The critical nature of the microbiology laboratory in infectious disease diagnosis calls for a close, positive working relationship between the physician and the microbiologists who provide enormous value to the health care team. This document, developed by experts in both adult and pediatric laboratory and clinical medicine, provides information on which tests are valuable and in which contexts, and on tests that add little or no value for diagnostic decisions. Sections are divided into anatomic systems, including Bloodstream Infections and Infections of the Cardiovascular System, Central Nervous System Infections, Ocular Infections, Soft Tissue Infections of the Head and Neck, Upper Respiratory Infections, Lower Respiratory Tract infections, Infections of the Gastrointestinal Tract, Intraabdominal Infections, Bone and Joint Infections, Urinary Tract Infections, Genital Infections, and Skin and Soft Tissue Infections; or into etiologic agent groups, including arboviral Infections, Viral Syndromes, and Blood and Tissue Parasite Infections. Each section contains introductory concepts, a summary of key points, and detailed tables that list suspected agents; the most reliable tests to order; the samples (and volumes) to collect in order of preference; specimen transport devices, procedures, times, and temperatures; and detailed notes on specific issues regarding the test methods, such as when tests are likely to require a specialized laboratory or have prolonged turnaround times. In addition, the pediatric needs of specimen management are also addressed. There is redundancy among the tables and sections, as many agents and assay choices overlap. The document is intended to serve as a reference to guide physicians in choosing tests that will aid them to diagnose infectious diseases in their patients.

OBJECTIVES:Blood culture contamination is a major problem in health care, with significant impacts on both patient safety and cost. Initiatives to reduce blood culture contamination require a reliable, consistent metric to track the success of interventions. The objective of our project was to establish a standardized definition of blood culture contamination suitable for use in a Veterans Health Administration (VHA) national data query, then to validate this definition and query. A secondary objective was to construct a national VHA data dashboard to display the data from this query that could be used in VHA quality improvement projects aimed at reducing blood culture contamination.METHODS:A VHA microbiology expert work group was formed to generate a standardized definition and oversee the validation studies. The standardized definition was used to generate data for calendar year 2021 using a Structured Query Language data query. Twelve VHA hospital microbiology laboratories compared the data from the query against their own locally derived contamination data and recorded those data in a data collection worksheet that all sites used. Data were collated and presented to the work group.RESULTS:More than 50,000 blood culture accessions were in the validation data set, with more than 1,200 contamination events. The overall blood culture contamination rate for the 12 facilities participating was 2.56% with local definitions and data and 2.43% with the standardized definitions and data query. The main differences noted between the 2 data sets were deemed to be issues in local definitions. The query and definition were then converted into a national data dashboard that all VHA facilities can now access.CONCLUSIONS:A standardized definition for blood culture contamination and a national data query were validated for enterprise-wide VHA use. To our knowledge, this represents the first reported standardized, validated, and automated approach for calculating and tracking blood culture contamination. This tool will be key in quality initiatives aimed at reducing contamination events in VHA.

