A composite severity score that is consistent with severe disease or dysentery could be a pragmatic clinical end point for severe shigellosis in vaccine trials, according to data published in Clinical Infectious Disease. Investigators compared characteristics of moderate to severe diarrhea (MSD) cases between children with culture positive Shigella and culture-negative, qPCR-attributable Shigella and derived a new clinical severity score.

In total, 5670 children in the Global Enteric Multicenter Study (GEMS) with culture-negative, qPCR-attributable Shigella, defined as an ipaH gene cycle threshold less than 27.9, were included.  Shigella was not detected by culture or qPCR at any Ct value in 3397 children (60%). Of the 745 children (13.1%) with Shigella isolated from culture, 727 cultures (97.5%) were able to be detected by qPCR. Of the 4925 culture-negative cases of MSD, qPCR-attributable Shigella infections were identified in 852 children (17.3%)  and qPCR-unattributable Shigella infections were identified in 676 children (13.7%).

Compared to the 745 patients with culture-positive Shigella MSD, the 852 patients with culture-negative/qPCR-attributable cases were more likely to be younger than 12 months, stunted, have a longer duration of diarrhea, and less likely to have high stool frequency or a fever. Investigators found no difference in dehydration, hospitalization, or severe classification from a modified Vesikari score.

The factors associated with mortality were ages younger than 12 months, diarrhea duration prior to presentation, vomiting, stunting, wasting, and hospitalization. Based on model-fit, the 3 primary clinical features maximally associated with mortality includes clinician decision to hospitalize, dehydration status, and diarrhea duration prior to presentation. A model-derived score assigning points for dehydration, hospital admission, and longer diarrhea duration was not significantly better at predicting 14-day mortality than a modified Vesikari score. During follow-up, 42 children (2.8%) with Shigella-attributable diarrhea died, and 22 of these deaths occurred within 14 days after presentation. There was no difference in risk of death between culture negative/qPCR-attributable shigellosis and culture-positive shigellosis (adjusted hazard ratio [aHR], 1.1; 95% CI, 0.5-2.6).

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This study was limited because of its exploratory nature, the limited number of deaths, and the use of AIC vs P-value to determine severity scores, which did not account for multiple comparisons. Because bacteria other than Shigella was more common in culture-negative/qPCR-attributable Shigella; investigators could not exclude the possibility that a small subset of this group had bacterial etiology other than Shigella.

Investigators found that the simplified severity score performed similarly to a modified Vesikari score. They concluded that “a composite severity score consistent with severe disease or dysentery may be a pragmatic clinical end point (confirmed by culture and secondarily, by qPCR) in vaccine trials.” The reliance on culture for microbiologic confirmation may miss substantial numbers of Shigella cases, investigators noted, but it is currently required to measure serotype specific immunity.

Disclosure: A study author declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


Pavlinac PB, Platts-Mills JA, Tickell KD, et al. The clinical presentation of culture-positive and culture-negative, qPCR-attributable shigellosis in the Global Enteric Multicenter Study and derivation of a Shigella severity score: implications for pediatric Shigella vaccine trialsClin Infect Dis. Published online October 12, 2020. doi:10.1093/cid/ciaa1545