CLN Article

The Sample



A Call to Reconsider Molecular Testing for C. Difficile

Based on the results of a prospective observational study of more than 1,400 hospitalized patients, researchers at University of California, Davis are warning that over-reliance on molecular tests for Clostridium difficile “is likely to result in overdiagnosis, overtreatment, and increased healthcare costs” (JAMA Intern Med 2015; doi:10.1001/jamainternmed.2015.4114).

The investigators compared clinical outcomes of patients with suspected C. difficile infection (CDI) who had stool samples tested by both PCR and toxin immunoassay. They found more than half who tested positive for C. difficile by PCR were negative by toxin immunoassay. In comparison to patients who were positive by both PCR and toxin immunoassay, those positive by PCR but negative by toxin immunoassay had lower C. difficile bacterial load, less antibiotic exposure, fecal inflammation, and diarrhea. They also had shorter duration of diarrhea, and no CDI-related complications. Just one of 162 PCR-positive/toxin-negative patients was considered to have CDI as a contributing factor to death.

“We found that virtually all of the bad, negative outcomes occurred in patients with positive toxin tests,” said the study’s lead author, Christopher Polage, an associate professor of pathology and infectious diseases at UC Davis Medical Center. “This suggests that we should really focus on toxin-positive patients for treatment. There may be room for trying to improve the sensitivity of toxin tests and look for additional tests to help identify patients at greatest risk for bad outcomes. Apart from this, we need to understand that most toxin-negative patients don’t need treatment and may not even be infected.”

Polage and his colleagues were interested in exploring clinical outcomes in patients with C. difficile because molecular tests for C. difficile have proliferated in recent years, as has the reported rate of CDI. Up until molecular tests became widely available in 2009, an estimated 95% of hospitals used toxin immunoassays. But by 2014, 44% of acute care hospitals participating in the National Healthcare Safety Network reported using molecular tests alone or in combination with other tests in the work-up of suspected CDI, according to the authors. The incidence of CDI has risen more than 200% since 2000. Initially this increase was attributed to a novel, hypervirulent strain of C. difficile, but individual hospitals have reported increases from 50% to 100% after switching from toxin immunoassays to molecular tests.

The authors found that 55.3% of patients who were C. difficile-positive by PCR were negative by toxin immunoassay and that they had clinical outcomes similar to patients in whom no C. difficile was detected. “These findings strongly suggest that most patients with negative toxin test results and C. difficile detected by PCR do not need treatment for CDI,” the authors wrote.

Retesting Recommended With Discordant Syphilis Test Results

A study of discordant syphilis immunoassay results in pregnancy concluded that routine retesting of women with initially positive chemiluminescence immunoassay (CIA) results, but negative rapid plasma reagin (RPR) and Treponema pallidum particle agglutination assay (TP-PA) results, is useful, as there is a “high likelihood” of false-positive CIA results in pregnancy (Clin Infect Dis 2015;61:1049–53).

Traditionally, most labs have used RPR or Venereal Disease Research Laboratory (VDRL) tests to screen for syphilis. However, recently automated enzyme immunoassays (EIA) and CIAs have become available, and consequently some labs have adopted a reserve screening algorithm, in which they perform EIA/CIA first, then reflexively test reactive samples with RPR/VDRL. This modified algorithm facilitates high-throughput testing, but also leads to discordant serologic results not identified with the standard algorithm.

The researchers looked at all pregnant women treated at Kaiser Permanente Northern California who had discordant syphilis screening results. Of the 194 included in the final analysis, 80% were CIA-positive, but RPR- and TP-PA-negative. Among the 77 in the latter group who were retested, 53% subsequently were CIA-negative. 

Thomas-Plot Analyses Complements Stand-Alone Biomarkers in Assessing Iron Deficiency

In a study of 445 patients referred for routine testing of iron status, Austrian researchers found that the prevalence of iron deficiency (ID) and the accuracy of detecting functional ID depend on the biomarker used and its definition (Clin Biochem 2015;48:891–6). Based on their findings, they recommend using Thomas-plot analyses—a plot of soluble transferrin receptor (sTfR) and reticulocyte hemoglobin content (CHr)—in combination with single-marker measurements such as serum ferritin and transferrin saturation (TSAT) to efficiently identify patients with ID.

Recently, awareness of the adverse consequences of ID has increased, but even with established biomarkers to assess ID, there is not complete international consensus on which markers to use in the workup of ID. Both acute and chronic inflammation—reflected in elevated C-reactive protein (CRP) values—affect serum ferritin and TSAT, so the authors wanted to explore the contribution of sTfr and CHr in assessing ID.

The sTfR/log ferritin ratio showed the best positive-predictive values to indicate functional ID in patients with and without acute-phase reaction, defined as CRP >0.5 mg/dL and ≤0.5 mg/dL, respectively.

Nearly All Pre-Operative PT, aPTT Tests Unnecessary

A study combining big data and applied compared effectiveness research has concluded that up to 94.3% of pre-operative prothrombin time (PT) tests and 99.9% of activated partial thromboplastin time (aPTT) tests were used as screening tests and therefore ordered unnecessarily (PLoS One 2015;10:e0133317.doi:10.1371/journal.pone.0133317).

The study involved prospectively collected data from 27 hospital and surgery center sites. The researchers compiled data from more than 1 million elective surgery patients; history and physical (H&P) records were available for 682,049, which were included  in the final analysis.

Overall, 26.2% of pre-surgical patients had PT tests performed, but the researchers determined that 94.3% were unnecessary given there were no findings in the patients’ H&Ps supporting this testing. Similarly, 23.3% of pre-surgical patients had aPTT tests, of which the researchers found 99.9% to be unnecessary based on indications noted in their H&Ps.

The researchers also found that 6.6% of PT tests and 7.1% of aPTT tests with no supporting H&P justification were positive. These test results could either be false-positives or unanticipated true positives, but given that bleeding conditions are likely to be diagnosed symptomatically before surgery, the authors speculated that the tests were likely false-positives.

“We…document routine pre-surgical practices for which there is no clinical justification and which can put patients at risk of false-positive findings,” the authors wrote. “Useless tests are clinically inappropriate because they consume resources, yet bring no benefit to patients or clinicians.” They went on to state that if their data set represented national testing practices in the U.S., considerable savings likely would be realized and many patients would no longer be put at risk due to “empty testing.”

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