations of diarrhoea associated with Shigella than in those who are not malnourished;9Black RE Brown KH Becker S Malnutrition is a determining factor in diarrheal duration, but not incidence, among young children in a longitudinal study in rural Bangladesh.Am J Clin Nutr. 1984; 39: 87-94Crossref PubMed Scopus (210) Google Scholar in turn, there is a significant negative relationship between diarrhoeal episodes associated with Shigella and linear growth.10Black RE Brown KH Becker S Effects of diarrhea asociated with specific enteropathogens on the growth of children in rural Bangladesh.Pediatrics. 1984; 73: 799-805PubMed Google Scholar Stunting has an established association with increased mortality in infants and young children.11Olofin I McDonald CM Ezzati M et al.Associations of suboptimal growth with all-cause and cause-specific mortality in children under five years: a pooled analysis of ten prospective studies.PLoS One. 2013; 8: e64636Crossref PubMed Scopus (272) Google Scholar Tickell and colleagues8Tickell KD Brander RL Atlas HE Pernica JM Walson JL Pavlinac PB Identification and management of Shigella infection in children with diarrhoea: a systematic review and meta-analysis.Lancet Glob Health. 2017; 5: e1235-e1248Summary Full Text Full Text PDF PubMed Scopus (40) Google Scholar subsequently reviewed the randomised controlled trials that have informed current WHO recommendations to administer antibiotics to all children with dysentery, assuming that most episodes are caused by Shigella. They recognised that studies have not addressed whether children with Shigella infection who present with watery diarrhoea rather than with dysentery also might benefit from treatment. Most Shigella infections manifest as watery diarrhoea without progressing to dysentery, so many children fall into this category but would not be considered eligible for treatment according to the WHO guidelines. The authors' findings suggest that these children are at risk for adverse outcomes from their Shigella infection because the association with death is stronger for all Shigella-associated diarrhoea than for dysentery alone. The implication is that the exclusion of Shigella-associated watery diarrhoea from treatment recommendations might be leaving many children vulnerable to acute and subacute adverse clinical manifestations. Further investigation is needed to determine how these children might be identified in low-resource settings and whether they might benefit from treatment. Those who study the burden of Shigella infection must be mindful to distinguish the severe illnesses that occur in the setting of pandemic S dysenteriae type 1. Although differences in the mortality could not be detected among patients admitted to hospital in the studies reviewed by Tickell and colleagues,8Tickell KD Brander RL Atlas HE Pernica JM Walson JL Pavlinac PB Identification and management of Shigella infection in children with diarrhoea: a systematic review and meta-analysis.Lancet Glob Health. 2017; 5: e1235-e1248Summary Full Text Full Text PDF PubMed Scopus (40) Google Scholar in its epidemic form, S dysenteriae type 1 is far more lethal than any other Shigella spp. Health-care professionals, affected patients, and those at risk can hope that S dysenteriae type 1 will recede into distant history, never to emerge again, while investigators continue to vigilantly study this formidable foe to prepare for growing antibiotic resistance and other new challenges yet to come. I declare no competing interests. Identification and management of Shigella infection in children with diarrhoea: a systematic review and meta-analysisCurrent WHO guidelines appear to manage dysentery effectively, but might miss opportunities to reduce mortality among children infected with Shigella who present without bloody stool. Further studies should quantify potential decreases in mortality and morbidity associated with antibiotic therapy for children with non-dysenteric Shigella infection. Full-Text PDF Open Access