Pediatric Laboratory Medicine Current Challenges and Future ...

AJCP / SPECIAL ARTICLE

Pediatric Laboratory Medicine Current Challenges and Future Opportunities Cheryl M. Coffin, MD,1,3 Marilyn S. Hamilton, MD, PhD,2 Theodore J. Pysher, MD,1,3 Philip Bach, PhD,3 Edward Ashwood, MD,1,4 Jeanne Schweiger,4 Dennis Monahan,4 Deborah Perry, MD,5 Beverly B. Rogers, MD,6 Carlo Brugnara, MD,7 Joe Rutledge, MD,8 Ronald Weiss, MD, MBA,1,4 Owen Ash, PhD,1,4 Harry Hill, MD,1,4 Wayne Meikle, MD,1,4 William Roberts, MD,1,4 and Sharon Geaghan, MD9 Key Words: Laboratory medicine; Pediatrics; Clinical pathology

Abstract The practice of pediatric laboratory medicine involves unique challenges related to development, nutrition, growth, and diseases during different periods of infancy, childhood, and adolescence. This article discusses key aspects of pediatric laboratory medicine faced by clinical pathologists, clinical laboratory scientists, and clinicians, including point-of-care testing, preanalytic variables, analytic factors, agespecific reference intervals, esoteric laboratory tests, clinical impact, and future opportunities. Although challenging, pediatric laboratory testing offers many opportunities for improved patient care, clinical- and laboratory-based research, and education.

© American Society for Clinical Pathology

In the 20th century, medical knowledge grew exponentially with changes in diagnostic, prognostic, and treatment parameters in nearly all medical specialties. Two such specialties include laboratory medicine and medical technology.1-3 At the same time, many changes in the health care environment have occurred, such as the formation of health management organizations, preferred provider groups, and related changes in laboratory contracts and carve-outs. These have lessened the focus on local consultative clinical pathology and pediatric laboratory medicine, two fields best practiced with a close collaboration between clinical pathologist and clinician.4-12 The potential result of more complex laboratory medicine and less pediatric consultation with an emphasis on global practices is a decline in the care of infants, children, and adolescents. Children are not little adults. Their unique development, nutrition, growth, and diseases create challenges for pediatric laboratory medicine.9 As a general rule, laboratory tests reflect the physiologic changes associated with diseases and their treatment. For pediatric patients, this assessment occurs within a context of growth and development. Reference intervals, as well, must reflect the pediatric patient’s growth and development; however, chronologic age may not always serve as the optimal basis for reference intervals.9,13 Prematurity, sexual development, and growth hormone treatment all are significant factors when establishing reference intervals. In addition, the baseline knowledge needed to effectively use a laboratory test varies with the age of the patient, yet the nuances of pediatric test interpretation may go unrecognized in the medical field.14-16 Testing frequency also varies in children because of the acuity of illness and the need for longterm follow-up in chronic conditions. Some procedures and Am J Clin Pathol 2002;117:683-690

