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April 2009

Editor:
Michael Bissell, MD, PhD, MPH

Serum amyloid P in systemic sclerosis
Cystatin C as a measure of kidney function in diabetes
Multidrug-resistant Salmonella enterica serotype Typhimurium
Use of PCR versus fluorescent antibodies to diagnose pediatric respiratory viruses
Platelets and protein S in cardiac surgery patients
Pharmacogenetic screening and chemotherapy treatment

Serum amyloid P in systemic sclerosis Serum amyloid P in systemic sclerosis

Serum amyloid P and C-reactive protein are closely related plasma proteins that comprise the highly con­served pentraxin family of homo­pen­tameric molecules. These molecules have specific calcium-dependent, ligand-binding properties and belong to the lectin fold superfamily. C-reactive protein (CRP) is the classic, nonspecific, acute-phase reactant, while serum amyloid P is a stable constitutive plasma protein, the level of which does not increase during the early acute-phase response but may rise modestly during chronic inflammation. Despite an abundance of information about the properties and behavior of these proteins, neither their normal physiologic functions nor their roles in the pathophysiology of disease are confirmed. The authors reported finding no evidence of reduced circulating serum amyloid P concentrations in a large group of well-characterized patients with systemic sclerosis (SSc), nor did they observe a relationship between serum amyloid P values and disease extent or activity in two sepa­rate studies—one cross-sectional (32 patients) and one longitudinal follow-up study (50 patients). Serum concentrations of serum amyloid P were measured by electroimmunoassay in a cross-sectional cohort of 20 patients with diffuse cutaneous SSc and 12 patients with limited cutaneous SSc and in a separate 12-month longitudinal cohort of 13 patients with diffuse disease and 37 patients with limited disease. The extent and severity of disease were characterized in detail at the time of serum sampling. Serum concentrations of C-reactive protein and serum amyloid A protein were measured by immunonephelometric assays. The authors found that serum amyloid P values were within the normal range, regardless of the extent and severity of disease, apart from a very few isolated raised values associated with acute intercurrent complications causing major acute-phase responses. The authors observed no reduced circulating concentrations of serum amyloid P in patients with SSc, nor evidence of an association between serum amyloid P levels and extent or severity of fibrosis.

Tennent GA, Dziadzio M, Triantafillidou E, et al. Normal circulating serum amyloid P component concentration in systemic sclerosis. Arthritis Rheum. 2007;56:2013–2017.

Correspondence: Dr. Glenys A. Tennent at g.tennent@medsch.ucl.ac.uk

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Cystatin C as a measure of kidney function in diabetes Cystatin C as a measure of kidney function in diabetes

Routine measurement of the urine albumin-to-creatinine ratio and estimation of glomerular filtration rate are strongly recommended for patients at high risk for kidney failure and cardiovascular disease, including diabetic patients. However, gold-standard procedures for glomerular filtration rate (GFR) measurement, based on the clearance of 51Cr-EDTA or iohexol, are impractical in the clinical setting and for larger research studies. And creatinine alone is unsatisfactory for estimating GFR and leads to delays in detecting earlier stages of kidney failure. In addition to renal function, serum creatinine depends on creatinine generation, extrarenal elimination, and tubular handling. By accounting for physiologic factors that affect creatinine, equations estimating GFR overcome some limitations. Cystatin C is a new, promising, and easily measurable marker for promptly detecting early kidney failure. It is produced at a constant rate by nucleated cells and released into the bloodstream and has a half-life of approximately two hours. Cystatin C is freely filtered and almost completely taken up and degraded, but not secreted, by proximal tubular cells. Several studies have used direct measures of GFR as the gold standard to compare cystatin C with creatinine and creatinine-derived estimates of GFR. Several studies have also been conducted in diabetic patients in whom cystatin C seems to outperform creatinine-based estimations. Nevertheless, the utility of cystatin C remains uncertain. Using iohexol plasma clearance as the reference GFR, the authors compared cystatin C with creatinine, the Cockcroft-Gault (C-G) formula, and the Modification of Diet in Renal Disease (MDRD) study equation for assessing early decreased renal function in 288 diabetic patients (125 type 1, 163 type 2) with renal impairment (GFR, 4–222 mL/min -1. [1.73 m2]-1). Relationships of cystatin C, creatinine, and iohexol clearance were linearized by plotting their reciprocals in a simple regression model. Diagnostic efficiency was calculated from receiver operating characteristic curves. The authors found that in this study population, cystatin C (P=.0013) was better correlated with GFR (r=0.857) than were creatinine (r=0.772), C-G (r=0.750), and MDRD (r=0.806), a result replicated in patients with normal renal function (P=.023, type 1; P=.011, type 2) but not in those with decreased GFR. Mean cystatin C concentrations showed step-by-step statistically significant increases as GFR decreased, allowing very early detection of reduced renal function. At 90 mL/min-1. (1.73 m2)-1 and 75 mL/min-1. (1.73 m2)-1 cut-points, diagnostic efficiencies of cystatin C (89 percent and 92 percent) were better than those of the other variables (79 to 82 percent and 85 to 86 percent, respectively; P=.01). The authors concluded that using cystatin C to measure renal function will foster early detection, prevention, and treatment strategies for diabetic nephropathy.

