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Testing in Refining a Differential Diagnosis

The use of laboratory tests in refining a differential diagnosis satisfies PV theory because a correct differential diagnosis should result in a relatively high prevalence of the disease under consideration. An example of testing in refining a differential diagnosis is the measurement of urinary vanillylmandelic acid (VMA) for the diagnosis of neuroblastoma. A simple spot test for VMA is not useful in general screening programs because of the low prevalence of neuroblastoma (3 cases/100,000) and the low sensitivity of the test (69%). Even though the specificity of urinary VMA is 99.6%, testing of 100,000 children would produce 2 true-positive test results, 400 false-positive results, and 1 false-negative result. The PV of a positive result in this setting is 0.5%, and the PV of a negative result is 99.99%, not much different from the assumption that neuroblastoma is not present. Testing for urinary VMA in a 3 yr old child with an abdominal mass, however, gives a useful result because the prevalence of neuroblastoma is at least 50% in 3 yr old children with abdominal masses. If 100 such children are tested and the prevalence of neuroblastoma in the group is assumed to be 50%, then a satisfactory PV is obtained.

Thus, in this situation, a test with low sensitivity is powerful in refining the differential diagnosis because the PV of a positive result is almost 100% in the setting of high prevalence.

Serologic Testing

Using laboratory testing to refine a differential diagnosis poses problems, as exemplified by serologic testing for Lyme disease, which is a tick-borne infection by Borrelia burgdorferi that has various manifestations in both early and late stages of infection (Chapter 214). Direct demonstration of the organism is difficult, and serologic test results for Lyme disease are not reliably positive in young patients presenting early with erythema chronicum migrans. These results become positive after a few weeks of infection and remain positive for a number of years. In an older population being evaluated for late-stage Lyme disease, some individuals will have recovered from either clinical or subclinical Lyme disease and some will have active Lyme disease, with both groups having true-positive serologic test results. Of individuals without Lyme disease, some will have true-negative serologic test results, but a significant percentage will have antibodies to other organisms that cross react with B. burgdorferi antigens.

This set of circumstances gives rise to a number of problems. First, the protean nature of Lyme disease makes it difficult to ensure a high prevalence of disease in subjects to be tested. Second, the most appropriate antibodies to be detected are imperfectly defined, leading to a wide variety of tests with varying false-positive and false-negative rates. Third, the natural history of the antibody response to infection and the difficulty of showing the causative organism directly combine to make laboratory diagnosis of early Lyme disease difficult. Fourth, in the diagnosis of late-stage Lyme disease in older subjects, the laboratory diagnosis is plagued by misleading positive (either false-positive or true-positive, but not clinically relevant) results, typically an enzyme-linked immunosorbent assay that uses whole B. burgdorferi organisms. In a review of 788 patients referred to a specialty clinic with the diagnosis of Lyme disease, the diagnosis was correct in 180 patients, 156 patients had true seropositivity without active Lyme disease, and 452 had never had Lyme disease, even though 45% of them were found to be seropositive by at least 1 test before referral.

A 2-step approach, similar to that used in HIV testing, is commonly used: a screening test that has high sensitivity (e.g., enzyme-linked immunosorbent assay) and excellent negative PV, followed by a very specific confirmatory test for verification of positive screening test results (e.g., Western blot to detect antibodies to selected bacterial antigens). Negative screening test results and negative verification test results are reported as negative. Positive verification test results are reported as positive. However, standardization of the testing procedures is difficult in North America, where only 1 pathogenic strain of B. burgdorferi is found, and is more difficult elsewhere in the Northern hemisphere, where as many as 3 pathogenic strains are present. Identification of microbial DNA in body fluids by polymerase chain reaction is definitive, but invasive.

Laboratory Screening

Screening profiles (Table 707-4) are used as part of a complete review of systems, to establish a baseline value, or to facilitate patient care in specific circumstances, such as: (1) when a patient clearly has an illness, but a specific diagnosis remains elusive; (2) when a patient requires intensive care; (3) for postmarketing surveillance and evaluation of a new drug; and (4) when a drug is used that is known to have systemic adverse effects. Laboratory screening tests should be used in a targeted manner to supplement, not supplant, a complete history and physical examination.

Table 707-4   — LABORATORY PROFILE AS A REVIEW OF SYSTEMS

LABORATORY TEST ASSESSMENT FACILITATED BY TESTS
Complete blood cell count and platelets Nutrition, status of formed elements
Complete urinalysis Renal function/genitourinary tract inflammation
Albumin and cholesterol Nutrition
ALT, bilirubin, GGT Liver function
BUN, creatinine Renal function, nutrition
Sodium, potassium, chloride, bicarbonate Electrolyte homeostasis
Calcium and phosphorus Calcium homeostasis

ALT, alanine aminotransferase; BUN, blood urea nitrogen; GGT, γ-glutamyltransferase.

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