Rapid Diagnostic Tests for the Diagnosis of Typhoid Fever

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Pakistan is currently facing its first known epidemic of extensively drug-resistant (XDR) typhoid, which, according to the National Institute of Health, Islamabad, has been detected in more than 2000 people, in 14 districts since 2017.

This XDR Salmonella entericaserovar Typhi (S. typhi) is resistant to five classes of antibiotics (chloramphenicol, ampicillin, trimethoprim-sulfamethoxazole, fluoroquinolones, and third-generation cephalosporins). Experts have identified only one remaining oral antibiotic, azithromycin, to combat it; one more genetic mutation could make typhoid untreatable in some areas.

This outbreak is a challenging public health situation and demands immediate necessary measures to curtail further transmission of S. typhi and to initiate timely diagnosis and prompt treatment. Accurate diagnosis is the key to management and prevention. Use of inappropriate and inaccurate tests can lead to incorrect diagnoses and can result in inappropriate treatment.

The World Health Organization (WHO) clearly states that definitive diagnosis of typhoid fever depends on the isolation of S. typhifrom blood, bone marrow or a specific anatomical lesion. Rapid diagnostic tests (RDT’s) like the Widal and the Typhidot are no longer recommended as part of the diagnostic workup because of their variable antibody response to the pathogen and because of cross-reactivity of S. typhi (and S. Paratyphi A) with other enteric bacteria1.

The Widal test has only moderate sensitivity and specificity. It can be falsely negative in up to 30% of culture-proven cases of typhoid fever. This may be because of prior antibiotic therapy that bluntsthe antibody response. False positive results may also occur in other clinical conditions, e.g. malaria, typhus, bacteraemia caused by other organisms, and in liver cirrhosis. In areas of endemicity, there is often a low background level of antibodies in the normal population.

The Typhidot test has low specificity and high sensitivity. In areas of high endemicity where the rate of typhoid transmission is high, the detection of specific IgG increases. Since IgG can persist for more than two years after typhoid infection, the detection of specific IgG cannot differentiate between acute and convalescent cases. Furthermore, false-positive results attributable to previous infection may occur. On the other hand, IgG positivity may also occur in the event of a current reinfection.

So, while point-of-care serologic tests have the advantage of rapid time-to-result and minimal laboratory infrastructure requirements, their limited accuracy means that they are no longer recommended as part of the diagnostic workup for suspected typhoid fever in high-burden countries, like ours. 2

The foremost drawback of a rapid diagnostic test and indeed of any nonculture-based method is the lack of an isolated organism and antimicrobial susceptibility results. Effective tailored treatment is crucial for the management of the disease and to recognize the spread of the XDR S. typhioutbreak.

It is hence recommended that blood cultures should be sent instead in all cases of suspected typhoid or enteric fever. Isolation of S. Typhi from blood or bone marrow has remained and still is considered the gold standard.

A Cochrane review conducted in 2017 further supports this stance against RDTs. The review assessed the accuracy of commercially-available rapid diagnostic tests and their prototypes (including TUBEX,

Typhidot, Typhidot-M, Test-it Typhoid, and other tests) for detecting typhoid and paratyphoid fever and it evidently states that the evaluated RDTs were not sufficiently accurate to replace blood culture as a diagnostic test for enteric fever. 3

It is essential for clinicians across Pakistan to recognize the drawbacks of these serologic tests in diagnosing typhoid fever and their use should be discouraged. Laboratories should discontinue offering these tests as part of their test menus. Reputed laboratories have already ceased accepting samples for Typhidot and Widaland are offering blood cultures as an alternative test of choice.It should also be emphasized that blood cultures can still be sent in cases where the patient has already been started on antibiotics.

We look forward to your continued support and contribution towards this national cause.

Please feel free to contact us on [email protected] or [email protected] if you have any questions or queries in this regard.

References:

  1. World Health Organization. (‎2003)‎. Background document: the diagnosis, treatment and prevention of typhoid fever. Geneva: World Health Organization.
    http://www.who.int/iris/handle/10665/68122
  2. Diagnostics for invasive Salmonella infections: current challenges and future directions. Vaccine. 2015 June 19; 33(0 3): C8–C15. doi:10.1016/j.vaccine.2015.02.030
  3. Rapid diagnostic tests for typhoid and paratyphoid (enteric) fever. Cochrane Database Syst Rev. 2017 May 26;5: CD008892. doi: 10.1002/14651858.CD008892.pub2.