American Association for Clinical Chemistry
Better health through laboratory medicine
August 2011 Clinical Laboratory News: Diagnostic Profiles

Industry Profiles


CRP, Procalcitonin Provide Better Diagnostic Value in Serious Pediatric Infections

A systematic literature review of studies involving lab tests used to assess serious infection in febrile children found that C-reactive protein (CRP) and procalcitonin provided the most diagnostic value, with no clear evidence that one is better than the other (BMJ 2011; doi:10.1136/bmj.d3082). The authors also concluded that measuring white blood cell count is less useful for ruling in serious infection and not useful for ruling out serious infection.

The study built on a previous review the authors conducted on the diagnostic value of presenting clinical features in identifying serious infection in children, and its objective was to review the diagnostic value of blood tests in ruling in and ruling out serious infection in these patients in ambulatory settings. The authors also sought to determine what value lab tests added to clinical signs and symptoms. All but two of the 14 studies included in the review took place in emergency departments.

The researchers concluded that the optimal cutoff for CRP and procalcitonin depends on whether the main clinical focus is on ruling in or ruling out serious infection. Rule in cutoffs of 80 mg/L for CRP or 2 ng/mL for procalcitonin both provide specificity >90%, but sensitivity of 40–50%. To rule out serious infection, cutoffs of 20 mg/L for CRP or 0.5 ng/mL for procalcitonin provided sensitivity of 80% and specificity of 70%. 

hs-cTnT and Copeptin Predict Risk in Chronic Stable Heart Failure

Austrian researchers recently reported that the combined use of high sensitivity cardiac troponin T (hs-cTnT) and copeptin is a powerful predictor of death and hospitalization for heart failure in patients with chronic stable heart failure (CHF) (Eur J Heart Fail 2011; doi:10.1093/eurjhf/hfr049). The prospective study followed 172 consecutively admitted patients with stable CHF, defined as New York Heart Association levels I-III and left ventricular ejection fraction <45%.

Overall, 58% of patients had hs-cTnT levels >14 pg/mL, the 99th percentile in a healthy population, and 55% had copeptin levels above normal, 16.4 pmol/L. hs-cTnT concentrations were higher in men and patients with ischemic cardiomyopathy, prior coronary artery bypass graft, diabetes, and renal failure, while copeptin levels were higher in patients with diabetes and renal failure.

hs-cTnT levels correlated significantly with copeptin, age, creatinine, and NT-proBNP, and patients who reached the study’s primary endpoint—composite all-cause mortality or hospitalization due to decompensated heart failure—had significantly higher hs-cTnT levels than those without an event, 29.92 pg/mL versus 17.21 pg/mL, respectively. Copeptin levels correlated significantly with hs-cTnT, creatinine, and NT-proBNP, and as with hs-cTnT, patients who reached the study’s primary endpoint had significantly higher copeptin levels than those without an event, 28.83 pmol/L versus 16.09 pmol/L, respectively. 
Bivariate Cox regression analysis showed that a copeptin level >16.4 pmol/L was a significant predictor of outcome in addition to hs-cTnT, and the combination of both markers showed a graded and highly significant association with impaired clinical outcome independent of NT-proBNP levels.

Renal Biomarkers Linked with Cognitive Decline in Diabetes

A consortium of researchers recently found the renal biomarkers albuminuria and cystatin C to be associated with cognitive impairment in diabetics at high risk for cardiovascular disease (Diabetes Care 2011; doi:10.2337/dc11–0186). The authors suggest that clinicians consider measuring these analytes to screen diabetics for cognitive decline in an effort to facilitate interventions that might slow further mental deterioration in such individuals.

The findings are from the Action to Control Cardiovascular risk in Diabetes Memory in Diabetes (ACCORD-MIND) Study, which involved 2,977 participants from the larger ACCORD study, a trial aimed at determining whether intensive glycemic control, improved cholesterol control, and intensive blood pressure control could reduce the rate of cardiovascular events more so than standard therapy.

ACCORD involved 10,251 patients with established type 2 diabetes and baseline HbA1c levels >7.5%. The ACCORD-MIND subjects were all at least 55 years old, had been randomized into the main ACCORD study <45 days, and participated in a 30-minute battery of four cognitive tests.

The mean age of the ACCORD-MIND cohort was 62.5 years, and participants had a mean HbA1c concentration of 8.3% and had had diabetes for a mean of 10 years. The researchers used the Modification of Diet in Renal Disease study equation to calculate estimated glomerular filtration rate (eGFR), and participants with eGFR <60 mL/min/1.73 m2 were classified as having moderate or severe reduction in kidney function. Those with eGFR ≥60 mL/min/1.73 m2 were considered to have normal or mild reduction in kidney function. Researchers used a 1.0 mg/L cutpoint to classify patients as having low versus elevated cystatin C levels. Participants with urine albumin/creatinine ratio (ACR) ≥30 µg/mg were defined as having albuminuria.

The researchers found that albuminuria was associated with worse performance on all four cognitive tests, and eGFR <60 mL/min/1.73 m2 was associated with worse performance on one of the four cognitive tests that assessed executive thinking associated with frontal-lobe function, but not the other three. Cystatin C levels were associated with worse performance on two of the cognitive tests.

Based on their findings, the researchers hypothesize that injury to the brain and kidneys share similar pathways as a result of microvascular disease processes. They called for a longitudinal study to assess this theory.

Landmark Serous Ovarian Cancer Genomic Analysis Completed

In a groundbreaking study, investigators from The Cancer Genome Atlas Research Network, a large consortium of institutions jointly funded and managed by the National Cancer Institute and National Human Genome Research Institute, recently completed an integrated genomic analysis of ovarian cancer (Nature 2011;474:609–615). The findings set the stage for developing therapies targeted at specific mutations, according to the authors.

The research team analyzed messenger RNA expression, microRNA expression, promoter methylation, and DNA copy number in 489 high-grade serous ovarian adenocarcinomas, as well as the DNA sequences of exons from coding genes in 316 of these tumors. They found that TP53 mutations had occurred in nearly all the tumors (96%). There also were low-prevalence but statistically recurrent somatic mutations in eight other genes, including NF1BRCA1BRCA2RB1CSMD3CDK12FAT3, andGABRA6BRCA1 and BRCA2 were mutated in 22% of tumors, owing to a combination of germline and somatic mutations. Overall, the researchers found that high-grade serous ovarian cancer “demonstrates a remarkable degree of genomic disarray.”

After univariate Cox regression analysis, the investigators found 108 genes to be correlated with poor survival, and 85 with good survival. Patients whose tumors had a gene expression signature associated with poor survival had an overall 23% shorter survival time.

The researchers also investigated whether any existing drugs might be used to treat the mutation patterns they found. They determined that about half the tumors with homologous recombination defects might benefit from poly ADP ribose polymerase inhibitors. They also found that inhibitors already exist for 22 genes in regions of recurrent amplification.