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tests considered “routine” at children’s hospitals, such as phlebotomies on very young patients and sweat chloride tests, may be uncommon, challenging, or unavailable in nonpediatric hospitals. Providers also must consider the technical aspects of pediatric laboratory testing, including, for example, the small specimen required for such a procedure. Laboratory testing is only the first of many challenges in pediatric medicine. Children often acquire diseases that differ from those of adults, and compared with adult disorders, many pediatric diseases are low in frequency. Neonatal screening programs are mandated throughout the United States, although the extent varies from state to state. Newborns are “immunologically naive,” have little or no infectious disease history, and are subject to relatively unique infections such as group B streptococcal infections, TORCH (toxoplasmosis, other agents, rubella, cytomegalovirus, herpes simplex) infections, and primary infections by all organisms. Responses to these infections can be unique, requiring special testing; for example, the rapid infectious mononucleosis heterophil antibody slide test (Monospot, Ortho Diagnostics, Raritan, NJ) results may be inaccurate in young children, and serologic tests for Epstein-Barr virus have limitations during the first several years of life. Premature birth can result in a set of diseases due to incomplete organ system development, especially those affecting the lungs and central nervous system. Metabolic disorders and genetic diseases, such as cystic fibrosis and sickle cell disease, are examples of diseases diagnosed during childhood. Among the diseases that span both childhood and adulthood, including enteroviral meningitis, some forms of diarrhea, and now cystic fibrosis, differences arise in disease frequencies and aspects of care. Cancer in childhood comprises a set of neoplasms for which the genetic alterations are much more important than the environmental factors. Pediatric transfusion medicine has many important differences from adult transfusion medicine; however, a comprehensive discussion is beyond the scope of this article. Pediatric care is provided in diverse environments, including the offices of primary care physicians and pediatricians and family medicine specialists, public health clinics, acute care facilities, general hospitals, children’s hospitals, and academic medical centers. As with adults, care is shifting more and more to the outpatient setting for preventive medicine and management of less severe illnesses and injuries. Consequently, hospitalized children, particularly those in children’s hospitals, are characterized by greater acuity of illness and metabolic instability than in previous eras. Test interpretation can become very complex. With the exception of children’s hospitals and some academic centers, few of these settings are likely to have access to a laboratory designed for the care of children. In these diverse settings, the knowledge base of the clinician ordering or interpreting 684

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laboratory tests can vary considerably. Finally, cost containment and “gate-keeping” efforts by third-party payers often dictate the laboratories in which tests must be performed and have increased the burden on primary care providers, as they may order more laboratory tests as a substitute for clinical consultation, but may not fully understand the subtleties of these tests or may apply the results within a diagnostic algorithm inappropriate for children. These are just some of the key issues and questions facing clinical pathologists, clinical laboratory scientists, and clinicians involved in pediatric laboratory medicine. Additional issues that will be summarized and elaborated on in this article include point-of-care testing, preanalytic factors in pediatric laboratory testing, analytic factors, age-specific reference intervals, esoteric laboratory tests, clinical impact and opportunities, and future considerations. It is important to remember that pediatric patients require a unique medical approach, as significant differences exist in this patient population in disease frequencies, specimen collection, test performance, and test interpretation. By drawing attention to these matters, we aspire to improve the health care of children and to promote academic and clinical collaborations among pediatric laboratory medicine specialists, pediatricians, and others caring for children.

Point-of-Care Testing Point-of-care testing has been broadly defined as testing in decentralized units and narrowly defined as testing performed physically next to the patient or by patients themselves.17 It may be done at the bedside, in a laboratory with special instrumentation, or at a particular site for a particular test, such as intraoperative parathyroid hormone tests in the operating room or blood gases and electrolyte determinations in the neonatal intensive care unit. Rapid turnaround time, decreased sample size, and large test availability make pointof-care testing especially appealing in pediatrics.18-21 Pointof-care testing is becoming increasingly important in children, as well as in adults, for streamlining the patient-care process and for monitoring the conditions of critically ill patients.22 Testing in hospitals, emergency departments, outpatient laboratories, and perinatal settings may be done because of the appeal of small samples, which reduce the risk of iatrogenic anemia and the need for transfusions. Point-of-care tests include blood gases, chemistry, coagulation, and infectious diseases such as Streptococcus groups A and B, influenza, and respiratory syncytial virus. The cost-effectiveness and influence on clinical outcome are not fully documented.23-26 The sensitivity of some point-of-care tests, such as rapid screening for EpsteinBarr virus infections or streptococcal pharyngitis, is not yet © American Society for Clinical Pathology


as good as tests available in central laboratories. The greater cost per test, the need to link point-of-care instruments to existing information systems to ensure patient identification, documentation of quality control and billing, and compliance with regulatory requirements of the Joint Commission on Accreditation of Healthcare Organizations and the Clinical Laboratory Improvement Amendments of 1988 constitute the most important challenges to point-of-care testing for both pediatric and adult care. Point-of-care testing should be based not on what tests can be done at the point-of-care but on what tests should be done to expedite the patient care process.22,27