Pucci L, Triscornia S, Lucchesi D, et al. Cystatin C and estimates of renal function: searching for a better measure of kidney function in diabetic patients. Clin Chem. 2007;53:480–488.

Correspondence: Laura Pucci at plaura@immr.med.unipi.it

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Multidrug-resistant Salmonella enterica serotype Typhimurium Multidrug-resistant Salmonella enterica serotype Typhimurium

An estimated 1.4 million people in the United States acquire salmonellosis each year, leading to approximately 14,800 hospitalizations and 400 deaths. Salmonella is found in the intestinal tract of animals, and the majority of human infections are caused by ingesting contaminated food. However, many infections are also acquired through contact with animals. Salmonellosis outbreaks have been associated with handling reptiles and amphibians, chicks, ducklings, kittens, and hedgehogs. The authors reported on an outbreak of multidrug-resistant Salmonella enterica serotype Typhimurium infections associated with commercially distributed pet rodents. In August 2004, isolates of Salmonella enterica serotype Typhimurium, which were in­distinguishable from one another by pulsed-field gel electrophoresis (PFGE), were obtained from eight hamsters from a Minnesota pet distributor. The authors conducted an investigation to determine whether human cases of salmonella could be linked to this rodent-borne strain. To identify cases of human infection with S. enterica serotype Typhimurium potentially related to pet rodents, they reviewed salmonella PFGE patterns submitted to the National Molecular Subtyping Network for Foodborne Disease Surveillance. Patients with isolates matching the hamster strain (or the parents of younger patients) were interviewed about exposure to pet rodents. Implicated rodents were traced to pet stores, distributors, and breeders. The authors identified matching S. enterica serotype Typhi­murium isolates from 28 patients in whom the onset of illness occurred between December 2003 and September 2004. Of 22 patients (or patients’ parents) interviewed, 13 (59 percent) in 10 states reported exposure to pet hamsters, mice, or rats, and two (nine percent) had secondary infections. The median age of the 15 patients with primary or secondary rodent exposure was 16 years, and six (40 percent) patients were hospitalized. Thirteen associated pet stores supplied by seven distributors were identified in 10 states. No single source of the rodents was identified. The outbreak strain of S. enterica serotype Typhimurium was cultured from a patient’s pet mouse and from seven hamsters from pet stores. Closely related S. enterica serotype Typhimurium isolates were cultured from rodent cages and reusable transport containers at a pet distributor. Human, rodent, and environmental isolates were resistant to ampicillin, chlora­mphenicol, streptomycin, sulfisoxazole, and tetracycline. The authors concluded that pet rodents probably are an underrecognized source of human salmonella infection.

Swanson SJ, Snider C, Braden CR, et al. Multidrug-resistant Salmonella enterica serotype Typhimurium associated with pet rodents. N Engl J Med. 2007;356:21–28.

