### Diagnosis Scenario

Typhoid fever is one of the prevalent disease conditions in a developing countries like the Philippines. In 1996, the Department of Health has reported an increase in morbidity and mortality secondary to typhoid fever. At present, the initial diagnosis is largely dependent on clinical presentation. Although, many consider blood culture as the gold standard for diagnosis, the results are not readily available (earliest is 3 days after specimen collection), and its appropriateness as the reference standard is questioned. In addition, the cost is prohibitive for many patients. The Typhidot test, developed by a Malaysian scientist for the rapid diagnosis of typhoid fever has recently been introduced and made commercially available. This test utilizes the principle of antigen-antibody reaction. It costs less than the blood culture, and results are supposed to be obtained within the day of the examination. However, variations exist with regards to conduct of this test. Not all hospital laboratories perform Typhidot test on a daily basis, i.e., there are specified days for which specimens submitted for this test are accumulated and the test is done only during such days. Thus, results will be delayed for specimens submitted on days not coinciding with such schedules.

A 40-year old female is admitted in a nearby hospital due to high grade fever for the past 5 days. Aside from anorexia and body malaise, she denies any other symptoms. At the emergency room she appeared to be dehydrated. Otherwise, all other physical examination findings were essentially normal. The initial diagnosis is enteric fever. Other disease conditions being considered are systemic viral infection, urinary tract infection and dengue fever. The resident-on-duty requested for a CBC, urinalysis, blood culture and a typhidot test. No antibiotics were started during this time. Results of the CBC and urinalysis are unremarkable. The results of the typhidot test are positive for IgM , and negative for IgG . The resident calls you at your clinic asking for help regarding interpretation of these test results. Together you pose the question, ‘in a patient with suspected typhoid fever, what is the accuracy of the Typhidot test for making the diagnosis?’ You advise her to do a search of the local literature using Herdin, a local database, and she successfully tracks and retrieves a recent article by Collantes & Velmonte on the accuracy of Typhidot test in the diagnosis of typhoid fever. (Phil J of Med – Infectious Dis 1997; 26:61-63.)

Read the article and decide:

• Are the results of this diagnostic article valid?
• Are the valid results of this diagnostic study important?
• Can you apply this valid, important evidence about a diagnostic test in caring for your patient?

### Completed Diagnostic Worksheet for EBM in Developing Countries

#### Citation

Collantes E, Velmonte MA. The Validity of the Typhidot Test in Diagnosing Typhoid Fever Among Filipinos. Phil J of Med – Infectious Dis 1997; 26:61-63.

#### Are the results of this diagnostic study valid?

Was there an independent, blind Comparison with a reference (“gold”) standard of diagnosis?
Yes, blood culture was done in all study patients. Although the authors stated that blood culture was the supposed gold standard, it seems an inappropriate reference or gold standard. The diagnosis at present is still predominantly dependent on the clinical course of the patients. Patients whose clinical course is highly suggestive of typhoid fever are given antibiotics for typhoid fever even while still awaiting the results of blood culture (which takes at least 3 days to be obtained) or even with negative culture results. In the article, there was confusion as to the real reference standard that was considered by the authors. They stated that blood culture is the gold standard but during the analysis, it seems that they considered the clinical diagnosis as the gold standard. However, the authors did not clarify whether clinical course was used for the diagnosis, per se and not diagnosis on admission.
Was the diagnostic test evaluated in an appropriate spectrum of patients (like those in whom it would be used in practice)?
Yes. The study was done in a tertiary general hospital in an urban area which admits various cases of Infectious and Tropical Diseases. These include the differential diagnoses in the scenario which are prevalent in the setting where the study was conducted.
Was the reference standard applied regardless of the diagnostic test result?
Yes. Although the authors said that this was a retrospective study, patients included were those with results of both the typhidot and blood culture. In addition prior to the study period, the consultants informed the residents of the service that both blood culture and typhidot tests should be requested for all patients suspected of typhoid fever.

#### Are the valid results of this diagnostic study important?

**An analysis completely different from what the authors did is presented in the following tables because of problems with the gold standard.

IgM Clin Dx of Ty (+) Dx of Ty fever (-) Likelihood Ratio
IgM (+) 96 0 (1*) 49.71
IgM (-) 16 57 0.14
Totals 112 58
* substituted 1 for 0 for computation purposes
IgG Blood Culture (+) Blood Culture (-) Likelihood Ratio
IgG (+) 87 36 1.23
IgG (-) 25 21 0.22
Totals 112 57

#### Can you apply this valid, important evidence about a diagnostic test in caring for your patient?

Is the diagnostic test available, affordable, accurate, and precise in your setting?
Variable in every setting. The price varies in the type of center where it is done. In a government hospital, indigent patients may avail of the laboratory free of charge. Even in private patients (those with capacity to pay) variations exist as some might be charged lower than US$12.50 but others could be charged at more than US$ 25.00. In addition, there is no data with regards to reliability of results from any center.
Can you generate a clinically sensible estimate of your patient’s pre-test probability (from patient data, from personal experience, from the report itself, or from clinical speculation)
Approximately 50% based on history/PE.
Will the resulting post-test probabilities affect your management and help your patient? (Could it move you across a test-treatment threshold? Would your patient be a willing partner in carrying it out?)
Using the (+) result of the IgM test brings the pre-test probability of 50% to a post-test probability to 98%, while using the IgG (+) result in a separate analysis (not serially) does not change the pre-test probability markedly ( a little over 50%). A negative IgM will result to a post-test probability of approximately 7.5%. The test results in IgM led to marked changes in the pre-test probability and definitely moved across a test-treatment threshold. However since this test is obtained only at one point in the course of the disease, treatment for typhoid fever might still be given if the clinical course turned out to be still highly suggestive of typhoid fever. It might be interesting to determine if a repeat typhidot test after several days would still yield similar results.