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August 2003
Coombs-negative ABO hemolytic disease of the newborn
The A and B antigenic sites are relatively weak on the newborn red
blood cell membrane, so there is relatively little anti-A or anti-B
antibody on the neonatal RBC in ABO hemolytic disease. Consequently,
the cord blood direct antiglobulin (DAT) test, or Coombs’ test,
is only weakly positive and may be negative unless a sensitive test
is used. Many hospital laboratories use the gel test, which is more
sensitive than techniques used previously for detecting immunoglobulin
G coating of newborn red blood cells. Nonetheless, significant jaundice
in DAT-negative neonates with ABO incompatibility is still frequently
attributed to isoimmunization. In these cases, no other cause of
jaundice is sought. Because unconjugated bilirubin levels can be
elevated due to increased bilirubin production or reduced elimination,
finding jaundice does not provide clear evidence of hemolysis. The
authors undertook a study to determine the rate of hemolysis as
determined by end-tidal carbon monoxide corrected for ambient air
(ETCOc), which is a measure of bilirubin production, in a group
of DAT-negative ABO-incompatible neonates, and compared these with
DAT-negative ABO-compatible neonates. They found no significant
difference between the mean 12-hour ETCOc levels in 60 DAT-negative
ABO-incompatible neonates and 171 DAT-negative ABO-compatible neonates,
despite a difference between the mean levels in 14 DAT-positive
ABO-incompatible neonates and the DAT-negative groups. Four neonates
in the DAT-negative ABO-incompatible group had elevated ETCOc levels,
and two were diagnosed with a specific hematologic abnormality-glucose-6-phosphate
dehydrogenase deficiency (G6PD) and elliptocytosis. The authors
concluded that a cause other than isoimmunization should be sought
in DAT-negative newborns with significant jaundice or increased
bilirubin production, even if those newborns are ABO incompatible.
Herschel M, Karrison T, Wen M, et al. Isoimmunization
is unlikely to be the cause of hemolysis in ABO-incompatible but
direct antiglobulin test-negative neonates. Pediatrics. 2002;110:127-130.
Reprints: Marguerite Herschel, MC 1051, Dept. of Pediatrics, University
of Chicago Children’s Hospital, 5841 S. Maryland Ave., Chicago,
IL 60637; mhersche@
midway.uchicago.edu
Use
of C-reactive protein for detecting occult pediatric bacterial infections
It is difficult to diagnose occult bacteremia in children. Studies
have established that 1.6 to eight percent of children who are three
to 36 months old and have temperatures of 39°C or higher will have
bacteremia. Discrimination on the basis of clinical findings has
not been sufficiently accurate. The best laboratory predictors of
bacteremia are the white blood cell count and absolute neutrophil
count, which have sensitivities and specificities of 70 to 86 percent.
C-reactive protein may be a valuable addition to this armamentarium
because it helps distinguish systemic bacterial infections from
viral infections in immunocompetent and immunodeficient children.
The kinetics of CRP metabolism are rapid enough to allow it to function
as a good marker of the rise and fall of the inflammatory component
in children. The authors conducted a study to assess the utility
of CRP in this context. They analyzed 256 children, ages three to
36 months, who were seen in an urban children’s hospital emergency
department. The children had received complete blood cell counts
and cultures as part of their evaluations and were prospectively
enrolled from February 2000 through May 2001. The children were
a median age of 15.3 months and had a median temperature at triage
of 40°C. Twenty-nine cases of occult bacterial infection were identified,
including 17 cases of pneumonia, nine cases of urinary tract infection,
and three cases of bacteremia. White blood cell counts ranged from
3.6 to 39.1 ¥ 109/µL, and absolute neutrophil counts ranged from
0.56 to 28.16 ¥ 109/L. The median CRP level was 1.7 mg/dL, with
a range of 0.2 to 43.3 mg/dL. Using logistic regression and receiver
operator characteristic curve analysis, the authors determined the
optimal cutoff point for CRP to be 4.4 mg/dL. This cutoff point
achieved a sensitivity of 63 percent and specificity of 81 percent
for detecting occult bacterial infection in this population. The
authors found that an ANC cutoff point of 10.6 ¥ 109/L offered the
best predictive model for detecting occult bacterial infection based
on a single test. Adding CRP to the ANC did little to enhance diagnostic
utility.
Isaacman DJ, Burke BL. Utility of the serum C-reactive
protein for detection of occult bacterial infection in children.
Arch Pediatr Adolesc Med. 2002;156:905-909.