Correspondence: Dr. Stephen J. Swanson at stephen.swanson@co.hennepin.mn.us

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Use of PCR versus fluorescent antibodies to diagnose pediatric respiratory viruses Use of PCR versus fluorescent antibodies to diagnose pediatric respiratory viruses

Detection of respiratory viruses is important to guide antiviral therapy, prevent nosocomial spread, provide surveillance, and, in some cases, decrease hospital costs and lengths of stay. Standard laboratory methods, such as staining with fluorescent antibodies and isolation by culture, have detected viruses in 13 percent to 45 percent of children with symptoms of respiratory illness. Among the disadvantages of fluorescent antibodies are the need for multiple rea­gents that may vary in sensitivity, potential variability in technical reading, and the need for an adequate num­ber of cells to examine each specimen. Several studies have found that polymerase chain-reaction (PCR) methods are more sensitive than fluorescent antibodies and culture for diagnosing acute respiratory virus infections. PCR is less affected by specimen quality and transport and provides an objective interpretation of results. Real-time PCR technology, which combines nucleic acid amplification with amplicon detection, provides results more quickly than conventional PCR, has in some cases shown improved sensitivity compared to conventional PCR, and provides a uniform platform for quantifying single and multiple pathogens in a single sample. The authors conducted a study in which they compared conventional fluorescent antibody methods to real-time PCR assays to detect respiratory syncytial virus (RSV), influenza virus type A (FluA), parainfluenza virus types 1, 2, and 3 (PIV1, PIV2, and PIV3), human metapneumovirus (MPV), and adenovirus (AdV). The study was conducted using 1,138 specimens collected over a one-year period from children with respiratory illnesses. At least one virus was detected in 436 (38.3 percent) specimens by fluorescent antibodies and in 608 (53.4 percent) specimens by PCR (P<.001). Specimen quality was inadequate for fluorescent antibodies in 52 (4.6 percent) specimens; 13 (25 percent) of these were positive by PCR. In contrast, 18 (1.6 percent) specimens could not be analyzed by PCR; one of these was positive using fluorescent antibodies. The number of specimens positive only by PCR among specimens found to be positive by PCR or fluorescent antibodies, or both, was 18 (7.0 percent) of 257 for RSV, 18 (13.4 percent) of 134 for FluA, 25 (64.1 percent) of 39 for PIV1, eight (88.9 percent) of nine for PIV2, 17 (30.1 percent) of 55 for PIV3, and 101 (76.5 percent) of 132 for AdV. MPV was detected in 6.6 percent of all specimens and 9.5 percent of the 702 specimens found to be negative using fluorescent antibodies. The mean number of virus copies per milliliter in specimens positive by both PCR and fluorescent antibodies was significantly higher, at 6.7 107, than that in specimens positive only by PCR, at 4.1 104 (P<.001). The authors concluded that PCR assays are significantly more sensitive than fluorescent antibody assays for detecting respiratory vir­uses, especially parainfluenza virus and adenovirus. Use of real-time PCR to identify viral respiratory path­ogens in children will improve diagnosis of respiratory illness.

Kuypers J, Wright N, Ferrenberg J, et al. Comparison of real-time PCR assays with fluorescent-antibody assays for diagnosis of respiratory virus infections in children. J Clin Microbiol. 2006;44:2382–2388.

Correspondence: Jane Kuypers at jane.kuypers@seattlechildrens.org

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Platelets and protein S in cardiac surgery patients Platelets and protein S in cardiac surgery patients

