In This Issue...

Direct NAAT for Suspected Pulmonary TB Yields Many Health System Benefits

Direct nucleic acid amplification testing (MTD) for suspected pulmonary tuberculosis results in significant positive health system benefits, particularly for patients with HIV infection or homelessness (Clin Infect Dis 2013;57:532–42). In comparison to not performing MTD, MTD significantly decreased the time to diagnosis in patients with acid-fast-bascilli-smear-positive specimens, reduced the number of days of unnecessary tuberculosis treatment among non-hospitalized patients, and reduced resources expended on contact investigation. Although diagnostic workups that included MTD generally cost more than those that did not, MTD testing was associated with incremental cost savings in diagnosing or excluding tuberculosis among patients with HIV or homelessness, and in excluding tuberculosis among those with substance abuse who also had smear-negative specimens.

The researchers conducted the study because MTD use is not universal, despite being recommended for use by CDC since 1996 on smear-positive specimens and since 2009 on smear-negative specimens from patients in whom the test result would alter tuberculosis case management. MTD testing can provide results within 24–48 hours, whereas sputum-smear microscopy is simple and inexpensive to perform but detects <50% of cultured-confirmed cases and has poor positive-predictive value (PPV) in individuals with HIV. The gold standard, culture, takes 2–8 weeks for results.

The authors found the PPV of MTD was 98% in patients who also had smear-positive specimens, while the negative-predictive value (NPV) was 94%. Among patients with smear-negative specimens, the PPV of MTD was 90% and NPV was 88%. Among patients suspected of having tuberculosis whose specimens did not undergo MTD, the PPV of smear was 77% and NPV was 78%.

Elevated Bilirubin Levels, Bilirubin Genotype Associated With Gallstone Disease

Long-term elevated bilirubin levels are associated with symptomatic gallstone disease (JAMA Intern Med 2013;173:1222–8). The findings have significance both clinically and scientifically, according to the authors. From a clinical standpoint, routine measurement of plasma bilirubin levels could signal physicians about patients at risk for developing gallstone disease. Scientifically, this study aids in understanding the pathways that lead to gallstone disease, possibly providing targets for treatment or prevention.

Calcium bilirubinate salts have been hypothesized to act as a nucleating factor for the precipitation of biliary cholesterol, thereby directly facilitating development of cholesterol gallstones. At the same time, increased production of bilirubin has been associated with increased risk of gallstone disease, but whether elevated bilirubin levels per se are associated with higher risk of gallstone disease is unclear.

The study had four aims: to test whether plasma bilirubin levels predict risk of symptomatic gallstone disease; to observe whether a variant in the bilirubin glucoronidating enzyme, UGT1A1, is associated with increased plasma bilirubin levels; to discern whether the UGT1A1 genotype is associated with increased risk of symptomatic gallstone disease; and to determine whether these genetic risks are similar to the estimated risk of observed plasma bilirubin levels.

During 34 years of follow-up, 3,374 out of 61,212 subjects developed symptomatic gallstone disease. Those with plasma bilirubin levels in the top decile had an increased risk of symptomatic gallstone disease in comparison to those in lower deciles, with a 1.57 hazard ratio overall. The authors found that the UGT1A1 genotype explained 20% of the total variation in bilirubin levels.

Elevated NT-proBNP, cTn Linked to Sub-Clinical Brain Disease

N-terminal brain natriuretic peptide (NT-proBNP) and cardiac troponin T (cTn) are independently associated with subclinical brain disease and might be useful in identifying individuals with asymptomatic brain injury (Stroke 2013;44:1803–8). The authors suggest that measurement of these biomarkers followed by magnetic resonance imaging (MRI) of the brain might facilitate interventions that could forestall cognitive decline in patients with brain injury.

The findings are from the Atherosclerosis Risk in Communities studies, a prospective study of 15,792 middle-aged individuals in four U.S. communities who had baseline examinations and testing between 1987–1989. At the third follow-up visit, which took place between 1993–1995, a subset of participants had brain MRIs, and a subsection of these individuals had a second MRI approximately 10 years later. In addition, NT-proBNP and cTn were analyzed from blood samples collected at the fourth follow-up visit from 1996–1998. The researchers established quartiles of NT-proBNP values, with >119.1 pg/mL as the cutoff for the highest and 2.5 – ≤29.6 pg/mL as the cutoff for the lowest, and quintiles for cTn, with the cutoff for the highest being ≥0.014 µg/L and the lowest being <0.003 µg/L.

After adjusting for risk factors, the researchers found that individuals in the highest NT-proBNP quartile had significantly more brain infarcts (BI) in comparison to those in the lowest quartile, with a 3.50 odds ratio. They also had more white matter lesions (WML), with a ß-coefficient of 0.09. Comparison of the follow-up MRI 10 years later revealed that individuals in the highest NT-proBNP quartile also had significantly more incident BIs and WML progression than those in the lowest quartile, with a 2.18 odds ratio and 0.22 ß-coefficient, respectively.

The findings were similar for cTn. Individuals in the highest quintile had more BI and WML on the initial MRI in comparison to those in the lowest quintile, with a 3.03 odds ratio and 0.11 ß-coefficient, respectively. At the time of the follow-up MRI, individuals in the highest cTn quintile also had more WML progression, with a ß-coefficient of 0.43.

Markers of Inflammation Associated With Pre-Eclampsia in Type 1 Diabetics

A longitudinal study of pregnant women with type 1 diabetes found elevated C-reactive protein (CRP), soluble E-selectin (sE-selectin), interleukin-1 receptor antagonist (IL-1ra), and interferon-γ-inducible protein-10 (IP-10), and lower eotaxin to be associated with development of pre-eclampsia (Diabetes Care 2012;36:2054–61). The findings support the need for larger studies to confirm the role of inflammation in pre-eclampsia and to define the utility of these markers in screening for pre-eclampsia and in developing preventive and therapeutic strategies for the disorder.

The study involved 151 pregnant women with established type 1 diabetes and 24 nondiabetic pregnant women recruited during their first trimester and followed throughout pregnancy. The investigators collected clinical data and blood and urine specimens from the women at weeks 12, 21, and 31, and defined pre-eclampsia as new-onset hypertension >140/90 mmHg accompanied by proteinuria >300 mg/24 h after 20 weeks' gestation in women who previously were normotensive. The study included at least 27 markers of inflammation.

After analysis and covariate adjustment, the researchers found that higher CRP, sE-selectin, and the cytokines IL-1ra and IP10, along with lower eotaxin, remained significantly associated with development of pre-eclampsia. These findings suggest that exacerbated maternal inflammatory responses confer susceptibility to pre-eclampsia.