Preanalytic Factors in Pediatric Laboratory Testing Preanalytic variables such as specimen collection, specimen handling, and sample size affect the quality of laboratory testing. In the pediatric population, patient age becomes a significant preanalytic phase factor,28 and specimen collection is unique.29-31 Phlebotomy for infants and children is technically challenging and requires special training and skill, particularly for sites such as scalp and jugular veins and umbilical artery catheters.32,33 The increased acuity of pediatric inpatients results in more blood draws, which increases the risk of iatrogenic anemia, may necessitate transfusion with its attendant risks, and makes the need for smaller samples even more compelling. As a general rule, no more than 5% of the infant total blood volume should be removed in a single draw, and the decision to transfuse should be based on the patient’s clinical condition, not the cumulative amount of blood removed. Line draws are relatively common among acutely ill pediatric patients, and contamination with heparin or other substances in the line fluid may affect laboratory results.31,34 Liquid anticoagulant in collection tubes also could potentially dilute the specimen when sample volumes are small. Skin puncture specimens (“capillary blood”) are more commonly obtained from children and consist of an admixture of blood from arterioles, venules, and capillaries with interstitial and intracellular fluids. The results from various analytes also deviate from those obtained with arterial or venous samples.29,31 When nurses obtain specimens from arterial or venous lines, the repeated training and education of the nursing staff and close interaction with laboratory personnel are necessary to ensure the reliability of laboratory data. Finally, newborn specimen hemolysis can negatively affect testing for hyperbilirubinemia because hemoglobin interferes with bilirubin detection. In addition to phlebotomy, there are other examples in which obtaining samples from children differs from adults, such as collecting urine by catheter or bagging, obtaining © American Society for Clinical Pathology

sputum or other respiratory specimens, performing gastric lavage for tuberculosis, or using nasal aspirates as opposed to swabs for influenza tests. Blood cultures on minimal volumes of only several drops are questionable in their usefulness and require careful interpretation. In most circumstances, a 24-hour urine specimen provides diagnostic discrimination, but the collection can be difficult even with hospitalization. Specimen handling also is important and can affect testing quality. Analyte stability can vary with temperature and sample type,35,36 so it is vital to transport specimens promptly to the laboratory for immediate processing and rapid testing. The small volumes of pediatric specimens increase the deleterious effects of substrate metabolism (such as glucose), hemolysis (by elevating potassium), and evaporation (by elevating sodium), so rapid separation of plasma into covered aliquot tubes is necessary. Rapid turnaround dictates use of anticoagulated whole blood or plasma instead of a clotted serum specimen. To minimize sample requirements, single specimens must be shared by several laboratory sections. Specimen flow in larger laboratories is optimized by splitting samples for parallel testing rather than serial testing without dividing a sample. In children’s hospitals, a single sample may be received in a syringe and used for a combination of tests, such as chemistry, blood gases, and CBC counts (with the limitation of heparin-related platelet clumping leading to an inaccurate platelet count). Transportation times affect the results of urinalysis, bacterial cultures, and glucose values. Although specimen collection and handling issues are not unique to pediatrics, they may be more problematic in this arena because of challenges associated with sample procurement, specimen volume, and evaporation.

Analytic Factors Analytic factors for laboratory testing include instrumentation, specimen handling within the laboratory, sample volume, analytic interferences, and turnaround time. The development of new instrumentation and technology has been influenced by the consolidation of hospitals and health care systems, the consolidation of the instrument and vendor market, and the resulting diminished competition. The pediatric testing market is perceived to be small compared with the adult market, and advances tailored to pediatric specimens and childhood disease offer fewer financial incentives to the instrument and reagent manufacturers. However, special instrument designs that require less blood are needed for the pediatric population; and interestingly, this design requirement could open additional testing markets beyond pediatrics, as the geriatric population often is more susceptible to anemia because of large phlebotomy volumes.37 Am J Clin Pathol 2002;117:683-690