Reprints: Dr. Daniel J. Isaacman, Division of Pediatric Emergency
Medicine, Children’s Hospital of the King’s Daughters, 601 Children’s
Lane, Norfolk, VA 23507; disaacma@chkd.com
Minimum
numbers necessary for ISI calibration of point-of-care coagulation
testing devices
The international sensitivity index calibration of prothrombin time
systems requires performing PT on 60 patients stabilized with long-term
warfarin treatment and 20 healthy subjects. A World Health Organization
international reference preparation for thromboplastin is used with
the manual PT technique to test the plasma from such samples in
parallel with the local PT procedure on the same samples. A criterion
of less than three percent coefficient of variation of the resultant
calibration slope is recommended. All of this leads to great complexity
given the large number of POC testing monitors that need to be compared.
Therefore, a simplified method for calibration of these monitors
is needed. One way to accomplish this would be to reduce the number
of blood samples required for this calibration. The authors established
the minimum numbers of fresh blood samples that should be used for
such a calibration. They used a Monte Carlo Bootstrap technique
to study two separate POC testing PT systems. The authors found
in more than 50,000 calibrations that there was little effect on
the mean ISI by reducing sample numbers to seven. There was, however,
progressively less certainty regarding the reliability of the calibration
under these circumstances. The precision of the calibrations and
the INR deviation were not markedly affected by reducing the number
of samples to half with the POC testing systems. But because ISI
calibration with the two POC testing systems was less precise than
conventional manual testing, the authors did not advise reducing
the number of samples.
Poller L, Keown M, Chauhan N, et al. Minimum numbers
of fresh whole blood and plasma samples from patients and healthy
subjects for ISI calibration of CoaguCheck and RapidPointCoag monitors.
Am J Clin Pathol. 2002;117:892-899.
Reprints: Dr. Leon Poller, ECAA Central Facility, School of Biological
Sciences, University of Manchester, Manchester, England
Evaluation
of allergic transfusion reactions
Allergic (urticarial) transfusion reactions are one of the most
common complications of blood component transfusion. ATRs are usually
benign, but severe reactions, such as anaphylactic/anaphylactoid
manifestations or hypotension, or both, can occur. The authors of
this study retrospectively evaluated 273 consecutive ATRs at one
institution during a nine-year period. All reactions reported to
the transfusion service were evaluated and reviewed by physicians
expert in blood banking/transfusion medicine. During the study period,
1,613 adverse reactions to transfusion were reported. Of these,
273 (17 percent) were identified as allergic. Red blood cells were
implicated in 123 (45.1 percent) ATRs; fresh frozen plasma in 66
(24.2 percent); platelets in 81 (29.7 percent); fresh frozen plasma
and pooled platelets in two (0.7 percent); and pooled cryoprecipitate
in one (0.3 percent). One ATR with hives was seen in a major ABO
mismatch transfusion, and five ATRs were associated with autologous
units of red blood cells. Severe reactions (anaphylactic or anaphylactoid)
were observed in 21 (7.7 percent) patients. Seven (33.3 percent)
of these 21 severe ATRs involved red blood cells, and 14 (66.7 percent)
involved fresh frozen plasma or platelet transfusions. Nine (42.9
percent) of the 21 severe ATRs had associated hypotension. The overall
incidence of anaphylactic or anaphylactoid reactions or severe allergic
reactions was 1.3 percent. The clinical manifestations were quite
variable, and various types of skin manifestations were observed.
Skin rashes were often localized to various parts of the body and
were sometimes generalized, but no consistent skin presentation
was identified. Twenty-six (9.5 percent) patients did not have skin
manifestations. The overall incidence of ATRs was estimated to be
one in 4,124 blood component transfusions, and severe ATRs occurred
in approximately one in 53,612 blood component transfusions. Considering
only red blood cells, platelets (doses), and fresh frozen plasma
transfusions, the overall incidence of ATRs was one in 2,338 transfusions,
and severe reactions were seen in one in 30,281 transfusions. The
authors concluded that ATRs are usually benign but can be associated
with severe clinical manifestations and autologous transfusion and
should be investigated thoroughly.
Domen RE, Hoeltge GA. Allergic transfusion reactions:
an evaluation of 273 consecutive reactions. Arch Pathol Lab Med.
2003;127: 316-320.
Correspondence: Dr. Ronald E. Domen, Dept. of Pathology, H160, Penn
State Milton S. Hershey Medical Center, P.O. Box 850, 500 University
Drive, Hershey, PA 17033; rdomen@psu.edu
Perirectal
cultures for VRE surveillance
The Centers for Disease Control and Prevention guideline for isolation
recommends contact isolation for patients colonized or infected
with "epidemiologically important microorganisms," including vancomycin-resistant
Enterococcus. Among the CDC recommendations for VRE is
active surveillance with perirectal cultures and isolation of patients
found to be colonized. The authors conducted a study to determine
whether the costs related to VRE bacteremia justify the costs of
preventive measures. They analyzed results from 10,400 perirectal
swabs taken on 54,052 patients admitted to two university hospitals.
