Clinical characteristics of enteric fever and performance of TUBEX TF IgM test in Indonesian hospitals

TL;DR

This study evaluates the clinical features of enteric fever and the diagnostic accuracy of the TUBEX TF test in Indonesian hospitals, finding that the test over-diagnoses the condition.

Contribution

The study provides real-world performance data of TUBEX TF in Indonesia and highlights the potential of IgG ELISA for better diagnosis.

Findings

Only 16.6% of clinically diagnosed enteric fever cases were confirmed by blood culture or PCR.

TUBEX TF over-diagnosed enteric fever by more than 50% compared to confirmatory tests.

S. Typhi IgG ELISA showed the best sensitivity and specificity for diagnosing enteric fever.

Abstract

Accurate diagnosis of enteric fever is challenging, particularly in low- and middle-income countries, due to the overlap of clinical and laboratory features with other pathogens. To better understand the difficulties in enteric fever diagnosis, we evaluated the characteristics of patients clinically diagnosed with enteric fever and the real-world performance of TUBEX TF, one of the most used tests in Indonesia.

Patients were recruited through the AFIRE (Etiology of Acute Febrile Illness Requiring Hospitalization) study at eight Indonesian hospitals. Blood culture was performed for all patients, and TUBEX TF was performed for suspected enteric cases. Salmonella PCR and ELISA tests were performed at a reference lab. Sensitivity and specificity of TUBEX TF and IgM and IgG anti-S. Typhi ELISA were determined. Of 301 patients clinically diagnosed with enteric fever, 50 (16.6%) were confirmed by blood culture and/or PCR. Confirmed cases were mostly school-aged children presenting with fever, anorexia, dizziness and/or abdominal pain with normal leukocyte count or leukopenia. TUBEX TF demonstrated a sensitivity of 97.6% to 70.7% and specificity of 38.3% to 67.2% at cutoffs of 4 and 6, respectively. Acute IgG demonstrated the best sensitivity and specificity, at 90.7% and 82.7%, respectively, and the best ROC characteristics.

A substantial proportion of enteric fever was misdiagnosed at all study hospitals, likely due to the overlap of clinical characteristics and lab parameters with those of other common pathogens. The TUBEX TF rapid serological assay demonstrated suboptimal performance in our setting and tended to over-diagnose enteric fever. The role of IgG from acute specimens for identification of enteric fever cases merits additional consideration.

Enteric fever is a major health problem in Indonesia. Blood culture, the gold standard for enteric fever diagnosis, is expensive and requires several days to produce a result, leading to diagnoses being made through rapid tests such as TUBEX TF in Indonesia and other LMICs. In a real-world setting, we found that TUBEX TF over-diagnosed enteric fever by more than 50% in comparison to blood culture and PCR. Over-diagnosis may result in over-treatment and the subsequent increase of antimicrobial resistance. Given the suboptimal performance of TUBEX TF, the use of readily available clinical and laboratory data to facilitate identification of enteric fever cases has been considered. In our study, the majority of enteric fever patients were school-aged children. Although non-specific, gradually increasing fever, gastrointestinal symptoms, and cough were often present; hematologic parameters did not distinguish enteric fever from other etiologies. Interestingly, diagnostic accuracy was better by S. Typhi IgM and best by S. Typhi IgG in acute specimens. These findings may reflect the inaccuracy or subjectivity of TUBEX TF. The surprisingly excellent performance of S. Typhi IgG ELISA merits further evaluation.

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