Diagnostic Value of Clinical Features to Distinguish Enteric Fever From Other Febrile Illnesses in Bangladesh, Nepal, and Pakistan

Abstract

Background: Enteric fever, a bacterial infection caused by Salmonella enterica serotypes Typhi and Paratyphi A, frequently presents as a nonlocalizing febrile illness that is difficult to distinguish from other infectious causes of fever. Blood culture is not widely available in endemic settings and, even when available, results can take up to 5 days. We evaluated the diagnostic performance of clinical features, including both reported symptoms and clinical signs, of enteric fever among patients participating in the Surveillance for Enteric Fever in Asia Project (SEAP), a 3-year surveillance study in Bangladesh, Nepal, and Pakistan.

Methods: Outpatients presenting with ≥3 consecutive days of reported fever and inpatients with clinically suspected enteric fever from all 6 SEAP study hospitals were eligible to participate. We evaluated the diagnostic performance of select clinical features against blood culture results among outpatients using mixed-effect regression models with a random effect for study site hospital. We also compared the clinical features of S. Typhi to S. Paratyphi A among both outpatients and inpatients.

Results: We enrolled 20 899 outpatients, of whom 2116 (10.1%) had positive blood cultures for S. Typhi and 297 (1.4%) had positive cultures for S. Paratyphi A. The sensitivity of absence of cough was the highest among all evaluated features, at 65.5% (95% confidence interval [CI], 55.0-74.7), followed by measured fever at presentation at 59.0% (95% CI, 51.6-65.9) and being unable to complete normal activities for 3 or more days at 51.0% (95% CI, 23.8-77.6). A combined case definition of 3 or more consecutive days of reported fever and 1 or more of the following (a) either the absence of cough, (b) fever at presentation, or (c) 3 or more consecutive days of being unable to conduct usual activity--yielded a sensitivity of 94.6% (95% CI, 93.4-95.5) and specificity of 13.6% (95% CI, 9.8-17.5).

Conclusions: Clinical features do not accurately distinguish blood culture-confirmed enteric fever from other febrile syndromes. Rapid, affordable, and accurate diagnostics are urgently needed, particularly in settings with limited or no blood culture capacity.

Keywords: Enteric fever; South Asia; clinical diagnosis; typhoid.

Figure 1.

Distribution of temperature at presentation among 20 899 outpatients presenting with 3 or more consecutive days of reported fever to SEAP study site hospitals in Bangladesh, Nepal, and Pakistan. The solid black vertical lines indicate the median intake temperature. Abbreviation: EF negative, blood culture negative for enteric fever; SEAP, Surveillance for Enteric Fever in Asia Project.

Figure 2.

Gastrointestinal symptoms among outpatients with 3 or more consecutive days of fever to SEAP study site hospitals in Bangladesh, Nepal, and Pakistan. Point estimates and confidence intervals were calculated using generalized estimating equations to account for clustering by study site hospital. Abbreviations: EF negative, blood culture negative for enteric fever; SEAP, Surveillance for Enteric Fever in Asia Project.

Figure 3.

Comparison of the characteristics of Salmonella Typhi, Salmonella Paratyphi, and enteric fever (Salmonella Typhi or Salmonella Paratyphi) among 20 899 outpatients presenting with 3 or more consecutive days of fever to SEAP study site hospitals in Bangladesh, Nepal, and Pakistan. Odds ratios and 95% confidence intervals were estimated using mixed-effect logistic regression models with a random effect for study site hospital. Abbreviation: SEAP, Surveillance for Enteric Fever in Asia Project.