Inpatients considered to be at high risk for VRE at the first hospital
underwent weekly perirectal surveillance cultures. The estimated
cost of culture and resulting isolation during a two-year period
were compared with the estimated excess cost from more frequent
VRE bacteremias at the second hospital, which was similar in size
and complexity but was not using surveillance cultures to control
the spread of VRE throughout the hospital. Cultures and isolation
cost approximately $253,099. At the first hospital, 193 (0.38 percent)
patients were culture positive, and only one showed VRE bacteremia.
At the second hospital, at which surveillance and isolation were
not practiced, 29 VRE bacteremias were recorded. The estimated attributable
cost of VRE bacteremias at the comparison hospital, which was $761,320,
exceeded the cost of surveillance by threefold. The authors concluded
that VRE surveillance, as recommended by the CDC, may be cost-effective.
Muto CA, Giannetta ET, Durbin LJ, et al. Cost-effectiveness
of perirectal surveillance cultures for controlling vancomycin-resistant
Enterococcus. Infect Control Hosp Epidemiol. 2002;23:429-435.
Reprints: Dr. Barry M. Farr, Box 473, University of Virginia Health
System, Charlottesville, VA 22908
Outcomes
in AIDS associated with adherence to M. avium complex prophylaxis,
antiretroviral therapy
Newer, more effective antiretroviral regimens and prophylactic treatments
for opportunistic infections have dramatically reduced rates of
morbidity and mortality from HIV disease. Adhering closely to these
treatment regimens is crucial to their success. Many studies have
shown a strong association between adherence to antiretroviral therapy
and successful suppression of HIV-1 RNA. Recent studies have also
shown that HIV-1 RNA levels independently predict survival and the
occurrence of opportunistic infections. In contrast, relatively
little is known about the association between adherence to potent
antiretroviral and opportunistic infection prophylactic regimens
and outcomes such as AIDS progression or the development of opportunistic
infections. The authors assessed the rate of adherence to antiretroviral
and Mycobacterium avium complex (MAC) prophylactic regimens.
They studied 643 patients who were enrolled in a trial of MAC prophylaxis.
Forty-two percent of the patients reported that they were not adhering
to the prophylactic regimen by week 56 of the study followup. Twenty-five
percent of the patients reported that they were not adhering to
the antiretroviral regimens. Not adhering to both regimens was associated
with higher HIV-1 RNA levels and a significant increase in the risk
of developing AIDS-defining complications or dying. The authors
concluded that these results underscore the clinical significance
of adhering to HIV therapy.
Cohn SE, Kammann E, Williams P, et al. Association
of adherence to Mycobacterium avium complex prophylaxis and
antiretroviral therapy with clinical outcomes in acquired immunodeficiency
syndrome. Clin Infect Dis. 2002; 34: 1129-1136
Reprints: Dr. Susan E. Cohn, University of Rochester Medical Center,
Infectious Disease Unit, 601 Elmwood Ave., Box 689, Rochester, NY
14642; susan_cohn@
urmc.rochester.edu
Probability-based
reference ranges for ratios of log-gaussian analytes
There may be complications in analyzing laboratory data when the
lab result and its associated reference range must be converted
or calculated from other test results and reference ranges from
a single patient visit. The basic concept of the reference range
involves upper and lower reference limits, which are estimated to
enclose a specified percentage (generally 95 percent) of the values
for a population from which the reference subjects have been drawn.
These upper and lower reference limits are typically assumed to
demarcate the estimated 2.5th and 97.5th percentiles of the underlying
distribution of values, respectively. An example of the problem
of the calculated result and reference range is provided in the
translation between a white blood cell differential absolute count
reference range and a WBC differential percentage reference range,
using the total WBC reference range. A naïve method for determining
this would calculate the upper and lower limits of the derived test
from the upper and lower limits of the measured values using the
same algebraic formula used for the derived measure. This method
and any others that do not rely on probability-based transformations
don’t maintain the distributional characteristics of the original
reference ranges. The authors proposed a probability-based approach
for the interconversion of reference ranges for ratios of 2 log-gaussian
analytes. The method involves a simple algebraic formula for calculating
the reference ranges of the derived measures while preserving the
probability relationships. The nonparametric method and a parametric
method that takes the log transformation estimate a reference range,
and then exponentiates are provided as comparators. The authors
showed, with example data, that the proposed method maintains the
distributional characteristics of the transformed reference range
measures, while the naïve method does not.