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In addition to less innovation in the area of pediatric instrumentation, automated laboratory equipment frequently cannot handle small specimens or samples directly from pediatric-sized tubes. For example, few instruments can handle such samples when they are in BD Microtainer tubes (Becton Dickinson, Franklin Lakes, NJ). Instrument test platforms frequently rely on high sample volume and high test volume with cost-effectiveness as the driving force. Although vendors have minimized specimen requirements to reduce reagent costs, the dead volumes and test-tube size remain substantial for many instruments. To allow automated testing, dead volumes less than 50 µL would be optimal for pediatric testing. The methods used for pediatric testing should not be subject to interference by bilirubin or hemolysis, both of which are commonly present in pediatric specimens. In contrast with frequent repeated testing that can be done on adult samples, small pediatric samples may preclude repeated testing to confirm abnormal results. Generally, specially made bar code labels are needed for small pediatric collection tubes because standard labels are too large. Robotic systems have been developed that rely on standard 5- to 7-mL test tubes and, consequently, cannot handle pediatric specimens for microanalysis. This incompatibility results in the manual processing of pediatric samples in larger laboratories. These factors make it difficult to maintain positive sample identification for pediatric specimens throughout the preanalytic, analytic, and postanalytic testing phases and into the medical record. For this to occur, instruments and laboratory robotic systems must be able to directly handle small pediatric-sized collection tubes and read pediatric-sized bar code labels. Such testing cannot be accomplished with today’s technology. Analytic interference is encountered more commonly in neonatal patients than in adults and represents a significant technical challenge. Specifically, high concentrations of bilirubin, lipids, and fetal hemoglobin are present in many neonatal specimens. Neonatal hyperbilirubinemia (bilirubin level, 25 mg/dL [427 µmol/L]) absorbs light at wavelengths at which many spectrophotometric methods measure a variety of analytes and can cause spurious test results in both chemistry and hematology laboratories. Intravenous nutrition supplemented with fat emulsions can result in specimen turbidity, which interferes with both spectrophotometry and nephelometric methods based on changes in light scatter. To diminish the effects of iatrogenic lipidemia, such specimens can be retested following ultracentrifugation or removal of a specific plasma volume and replacement with an equal volume of diluent. Fetal hemoglobin, normally present in significant quantities only in newborns and infants, interferes with accurate measurement of several hemoglobin derivatives. Carboxyhemoglobin and methemoglobin are critical to oxygen transport in the newborn and 686

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are important parameters for the management of neonates in the intensive care unit, but large amounts of fetal hemoglobin invalidate their conventional spectrophotometric measurement. Methemoglobin is a toxic byproduct of nitric oxide, which is a current therapy for persistent pulmonary hypertension of the newborn, and is overestimated at clinically relevant values when fetal hemoglobin is elevated. However, instrumentation appropriate to the neonatal setting can eliminate this technical issue. “Overdetermined” spectrophotometric systems use more wavelengths than hemoglobin derivatives to be directly measured and provide more accurate measurements in the presence of fetal hemoglobin than conventional systems. Turnaround time is a major issue in all laboratories, but it becomes a more significant issue for the pediatric patient. Often, the pediatric patient cannot provide a reliable clinical history, the physical findings may significantly underrepresent the severity of disease, and the patient’s condition can change rapidly, particularly for premature infants.22 Because of these factors, the demand for shorter turnaround times is constantly increasing. Turnaround time influences clinical decision making, treatment, and discharge planning. Tests that are ordered infrequently but require a rapid turnaround time may be economically unfeasible because reimbursement is not based on the urgency with which testing is performed. Increasing the test frequency is one approach to resolving this dilemma in an integrated or reference laboratory setting, but it may not be cost-effective in an individual children’s hospital laboratory. A large laboratory with many specimens in a run requires only 1 hour of technologist time, whereas a smaller laboratory requires the same labor costs, yet can run only 1 patient sample at a time. In addition, this 1 sample is reimbursed at the same rate as the larger laboratory’s full run; clearly, the larger laboratory has a financial advantage over the smaller laboratory. Integrated regional laboratories and reference laboratories with daily or more frequent test runs are one potential solution to at least part of this challenge, if preanalytic and postanalytic factors such as transportation and results reporting times can be optimized and if consultants with pediatric expertise are available.

