College of American Pathologists
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  Clinical Abstracts





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April 2001

Do repeat laboratory and clinical examinations help establish the diagnosis of appendicitis?
The clinical diagnosis of appendicitis is often difficult, existing on the long differential diagnosis for acute abdomen. Unnecessary surgery in this context may reach 20 to 30 percent. It is unclear from previous studies what the value of repeated measures of body temperature, white blood cell count, differential cell count, and C-reactive protein level are in this context. The authors studied 502 patients with suspected appendicitis who were admitted to two Swedish hospitals in 1992 and 1993. Seventy-two patients underwent surgery without further investigation and 430 were admitted for observation. Of the latter, 425 received repeated clinical and laboratory examinations for a median of six hours. Five of these patients had another surgical disease, such as intestinal obstruction or tubo-ovarian abscess, and were eliminated from the study. Of the remaining 420 patients, 147 had a final diagnosis of acute appendicitis. The discriminatory power of the repeat examination was assessed in terms of receiver operating characteristic curve area, which increased from 0.56 to 0.77 at admission and 0.75 to 0.85 after admission. The WBC count and differential cell counts were the best discriminators on repeat examination. The authors concluded that repeat observations are useful.

Anderson RE, Hugander A, Ram H, et al. Repeated clinical and laboratory examinations in patients with an equivocal diagnosis of appendicitis. World J Surg. 2000;24:479-485.

Reprints: Dr. R.E. Anderson, Dept. of Surgery, Ryhov Hospital, S-551, 85
Jönköping, Sweden

A common LIS as a driver of a successful laboratory network
The St. Francis Health System, Pittsburgh, Pa., is a successful multi-hospital integrated delivery system with a fully developed "hub-and-spokes" laboratory network for its laboratory services. A core laboratory and satellite rapid-response laboratories on-site in the various locations function together under a common integrated management team. The authors found that selecting and implementing a common laboratory information system (in this case, from Sunquest Information Systems) at all locations was fundamental to their ability to integrate other laboratory functions. The measurable financial improvements related to the common LIS reside in the control of operating expenses and the contribution of outreach testing. The combined effect of expense savings and outreach from 1996 through 1998 was $3.595 million. The purchase price of the LIS, $1.36 million, was amortized over five years. The straight-line depreciation amount along with all maintenance and support fees for the LIS through 1998 was $529,500. This yielded a benefit-to-cost ratio of 6:1 ($3.595 million/$529,500) and a net return on investment of approximately $3.066 million ($3.595 million - $529,500). Implementing the common LIS led to a facility redesign and redeployment of tests, equipment, and personnel throughout the network.

Workman RD, Lewis MJ, Hill BT. Enhancing the financial performance of a health system laboratory network using an information system. Am J Clin Pathol. 2000;114:9-15.

Reprints: Dr. Ronald D. Workman, Dept. of Pathology & Laboratory Medicine, St. Francis Health System, 400 45th St., Pittsburgh, PA 15201

Comparing two different measures of fetal lung maturity in diabetic and nondiabetic pregnancies
Biochemical fetal lung maturity is delayed in diabetic pregnancies, and while the exact mechanism for delayed lung maturation is not known, fetal hyperglycemia and secondary hyperinsulinemia have been found in infants of diabetic mothers. Several tests for fetal lung maturity are available. The first of these to become available was the lecithin-sphingomyelin ratio. The L/S ratio had been found, in early studies, to be lower in diabetic than nondiabetic pregnancies of the same gestational age. These findings have not been consistently reproduced over time. The current authors studied two other fetal lung maturity assays: the amniotic fluid surfactant/albumin ratio (S/A) and the amniotic fluid level of disaturated phosphatidylcholine (DSPC). They compared these analyses in 179 women with type 1 diabetes mellitus who delivered within 72 hours of amniotic fluid sampling and in two additional nondiabetic groups (300 for S/A and 1,231 for the DSPC levels). Serial hemoglobin A1 levels were used to establish the degree of glycemic control during pregnancy. There was a significant effect on S/A ratio due to diabetic status and gestational age, whereas DSPC showed an effect due to gestational age only.