Many clinicians are concerned that volunteers with nonalcoholic fatty liver disease (NAFLD) are included as healthy control subjects in laboratory reference interval testing and surreptitiously increase alanine aminotransferase (ALT) values. This view is supported by epidemiology studies reporting ALT elevations among patients at risk for NAFLD.1Prati D. Taioli E. Zanella A. et al.Updated definitions of healthy ranges for serum alanine aminotransferase levels.Ann Intern Med. 2002; 137: 1-10Crossref PubMed Scopus (1191) Google Scholar,2Ruhl C.E. Everhart J.E. Upper limits of normal for alanine aminotransferase activity in the United States population.Hepatology. 2012; 55: 447-454Crossref PubMed Scopus (116) Google Scholar In these studies, use of fixed ALT cutoffs that disregard the laboratory's reference intervals were suggested to more sensitively detect liver disease. These fixed ALT cutoffs were then incorporated into 4 US liver and gastrointestinal guidelines affecting clinical care and research. However, clinicians may be unaware that while fixed ALT cutoffs can be used in Europe and wherever global ALT assay standards are employed,3Schumann G. Bonora R. Ceriotti F. et al.IFCC primary reference procedures for the measurement of catalytic activity concentrations of enzymes at 37 degrees C. International Federation of Clinical Chemistry and Laboratory Medicine. Part 4. Reference procedure for the measurement of catalytic concentration of alanine aminotransferase.Clin Chem Lab Med. 2002; 40: 718-724Crossref PubMed Google Scholar these do not apply in North America where the same blood sample yields widely varying results when measured using different ALT assays.4Adeli K. Higgins V. Seccombe D. et al.National survey of adult and pediatric reference intervals in clinical laboratories across Canada: a report of the CSCC Working Group on Reference Interval Harmonization.Clin Biochem. 2017; 50: 925-935Crossref PubMed Scopus (27) Google Scholar,5Beste L.A. Icardi M. Hunt C.M. et al.Alanine aminotransferase results differ by analyzer manufacturer in a national integrated health setting, 2012-2017.Arch Pathol Lab Med. 2020; 144: 748-754Crossref PubMed Scopus (6) Google Scholar In the United States, analyzers and assays vary between laboratories and yield clinically important ALT measurement differences, especially within the normal range.5Beste L.A. Icardi M. Hunt C.M. et al.Alanine aminotransferase results differ by analyzer manufacturer in a national integrated health setting, 2012-2017.Arch Pathol Lab Med. 2020; 144: 748-754Crossref PubMed Scopus (6) Google Scholar These differences arise as ALT assays use diverse modalities (eg, colorimetric, spectrophotometric, electrochemical, and other)6Huang X.-J. Choi Y.-K. Im H.-S. et al.Aspartate aminotransferase (AST/GOT) and alanine aminotransferase (ALT/GPT) detection techniques.Sensors. 2006; 6: 756-782Crossref Scopus (316) Google Scholar and conditions (eg, pH, temperature, and use of pyridoxal 5′-phosphate) that alter enzymatic activity and ALT results.4Adeli K. Higgins V. Seccombe D. et al.National survey of adult and pediatric reference intervals in clinical laboratories across Canada: a report of the CSCC Working Group on Reference Interval Harmonization.Clin Biochem. 2017; 50: 925-935Crossref PubMed Scopus (27) Google Scholar,6Huang X.-J. Choi Y.-K. Im H.-S. et al.Aspartate aminotransferase (AST/GOT) and alanine aminotransferase (ALT/GPT) detection techniques.Sensors. 2006; 6: 756-782Crossref Scopus (316) Google Scholar Among these differences, pyridoxal 5′-phosphate (or vitamin B6) is a critical coenzyme for aminotransferase activity and may be deficient in alcoholic and malnourished patients.7Diehl A.M. Potter J. Boitnott J. et al.Relationship between pyridoxal 5′-phosphate deficiency and aminotransferase levels in alcoholic hepatitis.Gastroenterology. 1984; 86: 632-636Abstract Full Text PDF PubMed Scopus (107) Google Scholar Without its addition to ALT assays, spuriously low ALT values can be observed in some patients. The addition of pyridoxal 5′-phosphate to ALT assays enhances the consistency of ALT measurements. Pyridoxal 5′-phosphate is frequently missing in ALT assays performed in the United States, and clinicians may be unaware of whether it is used or how it may affect results in their laboratory. To increase the sensitivity of ALT to identify asymptomatic liver disease (eg, NAFLD and chronic hepatitis C), the use of a fixed "normal" ALT cutoff was promoted in an influential Italian analysis of blood donors.1Prati D. Taioli E. Zanella A. et al.Updated definitions of healthy ranges for serum alanine aminotransferase levels.Ann Intern Med. 2002; 137: 1-10Crossref PubMed Scopus (1191) Google Scholar After excluding hepatitis B and C and HIV, ALT was assessed in nearly 4000 donors at low risk for NAFLD (with normal glucose, triglycerides, and cholesterol; body mass index < 25 kg/m2; and no medication use). In this low-risk group, Prati et al1Prati D. Taioli E. Zanella A. et al.Updated definitions of healthy ranges for serum alanine aminotransferase levels.Ann Intern Med. 2002; 137: 1-10Crossref PubMed Scopus (1191) Google Scholar defined the upper limit of normal (ULN) for ALT as 30 U/L for men and 19 U/L for women within a single laboratory using a single method and without prospectively assessing these cutoffs. Use of these suggested ALT ULN is inappropriate in the United States where ALT results vary significantly by laboratory analyzer and assay method.8Medicare, Medicaid and CLIA programs; regulations implementing the Clinical Laboratory Improvement Amendments of 1988 (CLIA)—HCFA. Final rule with comment period.Fed Regist. 