Age-Specific Reference Intervals Age-specific reference intervals are key in all types of pediatric laboratory testing.9,13,38-40 The number of agespecific reference intervals needed to properly characterize the effects of growth and development varies for different laboratory tests, reflecting differences in organ growth, development, and physiologic function at different ages. Physiology and development may not be synchronous with age, as in premature infants, in puberty, or with growth hormone © American Society for Clinical Pathology


therapy (which causes a markedly elevated alkaline phosphatase level compared with other patients of the same age). Endocrinology and chemistry results, as well as coagulation, serology, and hematology results, are subject to age-specific variability. This is a significant issue for coagulation tests because of the test volumes required, physiologic and developmental variability, and the fact that coagulation reagents are more likely to be optimized for anticoagulation monitoring than for genetic disorders that occur in childhood, such as hemophilia and some thrombotic disorders. Serologic test results are influenced by the transplacental passage of maternal IgG and by immunization responses in infants and children. In hematology, the automated differential uses algorithms in children that differ from those used in adults. Clearly, determining age-specific reference intervals is crucial for pediatric diagnosis and monitoring, yet obtaining samples for this determination can be quite challenging. Collecting samples from healthy children is difficult, particularly from “normal” premature infants, term infants, and toddlers. The influences of prematurity on laboratory test results are poorly understood and have not been assessed systematically. Moreover, currently available laboratory information systems do not permit the automatic calculation of a patient’s age related to prematurity, nor can reference intervals be separated by gestational age. Different rates of organ maturation occur after premature birth, but because of concerns about blood volume depletion in premature infants, it has been difficult to study reference intervals. Interpretation relies on the clinical experience of neonatologists to appropriately extrapolate reference intervals. Finally, recruiting children as research subjects poses ethical dilemmas,41 and protocols with institutional review board approval and informed consent are required for reference interval studies on normal, healthy children. On the other hand, not developing reference intervals can be both costly and devastating because of the potential for inaccurate diagnosis or patient misclassification, delayed diagnosis, added patient morbidity, inappropriate treatment, and the subsequent unnecessary diagnostic procedures related to inaccurate reference interval comparisons. Alternative ways of developing reference intervals for established tests require further study and could include mathematical approaches, extrapolation, and establishment of decision limits.38,42,43 Mathematical analysis of results from pediatric patients may yield appropriate reference intervals for some tests, such as vitamin B12 and folate.38 However, statistics alone cannot be used for all tests. If there are anchors from well-executed reference studies, then patient databases can be used to transfer values from the study population to other laboratories. The question of what to do when a particular test is transferred from one type of technology to another is not completely resolved. Also, computer systems do not © American Society for Clinical Pathology

account for the continuous nature of reference intervals but depend on the individuals setting the intervals to provide adequate resolution. Disease vs nondisease cutoff ranges are as challenging to form as age-specific reference intervals, and data are difficult to find. Consensus guidelines established for adults may not apply to children, as is the case for cholesterol and hyperlipidemias. 15 Drug-of-abuse testing in children is another area in which data are very limited but could have important implications for growth, development, and overall patient care.14,16 Last, metabolism differs in children, and different antibiotics are approved for children vs adults.

Esoteric Laboratory Tests Reference laboratory use and esoteric testing are particularly challenging for pediatric care. In the adult hospital laboratory, typically only one or several reference laboratories are used. In contrast, pediatric laboratories outsource to a large number of reference laboratories because of the rarity of diseases being evaluated, the biased experience and preferences of subspecialists, the assessment of unusual congenital disorders, the increasing use of genetic testing, and the limited availability of pediatric esoteric testing. Send-out tests constitute a relatively small proportion of the test volume in children’s hospital laboratories, but the extent of the send-out menu, the volume and frequency of send-out tests, and the variety of laboratories used require special resources. Also, children who are being treated at other health care facilities are sometimes referred to pediatric laboratories for phlebotomy services on esoteric tests because the original facility is not familiar with the specimen handling instructions or does not have properly trained personnel. The selection of reference laboratories involves complex decision-making processes. Very rare tests may be performed in only one or a few laboratories nationwide or perhaps worldwide and perhaps only for research purposes. Handling information within the hospital laboratory is very complicated when tests are sent to numerous reference laboratories. Esoteric tests in children more often are ordered and interpreted by specialists, but even if this is not the case, difficulties may be encountered with test interpretation and clinical decision making. Consequently, the need for direct consultations between clinicians and pediatric clinical pathologists in the hospital or experts in the reference laboratory may increase. For the reference laboratory that performs pediatric testing, significant logistic challenges exist. If samples are small or suboptimal, the reference laboratory must develop special means to handle the specimen. Also, efficient communication affects the ordering process, test identification, result Am J Clin Pathol 2002;117:683-690