Delgado JC, Greene MF, Winkelman JW, et al. Comparison of disaturated phosphatidylcholine and fetal lung maturity surfactant/albumin ratio in diabetic and nondiabetic pregnancies. Am J Clin Pathol. 2000;113:233-239.

Reprints: Dr. Milenko J. Tanasijevic, Clinical Laboratories, Amory 215a, Brigham and Women’s Hospital, 75 Francis St., Boston, MA 02115

Role of increased serum neopterin in coronary artery disease in women
Neopterin is an intracellular redox cofactor that modifies the activity of nitric oxide synthase. This, in turn, activates the translocation of nuclear factor kappa B subunits to the nucleus, which then upregulates proinflammatory gene coding for cytokines, such as interleukin-6 and tumor necrosis factor alpha. When this mechanism is activated in vascular tissue, it leads to an increase in the inflammatory tone within the vascular wall. Atherosclerosis, now recognized to be an inflammatory condition, has been reported to be associated with increased neopterin levels. A study was conducted that prospectively examined serum neopterin levels by immunoassay in 114 women with angina pectoris who were consecutively seen at a university hospital in London. Eighty-two of the women had chronic stable angina and 32 had unstable angina. Twelve women with chronic stable angina and nine with unstable angina were readmitted with unstable angina or nonfatal myocardial infarction or died of MI. Among those with initial chronic stable angina, the baseline levels of neopterin were higher in those who experienced one of the major cardiac events (7.1 nmol/L) than in those who did not (5.7 nmol/L), even after adjusting for several other variables. The mean concentration of serum neopterin overall was significantly higher (7.6 nmol/L) in women with initial unstable angina than in those with chronic stable angina (5.9 nmol/L). The neopterin levels of all women who developed major cardiac events were similarly elevated.

Garcia-Moll X, Cole D, Zouridakis E, et al. Increased serum neopterin: a marker of coronary artery disease activity in women. Heart. 2000;83:346-350.

Reprints: J.C. Kaski, Coronary Artery Disease Research Unit, Dept. of Cardiological Sciences, St. George’s Hospital Medical School, Cranmer Terrace, London SW17 0RE, England;

Epilepsy and postmortem serum prolactin levels
Serum prolactin levels are increased 2- to 12-fold in certain types of epilepsy, namely tonic/clonic seizures and complex partial seizures, but not after simple partial or pseudo seizures. Sudden unexpected death in epilepsy (SUDEP) is generally an unwitnessed phenomenon and is inferred from the state and disposition of the body. Postmortem prolactin levels are known to reflect antemortem concentrations. The authors measured postmortem prolactin levels in 10 cases of SUDEP, 11 epileptic patients dying of other causes, 10 nonepileptic patients dying in a physiologically stressed state, and eight nonepileptic patients dying suddenly. None of the groups studied showed significantly elevated serum prolactin levels, causing the authors to conclude that postmortem prolactin level does not correlate with SUDEP, even if there is evidence of a terminal seizure. Since it takes 15 to 20 minutes for prolactin to peak after a seizure in life, it is possible that the time between seizure onset and death in SUDEP is not sufficient enough for prolactin to increase. Prolactin levels, therefore, cannot be used to establish whether SUDEP is always accompanied by a terminal seizure.

Opeskin K, Clarke I, Berkovic S. Prolactin levels in sudden unexpected death in epilepsy. Epilepsia. 2000;41:48-51

Reprints: Dr. K. Opeskin, Dept. of Forensic Medicine, Monash University, Melbourne, Australia;

Does adding free and total PSA levels improve prostate cancer screening?
A case-control study was employed with available stored serum samples to determine, retrospectively, if adding a free (uncomplexed) PSA level to a total PSA level offers any advantage. The study used archived serum samples from four different cohorts-one in the United Kingdom, one in the United States, and two in Finland-containing 49,261 men who were healthy at the time specimens were collected. Of those studied, 247 were verified as having died of prostate cancer or having developed the disease, and 953 men who did not develop prostate cancer were matched to cases for age, study location, and duration of sample storage. The sensitivity over the three years following specimen collection increased from 95 percent using PSA alone to 97 percent using free and bound PSA. The corresponding sensitivities over the six years following specimen collection increased from 52 to 56 percent. Thus combining the two assays provides only moderately increased sensitivity.

