American Association for Clinical Chemistry
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October 2011 Clinical Laboratory News: Diagnostic Profiles

Diagnostic Profiles

Procalcitonin Algorithims Proposed To Guide Antibiotic Therapy

A recent systematic review of clinical trials involving the use of procalcitonin (PCT)-based algorithms found that measuring PCT for antibiotic decisions in patients with respiratory tract infections and sepsis appears to lower antibiotic exposure without worsening the mortality rate (Arch Intern Med 2011;171:1322–1331). Based upon their findings, the researchers proposed specific procalcitonin algorithms for low-, moderate-, and high-acuity patients as a basis for future trials aimed at reducing overuse of antibiotics.

The authors conducted the study out of concerns about the overuse of antibiotics and studies showing that patients with antimicrobial-resistant infections have longer and costlier hospitalizations and higher mortality rates. They also were intrigued by emerging evidence suggesting that PCT is a promising candidate biomarker to help physicians decide more rationally about antibiotic therapy in patients with infections.

The researchers conducted a literature search and found 14 randomized controlled trials of moderate quality that used PCT levels to inform decisions about antibiotic usage. In all, the studies covered 4,467 patients in primary care, emergency, and inpatient and intensive care settings who had respiratory tract infections or sepsis. Overall, there was no significant difference in mortality in patients whose care had been guided by a PCT algorithm versus controls who received regular care, with a summary odds ratio of 0.91. However, there was a marked reduction in antibiotic exposure in all patient populations.

Based upon their review, the authors proposed PCT-based algorithms to guide antibiotic use. For patients with a low pre-test probability of bacterial infection, antibiotic use would be discouraged for levels <0.25 µg/L and encouraged for levels >0.25 µg/L. For patients at moderate risk or acuity, the authors proposed serial PCT measurements depending on the initial concentration, with antibiotics discontinued when PCT levels drop to <0.25µg/L or by ≥80-90% of the peak value once the patient has improved clinically. In patients at high-risk or in ICU settings, the investigators recommended monitoring PCT levels after the start of antibiotics, with a cutoff of <0.50 µg/L or a reduction of ≥80-90% from baseline for considering discontinuing antibiotics. The authors cautioned that these algorithms need further evaluation in prospective clinical trials.

Chronic Kidney Disease, Atrial Fibrillation Linked

A consortium of researchers has determined that kidney damage and impaired kidney function are associated with increased risk of atrial fibrillation (AF) independent of other risk factors (Circulation 2011; 123: 2946–2953). The authors suggest that future studies should focus on better understanding the specific mechanisms for this association, and that strategies for preventing AF will need to consider chronic kidney disease (CKD) as a preventable risk factor in controlling the condition.

While there is a good biological basis for an association between CKD and AF, the three previous prospective studies that examined this issue had conflicting results and none explored whether any CKD-AF association varied by race, sex, or the presence of cardiovascular disease (CVD) and risk factors.

The study involved a cohort of 10,328 Atherosclerosis Risk in Communities (ARIC) study participants who did not have AF at baseline. ARIC was a community-based study of CVD in four states who were recruited between 1987 and 1989, had an initial examination and testing, and were followed through 1996–1998 in three subsequent rounds of testing and exams. The authors used a cystatin C-based estimated glomerular function rate (eGFRcys) formula and albumin-to-creatinine ratio (ACR) to assess kidney function. Incident AF was assessed after the fourth ARIC visit through hospital discharge codes and death certificates.

During a median follow-up of 10.1 years, the authors found that even mildly decreased kidney function was associated with higher AF risk, independent of lifestyles, clinical factors, and CVD, and was similar in men, women, whites, and blacks. The incidence of AF in individuals with eGFRcys 15–29 mL * min–1 * 1.73 m–2 was about three times higher compared with individuals who had eGFRcys in the optimal range after adjustment for multiple potential confounders. Similarly, in comparison to patients with ACR <30 mg/g the hazard ratio for AF was 2.0 in those with an ACR 30–299 mg/g and 3.2 in those with ACR ≥300 mg/g.

Persistent HPV Infection Confers Greatest Risk

A long-term prospective study of human papillomavirus (HPV) infection confirmed that women with persistent HPV are at greatly increased risk for cervical cancer, suggesting that it is useful to perform repeat HPV testing to improve the predictive value and specificity of cervical cancer screening (J Natl Cancer Inst 2011;103:1–10). The findings also suggest that HPV testing should be included in cancer screening programs for the general population, according to the authors.

While much is known about HPV and the HPV-cancer link, HPV testing has a low positive predictive value, and very few long-term studies have examined cervical cancer risk after persistent HPV infection among young women.

The study included 11,923 women age 30–65 at a baseline examination in 1991–1992 who consented to HPV DNA and genotype testing and cytology. Of these, 6,923 were reexamined in 1993–1995 and followed for a mean of 14.5 years through cancer and death registries to identify those who developed cervical cancer.

In comparison to HPV-negative women, those with baseline infection of 12 carcinogenic HPV types had a 20 times higher risk of carcinoma in situ (CIS) or invasive cervical cancer (ICC). Persistence of these HPV types was “critical” to the magnitude of CIS or ICC risk, according to the authors. Depending on the HPV type, risk was elevated two to 10-fold in comparison to these types being present during only one screening. The cumulative risk of cervical cancer following persistent HPV infection increased with age, rising from 5.5% in women 30–44 years to 18.1% in those 55 years or older.

Baseline HPV infections that cleared rather than persisted were associated with a very low risk of cervical cancer, demonstrating that overt HPV persistence rather than one-time infection is associated with higher risk.