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storage and delivery, the pathway from the ordering physician to the reference laboratory and back again, shipping times, and time-sensitive procedures. Computer interfaces improve turnaround time, accuracy, information access, and the passage of information back and forth between the originating laboratory and the reference laboratory; however, the ordering physician is often omitted from this interface transaction. Once completed, the test result must go to someone who can interpret it and recommend appropriate action for the pediatric patient. Endocrine and genetic tests in particular require the expertise of subspecialists. Consultations about test logistics, test selection, and interpretation may be available 24 hours a day through the reference laboratory’s client services department, but highly specialized laboratory medicine services may not be as readily available in other settings. Last, reimbursement also may be an issue because of insurance coverage, turnaround times, and other factors.

Clinical Impact and Opportunities Laboratory test utilization and ordering patterns have unique expressions in children. Few algorithms exist for pediatric testing, and test ordering patterns are not always evidence-based. The number and prevalence of common diseases in adults is larger than in children, so that greater priority is given to the development of algorithms and care pathways for adults. Although diseases in children differ from those in adults, the concentration of pediatric subspecialists in professional organizations, such as the Children’s Oncology Group, may lead to a high degree of consistency in diagnosis and treatment. It is difficult to change physician ordering patterns, and laboratory medical specialists must understand the impediments to change. Understanding the reasons behind the ordering patterns may facilitate the design of educational interventions that will improve test ordering patterns. Specific areas for algorithm development in pediatric laboratory testing include endocrine testing, metabolic disorders, infectious diseases, immunologic disorders, and genetic testing. Pediatric endocrine tests often require hormonal stimulation and involve intravenous line placement, medications, and sequential phlebotomies of large sample volumes. Minimum sample sizes and reference intervals are important practical considerations when obtaining these samples. Additional factors for the reference population include age, pubertal status, and health status. Genetic and metabolic disorders are another significant area, since a substantial proportion of pediatric admissions are for inherited conditions such as sickle cell anemia and cystic fibrosis. In the newborn, organic acidurias and amino acid abnormalities 688

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typically have a common set of clinical manifestations and include a broad spectrum of unique and rare deficiencies. The rarity of primary disorders leads to challenges in accurate test interpretation. Although approximately 20% of amino and organic acid test results are abnormal, most abnormal results are caused by drugs, dietary constituents, or acidoses of other causes rather than by an inherited metabolic defect (oral communication, Denis Lehotay, PhD, December 2000). Laboratories that perform testing for metabolic disorders require an adequate test volume for technical and interpretive proficiency and accuracy. Pediatric subspecialists usually want to communicate with the laboratory about the nuances of interpretation for unusual metabolic tests, such as those for genetic and mitochondrial disorders. Infectious diseases account for a significant proportion of pediatric illnesses, and an algorithmic approach when evaluating pediatric febrile illnesses and sepsis may have a significant effect on clinical management, outcome, and overall hospital costs.4-6,44 Immunologic tests require careful agematched reference intervals. Genetic testing is growing exponentially, but the necessity of diagnosing a disease at the genetic level is unclear when the effort and price are greater and the clinical usefulness is unproven; one example is the confirmation of cystic fibrosis by DNA testing for the Delta F 508 gene deletion and common exon II mutations when a sweat chloride elevation is still acceptable. Early detection of APC (adenomatous polyposis coli) mutation by nucleic acids instead of by clinical means is another example. Genome-based and pharmacogenomic tests are emerging technologies.