Trost DC, Hu M, Brailey AG, et al. Probability-based
construction of reference ranges for ratios of log-gaussian analytes.
Am J Clin Pathol. 2002;117:851-856.
Reprints: A.G. Brailey, Pfizer Global Research and Development,
50 Pequot Ave., New London, CT 06320
Carotenoid
levels in kids
Carotenoids are compounds with vitamin A-like chemical structures
and antioxidant properties that are found primarily in plants, especially
fruits and vegetables. Five of these compounds-α-carotene,
β-carotene, β-cryptoxanthin, lutein and zeaxanthin, and
lycopene-are the principle chemical entities that have measurable
concentrations in human blood. Epidemiologic studies suggest that
carotenoid intake or circulating concentrations of these compounds
are inversely correlated to all-cause mortality, cardiovascular
disease, various cancers, insulin resistance, and other conditions.
Consequently, knowledge of the distribution of concentrations of
these compounds in the population at large is considered to be of
some value. The authors examined the distributions and determinants
of concentrations of the five aforementioned compounds in U.S. children
and adolescents who participated in the third National Health and
Nutrition Examination Survey (NHANES III). They conducted a cross-sectional
study of 4,231 subjects who ranged in age from six to 16 years.
The authors adjusted for age, gender, race or ethnicity, poverty-income
ratio, body mass index status, and concentrations of high-density
lipoprotein and non-HDL cholesterol, C-reactive protein, and cotinine.
After these adjustments, only HDL cholesterol (P<0.001)
and non-HDL cholesterol (P<0.001) concentrations were
directly related to all of the carotenoid concentrations. Age (P<0.001)
and body mass index status (P<0.001) were inversely
related to all carotenoid concentrations, except those of lycopene.
Young males had slightly higher carotenoid concentrations than did
young females, but the differences were significant only for lycopene
(P=0.029). Various ethnic differences were also found in
the distributions of these compounds. C-reactive protein concentrations
were inversely related to concentrations of b-carotene (P<0.001),
lutein and zeaxanthin (P<0.001), and lycopene (P=0.023).
Cotinine concentrations were inversely related to concentrations
of α-carotene (P=0.002), β-carotene (P<0.001),
and β-cryptoxanthin (P<0.001). The authors concluded
that their findings may serve as valuable reference range information
for these analytes in U.S. children and adolescents.
Ford ES, Gillespie C, Ballew C, et al. Serum carotenoid
concentrations in U.S. children and adolescents. Am J Clin Nutr.
2002;76:818-827.
Reprints: E.S. Ford, Centers for Disease Control and Prevention,
1600 Clifton Rd., MS E-17, Atlanta, GA 30333; esf2@cdc.gov
A
disease-susceptibility gene for coronary artery disease
Pseudoxanthoma elasticum is an inherited disorder involving dystrophic
mineralization of elastic tissues of the skin, retina, and arterial
walls. The frequency of PXE in the general population is not known
because it is likely that individuals with a mild clinical phenotype
escape diagnosis. The molecular basis of PXE appears to be a mutation
in an ATP-binding cassette (ABC) transporter gene (ABCC6). Accelerated
atherosclerosis, leading to myocardial infarction at a young age,
appears to be a cardiovascular manifestation of PXE. PXE has, on
several occasions, been an incidental finding in patients with premature
cardiovascular disease. It has been impossible to assess whether
being a carrier of a single ABCC6 gene mutation on one allele would
confer additional risk for coronary artery disease. The authors
conducted a case-control study involving 441 patients no older than
50 years of age who had definite CAD and 1,057 age- and gender-matched,
population-based controls who were free of CAD to assess the relationship
between the frequent R1141X mutation in the ABCC6 gene and the prevalence
of premature CAD. The prevalence of the R1141X mutation was 4.2
times higher among patients than among controls. Therefore, subjects
with the R1141X mutation had an odds ratio for a coronary event
of 4.23, which represents a sharply increased risk of premature
CAD.
Trip MD, Smulders YM, Wegman JJ, et al. Frequent
mutation in the ABCC6 gene (R1141X) is associated with a strong
increase in the prevalence of coronary artery disease. Circulation.
2002;106:773-775.
Reprints: Mieke D. Trip, Dept. of Cardiology, Academic Medical Centre,
Meilbergdreef 9, 1105 AZ Amsterdam, Netherlands; m.d.trip@amc.uva.nln
Clinical
pathology abstracts editors
Michael Bissell, MD, PhD, MPH, professor and director of clinical
services and vice chair, Department of Pathology, Ohio State University
Medical Center, Columbus.
Ronald Domen, MD, professor of pathology, medicine, and humanities,
Penn State University College of Medicine, Hershey, Pa.
bruene@rhrk.uni-kl.de
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