The Clinical Presentation of Culture-positive and Culture-negative, Quantitative Polymerase Chain Reaction (qPCR)-Attributable Shigellosis in the Global Enteric Multicenter Study and Derivation of a Shigella Severity Score: Implications for Pediatric Shigella Vaccine Trials

• Authors: Robert Breiman, Emory University; Patricia B Pavlinac, University of Washington; James A Platts-Mills, University of Virginia; Kirkby D Tickell, University of Washington; Jie Liu, University of Virginia; Jane Juma, Kenya Medical Research Institute (KEMRI); Furqan Kabir, Aga Khan University; Joseph Nkeze, University of Maryland Baltimore; Catherine Okoi, The Gambia at the London School of Hygiene and Tropical Medicine; Darwin J Operario, University of Virginia; Jashim Uddin, University of Virginia; Shahnawaz Ahmed, International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR, B); Pedro L Alonso, University of Barcelona; Martin Antonio, The Gambia at the London School of Hygiene and Tropical Medicine; Stephen M Becker, Science Applications International Corporation (SAIC), Richmond; Abu SG Faruque, International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR, B); Barry Fields, Kenya Office of the US Centers for Disease Control and Prevention,, Nairobi; Jean Gratz, University of Virginia; Rashidul Haque, Emory University; Anowar Hossain, nternational Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR, B); M Jahangir Hossain, The Gambia at the London School of Hygiene and Tropical Medicine; Sheikh Jarju, The Gambia at the London School of Hygiene and Tropical Medicine; Farah Qamar, Aga Khan University; Najeeha T Iqbal, Aga Khan University; Brenda Kwambana, The Gambia at the London School of Hygiene and Tropical Medicine, Banjul; Inacio Mandomando, Centro de Investigação em Saúde da Manhiça, Maputo; Timothy L McMurry, University of Virginia; Caroline Ochieng, Kenya Medical Research Institute (KEMRI); John B Ochieng, Kenya Medical Research Institute (KEMRI); Melvin Ochieng, Kenya Medical Research Institute (KEMRI); Clayton Onyango, Kenya Office of the US Centers for Disease Control and Prevention,, Nairobi; Sandra Panchalingam, University of Maryland, Baltimore; Adil Kalam, Aga Khan University; Fatima Aziz, Aga Khan University; Shahida Qureshi, Aga Khan University; Thandavarayan Ramamurthy, National Institute of Cholera and Enteric Diseases, Kolkata; James H Roberts, University of Virginia; Debasish Saha, The Gambia at the London School of Hygiene and Tropical Medicine, Banjul; Samba O Sow, Centre pour le Développement des Vaccins; Suzanne E Stroup, University of Virginia; Dipika Sur, National Institute of Cholera and Enteric Diseases, Kolkata; Boubou Tamboura, Centre pour le Développement des Vaccins, Bamako; Mami Taniuchi, University of Virginia; Sharon M Tennant, University of Maryland School of Medicine, Baltimore; Anna Roose, University of Maryland School of Medicine, Baltimore; Deanna Toema, University of Maryland School of Medicine, Baltimore; Yukun Wu, Sanofi Pasteur; Anita Zaidi, Bill and Melinda Gates Foundation; James P Nataro, University of Virginia; Myron M Levine, University of Maryland School of Medicine, Baltimore; Eric R Houpt, University of Virginia; Karen L Kotloff, University of Maryland School of Medicine, Baltimore
• Journal Title: CLINICAL INFECTIOUS DISEASES
• Volume: Volume 73, Number 3
• Publisher: OXFORD UNIV PRESS INC | 2021-08-01, Pages E569-E579
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1093/cid/ciaa1545
• Subjects: Health Sciences, Medicine and Surgery
• Keywords: Science & Technology; Life Sciences & Biomedicine; Immunology; Infectious Diseases; Microbiology; MIDDLE-INCOME COUNTRIES; DIARRHEAL DISEASE; YOUNG-CHILDREN; INFANTS; GEMS; ETIOLOGY; RISK; BURDEN; DEATH

Abstract

Background: Shigella is a leading cause of childhood diarrhea and target for vaccine development. Microbiologic and clinical case definitions are needed for pediatric field vaccine efficacy trials. Methods: We compared characteristics of moderate to severe diarrhea (MSD) cases in the Global Enteric Multicenter Study (GEMS) between children with culture positive Shigella to those with culture-negative, quantitative polymerase chain reaction (qPCR)-Attributable Shigella (defined by an ipaH gene cycle threshold <27.9). Among Shigella MSD cases, we determined risk factors for death and derived a clinical severity score. Results: Compared to culture-positive Shigella MSD cases (n = 745), culture-negative/qPCR-Attributable Shigella cases (n = 852) were more likely to be under 12 months, stunted, have a longer duration of diarrhea, and less likely to have high stool frequency or a fever. There was no difference in dehydration, hospitalization, or severe classification from a modified Vesikari score. Twenty-Two (1.8%) Shigella MSD cases died within the 14-days after presentation to health facilities, and 59.1% of these deaths were in culture-negative cases. Age <12 months, diarrhea duration prior to presentation, vomiting, stunting, wasting, and hospitalization were associated with mortality. A model-derived score assigned points for dehydration, hospital admission, and longer diarrhea duration but was not significantly better at predicting 14-day mortality than a modified Vesikari score. Conclusions: A composite severity score consistent with severe disease or dysentery may be a pragmatic clinical endpoint for severe shigellosis in vaccine trials. Reliance on culture for microbiologic confirmation may miss a substantial number of Shigella cases but is currently required to measure serotype specific immunity.