Wald NJ, Watt HC, George L, et al. Adding free to total prostate-specific antigen levels in trials of prostate cancer screening. Br J Cancer. 2000;82:731-736.

Reprints: N. J. Wald, CRC Cancer Screening Group, Dept. of Environmental & Preventive Medicine, Wolfson Institute of Preventive Medicine, St. Bartholomew's and the Royal London School of Medicine & Dentistry, Charterhouse Square, London EC1M 6BQ, England

Serum progesterone as an indicator of nonviable pregnancy
The standard protocol for diagnosing nonviable pregnancy is a combination of serum b-hCG and progesterone coupled with vaginal and pelvic ultrasonography. Studies have suggested that a single progesterone measurement is just as sensitive as serial b-hCG doubling times for predicting early gestational viability. Use of a single progesterone measurement removes the time delay associated with serial measurements. The authors have developed an algorithm for using progesterone in this context that includes an indeterminate zone (at 25 to 50 nmol/L). They compared the sensitivity, specificity, and predictive value of single serum progesterone measurements of less than 45 nmol/L for identifying nonviable pregnancies. This was done on 137 pregnant patients presenting to the emergency department of a tertiary care academic medical center with pain or bleeding and 123 consecutive infertility clinical patients who became pregnant during treatment. The Abbott AxSym was used for the progesterone assays and showed sensitivities of 88.6 and 58.8 percent in the emergency and fertility clinic patients, respectively. The specificities for the test in the same groups were 87.5 and 100 percent, respectively. The predictive value of serum progesterone for nonviable pregnancy thus varies with patient population.

Perkins SL, Al-Ramahi M, Claman P. Comparison of serum progesterone as an indicator of pregnancy nonviability in spontaneously pregnant emergency room and infertility clinic patient populations. Fertil Steril. 2000;73:499-504.

Reprints: Dr. Sherry L. Perkins, Dept. of Laboratory Medicine, Ottawa Hospital—Civic Campus, 1053 Carling Ave., Ottawa, Ontario K1Y 4E9, Canada; fax: 613-761-5401;

Decreased fibronectin in amyotrophic lateral sclerosis
The range of biologic function for fibronectin in its plasma and cellular forms is not known. Its affinity for endothelial cells and thrombi give it a potential role in wound-healing. Markers for the increased metabolism of connective tissue, namely increased levels of type III procollagen and serum hyaluronic acid and decreased levels of serum 7S collagen, have been observed in amyotrophic lateral sclerosis. The authors sought to examine the levels of plasma fibronectin in patients with ALS. They measured the levels in 67 subjects: 28 ALS patients, 18 patients with other neurological diseases, and 21 healthy control subjects. The fibronectin levels were 186.6 ± 93.3 µ/dL in the ALS patients, 271.7 ± 122.6 µg/dL in the group with other neurologic diseases, and 325.7 ± 114.4 µg/dL in the control subjects. The ALS group differed significantly from the other two groups, which did not differ significantly from one another. Fibronectin levels also were compared with duration of illness in the ALS patients and the group of patients with other neurologic diseases. A significant negative correlation was noted in the ALS group but not in the other groups.

Ono S, Imai T, Shimizu N, et al. Decreased plasma levels of fibronectin in amyotrophic lateral sclerosis. Acta Neurol Scand. 2000;101:391-394.

