A-Z Index × Submit A-Z Index × Submit A-Z Index Search Dropdown × Submit Facebook Twitter LinkedIn Syndicate Emerging Infectious Disease journal ISSN: 1080-6059 Disclaimer: Early release articles are not considered as final versions. Any changes will be reflected in the online version in the month the article is officially released.
Existing methods to identify patients infected with Salmonella enterica serovar Typhi or Paratyphi are not adequately accurate, affordable, or efficient. We evaluated the performance of antibodies to Salmonella Typhi hemolysin E (HlyE) and lipopolysaccharide (LPS) in Bangladesh, Nepal, and Pakistan for enteric fever case identification. We measured plasma concentrations of HlyE and LPS IgA in blood culture–confirmed enteric fever case-patients and in febrile controls with laboratory-confirmed alternative etiologies. Combining LPS and HlyE IgA discriminated enteric fever cases from other febrile illnesses with an area under the receiver operating characteristic curve (AUC) of 0.93 (specificity 86% at a fixed 90% sensitivity). LPS IgA alone performed nearly as well (AUC 0.92). In children < 5 years of age, the combined biomarkers outperformed either biomarker alone (AUC 0.96 vs. 0.94 for HlyE, 0.93 for LPS). Our findings support use of HlyE and LPS IgA–based assays for enteric fever diagnosis in endemic settings.
Enteric fever is a systemic infection caused by gram-negative bacteria Salmonella enterica serovars Typhi and Paratyphi. Enteric fever is transmitted through contaminated food and water and is common where sanitation is inadequate ( 1 ). Accurate diagnosis is challenged by nonspecific clinical manifestation and poor-performing diagnostics ( 2 – 4 ). Definitive identification requires Salmonella Typhi or Paratyphi isolation from blood or bone marrow, which is performed in a microbiology laboratory and produces results after several days. Blood culture is highly specific but poorly sensitive, expensive, slow, and widely inaccessible where the disease is most common ( 5 , 6 ); Widal serum-agglutination test is frequently used despite poor accuracy in endemic settings ( 7 ). In a previous evaluation, commercial typhoid rapid diagnostics failed to perform with both sensitivity and specificity >90% ( 8 ).
Two antigens, pore-forming cytotoxin hemolysin E (HlyE) and Salmonella Typhi lipopolysaccharide (LPS), have shown promise for typhoid serodiagnostic assays; previous studies were limited by small sample size and narrow geographic scope ( 9 – 11 ). In a pediatric cohort in Nigeria, LPS-specific and HlyE-specific IgA provided good discrimination between Typhi and other bacteremias; the receiver operator characteristic (ROC) area under the curve (AUC) for LPS-specific IgA was < 0.90 (AUC 0.74) for HlyE-specific IgA ( 12 ). In previous work studying Salmonella Typhi cases and other bacteremias in Nepal, we found the combination of HlyE and LPS IgA was 90% sensitive and 92% specific (AUC 0.95) ( 9 ). Those studies did not include Salmonella Paratyphi A cases; controls had primarily other bacteremias or no etiology identified. The same biomarkers demonstrated high accuracy in a dual-antigen lateral flow format in Pakistan (AUC 0.93) ( 13 ) and Bangladesh (AUC 0.97) ( 14 ).
The multisite SeroEpidemiology and Environmental Surveillance (SEES) Study measured longitudinal HlyE and LPS antibody responses in blood culture–positive enteric fever cases and estimated enteric fever seroincidence in disease-endemic com…