In contrast to a bleeding diathesis leading to increased perioperative blood loss in cardiac surgery patients, little attention has been paid to the presence of thrombophilic disorders in this population. Thromboembolic complications may be caused by pre-existing coagulopathy that is known or unknown when a patient is admitted for cardiac surgery. A thorough past medical history examination of any patient slated for cardiac surgery helps identify those with prior thromboembolic events, such as deep venous thrombosis, pulmonary embolism, and unexpected graft occlusion. In this subpopulation of patients with prior thromboembolic events, a more elaborate laboratory work­up is necessary to identify the underlying disorder. The disorder may be antiphospholipid syndrome, antithrombin III deficiency, factor V Leiden mutation, protein C or protein S deficiency, or others. For any patient who is a carrier of a thrombophilic disorder, surgery and immobilization represent periods of increased risk for the occurrence of venous thromboembolism. The authors reported on seven patients with hereditary heterozygous and symptomatic protein S deficiency who were undergoing cardiac surgery. They retrospectively reviewed the clinical data, operative and postoperative courses, and long-term results on all seven study patients. Six were operated on using cardiopulmonary bypass and one with an off-pump procedure. Procedures performed were emergent pulmonary embolectomy (patient one), aortic valve replacement and coronary artery bypass grafting (CABG, patient two), re-CABG (patients three and seven), and CABG (patients four, five, and six). In patients one, two, three, and seven, the diagnosis was made perioperatively. Patients four, five, and six were treated with a modified regimen of warfarin or protamine. The latter three patients had an uneventful perioperative course without thromboembolic complications. At followup, all but one of the seven patients were on continuous warfarin and were well, without additional thromboembolic events. The authors concluded that in patients with a past medical history of thromboembolic events or a perioperative thromboembolic complication, elaborate labora­tory investigation should lead to a def­i­nite diagnosis. For instance, patients with protein S deficiency undergoing cardiac surgery belong to a high-risk subgroup. Although rare, this and other coagulation disorders can be a critical issue in cardiac surgery. For such patients, the authors suggest perioperative warfarin therapy with a target international normalized ratio of 2.0 and incomplete protamine anta­gonism to minimize the risk of a peri­operative thromboembolic event.

Massoudy P, Thielmann M, Muller-Beissenhirtz H, et al. Thrombophilia in cardiac surgery—patients with protein S deficiency. Ann Thorac Surg. 2006;82:2187–2191.

Correspondence: Dr. Parwis Massoudy at parwis.massoudy@uni-essen.de

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Pharmacogenetic screening and chemotherapy treatment Pharmacogenetic screening and chemotherapy treatment

The anticancer drug docetaxel shows unpredictable interindividual variability in efficacy and toxicity. Potential causes of such variability in drug effects include the pathogenesis and severity of the disease be­ing treated, occurrence of unintended drug interactions, and impairment of hepatic and renal function. Despite the potential importance of these clinical variables in determining drug effects, it is recognized that inherited differences in metabolism and excretion can have an even great­er effect on the efficacy and toxicity of drugs. The metabolism of docetaxel (Taxotere) consists of a CYP3A-mediated oxidation of the tert-butylpro­pi­on­ate side chain, which results in the formation of four metabolites with reduced cytotoxic activity. The elimination pathway is mediated by the membrane-localized, energy-dependent drug efflux ABC transporter P-glycoprotein (ABCB1; MDR1). Several polymorphisms have been described in the CYP3A and ABCB1 genes. The exact functional significance of polymorphisms in the CYP3A4 gene is not yet known. The C3435T polymorphism is often simultaneously found with C1236T and G2677T/A. These polymorphisms may also have an effect on the pharmacokinetics of substrates of ABCB1, but results of the in vivo relevance of ABCB1 polymorphisms have been contradictory. The authors investigated the relationship between docetaxel pharmacokinetics and ABCB1 and CYP3A genotypes in more detail. They investigated the presence of C1236T, G2677T/A, and C3435T in ABCB1; CYP3A4*1B, CYP3A4*2, CYP3A4*3, and CYP3A4*12; and CYP3A5*2 and CYP3A5*3 variant alleles in 92 cancer patients treated with docetaxel. The authors obtained whole blood samples from patients with solid tumors treated with docetaxel to quantify exposure to the drug. They found that the homozygous C1236T polymor­phism in the ABCB1 gene (ABCB1*8) was significantly correlated with decreased docetaxel clearance (–25 percent; P=.0039). No other relationships between polymorphisms and pharmacokinetic variables reached statistical significance. Furthermore, no relationship could be identified between haplotypes of CYP3A and ABCB1 and pharmacokinetics. The authors concluded that the polymorphism C1236T in the ABCB1 gene was significantly related to docetaxel clearance. This finding may provide a meaningful tool to explain interindividual differences in docetaxel treatment in daily practice.

Bosch TM, Huitema ADR, Doodeman VD, et al. Pharmacogenetic screening of CYP3A and ABCB1 in relation to population pharmacokinetics of docetaxel. Clin Cancer Res. 2006;12:5786–5793.

Correspondence: Tessa M. Bosch at aptbo@slz.nl

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Dr. Bissell is professor, Department of Pathology, Ohio State University, Columbus.