Reprints: Seiitsu Ono, Dept. of Neurology, Teikyo, University School of Medicine, Ichihara Hospital, 3426-3, Anesaki, Ichihara, Chiba 2999-0111, Japan

Decreased DHEAS levels in chronic heart failure
Dehydroepiandrosterone sulfate (DHEAS), the major secretory steroid product of the adrenal glands, is stimulated by adrenocorticotropic hormone (ACTH). DHEAS levels peak in the second decade and decline 10 percent per decade thereafter. Decreased levels of DHEAS have been reported in males with chronic heart failure but not in female chronic heart failure patients. The authors examined DHEAS and cortisol levels in 49 Japanese male patients with chronic heart failure and 32 age-matched control subjects. They also measured atrial natriuretic peptide and brain natriuretic peptide, two markers of chronic heart failure, as well as thiobarbituric acid-reactive substances (TBARS), a marker of oxidative stress. The patients with chronic heart failure had significantly lower DHEAS levels than did the controls, though cortisol levels did not differ significantly between the groups. When stepwise regression analysis was used to determine other relationships between the variables, DHEAS plasma level showed significant correlation with age and plasma brain natriuretic peptide level, and the ratio of cortisol/DHEAS significantly correlated with artrial natriuretic peptide and TBARS levels. The authors concluded that patients with chronic heart failure showed decreased DHEAS levels in proportion to disease severity, and this is associated with oxidative stress in these patients.

Moriyama Y, Yasue H, Yoshimura M, et al. The plasma levels of dehydroepiandrosterone sulfate are decreased in patients with chronic heart failure in proportion to the severity. J Clin Endocrinol Metab. 2000;85:1834-1840.

Reprints: Dr. Hirofumi Yasue, Dept. of Cardiovascular Medicine, Kumamoto University School of Medicine, 1-1-1 Honjo, Kumamoto 860-8556, Japan;

Differentiation of chemical from bacterial meningitis following neurosurgical procedures
Differentiating chemical (sterile) meningitis from bacterial meningitis following neurosurgery can be problematic. The authors respectively studied 70 patients who had undergone a spinal tap following a neurosurgical procedure. (Those with shunts or reservoirs were excluded.) Postoperative meningitis was diagnosed if the patient had more than 5 WBC/µL (>5 x 106/L) in nonbloody spinal fluid, a WBC:RBC ratio greater than 1:100, or positive cultures. The authors excluded patients who had five to 25 WBC/µL (5-25 x 106/L) and no headache, change in mental status, or fever not felt secondary to possible meningitis, and who had negative Gram stain results and cultures. Chemical meningitis was defined as meningitis with negative spinal fluid Gram stain, negative cultures, and patient recovery without the use of antibiotics. Bacterial meningitis was defined as positive spinal fluid cultures for a significant organism. Patients with CSF pleocytosis and negative cultures but with a parameningeal focus of infection were classified as having bacterial infections. Patients with negative spinal fluid Gram stains and cultures who received antibiotics after their spinal tap were classified as "indeterminate-cause." Spinal fluid WBC counts in patients with chemical meningitis ranged from 39 to 7,200 µL (39-7,200 x 106/L). Four of 20 patients with bacterial meningitis and no patient with chemical meningitis had a WBC count greater than 7,500 WBC/µL. Spinal fluid glucose levels were less than 40 mg/dL (or less than one-half of blood glucose levels in nondiabetics or less than one-third of blood glucose levels in diabetics) in eight of 17 patients with bacterial meningitis and in six of 30 patients with chemical meningitis. (The chemical meningitis patients with decreased CSF glucose levels usually had a high CSF RBC count—greater than 15,000/µL in five of six patients.) A glucose level of less than 10 mg/dL was seen only in patients with bacterial or intermediate-cause meningitis. The mean CSF protein was similar in all groups. Five of 20 patients with bacterial meningitis had positive Gram stains, and cultures grew mixed organisms in three cases and a single organism in 17 cases. Staphylococcus aureus was the common etiologic organism found (eight of 20 patients). Chemical meningitis is a common complication after neurosurgery. Spinal fluid findings can be similar in chemical and bacterial meningitis, however a spinal fluid WBC count of more than 7,500/µL and a glucose level of less than 10 mg/dL were present only in patients with bacterial meningitis.

Forgacs P, Geyer CA, Freidberg SR. Characterization of chemical meningitis after neurological surgery. Clin Infect Dis. 2001;32:179-185.

Reprints: Dr. Pierre Forgacs, Section of Infectious Diseases, Lahey Clinic Medical Center, 41 Mall Rd., Burlington, MA 01805