Conclusions and Future Considerations Although challenging, pediatric laboratory testing offers many opportunities for clinical and educational improvements and for clinically based research ❚Table 1❚. Today and in the future, information access, pathology consultation, and the industrial development of instruments requiring smaller samples will be critical to the enhanced delivery of pediatric laboratory medicine. Online communication and Web site development will facilitate the consolidation of diverse information about clinical pathology, molecular genetics, and laboratory medicine. However, concerns exist in the areas of data capture, security, confidentiality, and the use of integrated medical record systems. Many aspects of pediatric testing are not yet standardized, including reference intervals for the very young, diagnostic algorithms, reflex testing, decision levels, and use of screening vs definitive testing. Given the low volumes of both testing and clinically affected patients with rare disorders, long-term improvements © American Society for Clinical Pathology


❚Table 1❚ Challenges and Potential Solutions in Pediatric Laboratory Medicine Challenge or Issue Sample sizes for children must be small because of anemia risk Small sample sizes drive specimen collection methods in children Automated equipment and instruments are generally unable to handle small samples from pediatric patients Special bar code labels are not available for small tubes Age-specific reference intervals are essential but not widely available or current Mathematical approaches may be useful for determining some age-specific reference intervals Disease and nondisease cutoff intervals for some laboratory tests are based on adult consensus guidelines Reference testing for esoteric tests is more frequent and varied in pediatric patients than in adults Educational materials for pediatric laboratory medicine and current information are limited Advocacy for pediatric laboratory medicine needs greater visibility and strengthening Algorithms for pediatric laboratory testing are very limited Pediatric pathology training tends to emphasize anatomic pathology more than clinical pathology

likely will come from collaborative efforts among laboratories. Multi-institutional collaborations promoting access to expert clinical pathology consultations will provide opportunities for the integration of information, expertise, and even highly esoteric testing. In the future, specific multi-institutional projects can address the challenges of age-specific reference interval development, algorithm and practice guideline development, and environmental comparisons of different practices. We are optimistic that ongoing work in these areas ultimately will lead to improvements in care and health for pediatric patients. From the 1Department of Pathology, University of Utah School of Medicine, Salt Lake City; 2Department of Pathology, Children’s Mercy Hospitals and Clinics, Kansas City, MO; 3Primary Children’s Medical Center, Salt Lake City; 4ARUP Laboratories, Salt Lake City; 5Department of Pathology, Children’s Hospital, Omaha, NE; 6Department of Pathology, Children’s Medical Center, Dallas, TX; 7Department of Pathology, the Children’s Hospital and Harvard Medical School, Boston, MA; 8Department of Pathology, Children’s Hospital & Medical Center, Seattle, WA; and 9Department of Pathology, Stanford University, Palo Alto, CA. Supported by the CHILDx (Children’s Health Improvement Through Laboratory Diagnostics) at the University of Utah and ARUP Laboratories, Salt Lake City. Address reprint requests to Dr Coffin: Primary Children’s Medical Center, 100 N Medical Dr, Salt Lake City, UT 84113. Acknowledgments: Andrea Jones, ARUP Laboratories, provided editorial assistance, and Kristi Herrin and Michelle González typed the manuscript.


Potential Solution Advocate for instrumentation that can handle small tubes, small bar codes, and small specimens Similar instrumentation changes as described above Special instrument designs must be developed to handle smaller volumes and to reduce dead volumes Special bar coding systems must be developed for small specimens Propose, fund, and perform a reference interval study with samples obtained from healthy children Assess mathematical approaches, including calculation and extrapolation from large databases, for development of pediatric reference intervals Design and perform more correlative laboratory studies based on specific age and diagnostic subsets of children and adolescents Survey children’s hospitals and other hospitals with significant pediatric services about referral test practices Develop a Web site for pediatric laboratory medicine Form a multi-institutional collaborative group of pathologists and other pediatric subspecialists interested in promoting the field of pediatric laboratory medicine Perform studies comparing different laboratory tests for a particular disease or diagnosis and develop rational testing algorithms based on clinical needs and results of comparative studies Incorporate pediatric pathology into all levels of residency training and develop fellowship programs with greater emphasis on pediatric clinical pathology

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