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.

Pavlinac, PBORCID logo; Platts-Mills, JA; Tickell, KD; Liu, J; Juma, J; Kabir, F; Nkeze, J; Okoi, C; Operario, DJ; Uddin, J; +42 more...Ahmed, S; Alonso, PL; Antonio, MORCID logo; Becker, SM; Breiman, RF; Faruque, AS; Fields, B; Gratz, J; Haque, R; Hossain, A; Hossain, MJORCID logo; Jarju, S; Qamar, F; Iqbal, NT; Kwambana, B; Mandomando, I; McMurry, TL; Ochieng, C; Ochieng, JB; Ochieng, M; Onyango, C; Panchalingam, S; Kalam, A; Aziz, F; Qureshi, S; Ramamurthy, T; Roberts, JH; Saha, D; Sow, SO; Stroup, SE; Sur, D; Tamboura, B; Taniuchi, M; Tennant, SM; Roose, A; Toema, D; Wu, Y; Zaidi, A; Nataro, JP; Levine, MM; Houpt, ER; Kotloff, KL and (2021) 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. Clinical Infectious Diseases, 73 (3). e569-e579. ISSN 1058-4838 DOI: 10.1093/cid/ciaa1545
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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.


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