1992; 57: 7002-7186PubMed Google Scholar,9College of American Pathologists. Laboratory Accreditation Program.https://www.cap.org/laboratory-improvement/accreditation/laboratory-accreditation-programGoogle Scholar Because of these sources of variation, Valenti et al10Valenti L. Pelusi S. Bianco C. et al.Definition of healthy ranges for alanine aminotransferase levels: a 2021 update.Hepatol Commun. 2021; 5: 1824-1832Crossref PubMed Scopus (33) Google Scholar advised the following: "While waiting for a harmonization of laboratory techniques, clinicians should be aware of which method has been used in each patient and apply the appropriate threshold." Despite the evidence supporting the use of ALT reference intervals, fixed ALT cutoffs have been applied inappropriately in 4 US liver and gastrointestinal guidelines11Terrault N.A. Bzowej N.H. Chang K.M. et al.AASLD guidelines for treatment of chronic hepatitis B.Hepatology. 2016; 63: 261-283Crossref PubMed Scopus (1553) Google Scholar, 12Terrault N.A. Lok A.S.F. McMahon B.J. et al.Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance.Hepatology. 2018; 67: 1560-1599Crossref PubMed Scopus (2446) Google Scholar, 13Kwo P.Y. Cohen S.M. Lim J.K. ACG clinical guideline: evaluation of abnormal liver chemistries.Am J Gastroenterol. 2017; 112: 18-35Crossref PubMed Scopus (620) Google Scholar, 14Rinella M.E. Neuschwander-Tetri B.A. Siddiqui M.S. et al.AASLD practice guidance on the clinical assessment and management of nonalcoholic fatty liver disease.Hepatology. 2023; 77: 1797-1835Crossref PubMed Scopus (240) Google Scholar and in the American Association of Clinical Endocrinology clinical practice guideline for NAFLD,15Cusi K. Isaacs S. Barb D. et al.American Association of Clinical Endocrinology clinical practice guideline for the diagnosis and management of nonalcoholic fatty liver disease in primary care and endocrinology clinical settings: co-sponsored by the American Association for the Study of Liver Diseases (AASLD).Endocr Pract. 2022; 28: 528-562Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar which affects clinical care and research.16Takyar V. Nath A. Beri A. et al.How healthy are the "healthy volunteers"? Penetrance of NAFLD in the biomedical research volunteer pool.Hepatology. 2017; 66: 825-833Crossref PubMed Scopus (25) Google Scholar,17Green D.M. Wang M. Krasin M.J. et al.Serum alanine aminotransferase elevations in survivors of childhood cancer: a report from the St. Jude Lifetime Cohort Study.Hepatology. 2019; 69: 94-106Crossref PubMed Scopus (10) Google Scholar The 2016 American Association for the Study of Liver Diseases (AASLD) guidelines for treatment of chronic hepatitis B reported the following: "It is recognized that the normal ALT levels of healthy adults are 30 U/L for males and 19 U/L for females"11Terrault N.A. Bzowej N.H. Chang K.M. et al.AASLD guidelines for treatment of chronic hepatitis B.Hepatology. 2016; 63: 261-283Crossref PubMed Scopus (1553) Google Scholar and advised "Thus, using these ALT cutoffs for normal, the recommendation to consider treatment of adults with ALT values of 2 times the ULN (>60 U/L for males and >38 U/L for females…"11Terrault N.A. Bzowej N.H. Chang K.M. et al.AASLD guidelines for treatment of chronic hepatitis B.Hepatology. 2016; 63: 261-283Crossref PubMed Scopus (1553) Google Scholar The American College of Gastroenterology (ACG) clinical guideline on the evaluation of abnormal liver chemistries codified its ALT thresholds as "A true healthy normal ALT level ranges from 29 to 33 IU/l for males, 19 to 25 IU/l for females and levels above this should be assessed by physicians."13Kwo P.Y. Cohen S.M. Lim J.K. ACG clinical guideline: evaluation of abnormal liver chemistries.Am J Gastroenterol. 2017; 112: 18-35Crossref PubMed Scopus (620) Google Scholar Incorporating this ACG guideline, the AASLD 2018 hepatitis B guidance updated their 2016 guideline as follows: "The ULN for ALT in healthy adults is reported to be 29-33 U/L for males and 19-25 U/L for females. An ULN for ALT of 35 U/L for males and 25 U/L for females is recommended to guide management decisions."12Terrault N.A. Lok A.S.F. McMahon B.J. et al.Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance.Hepatology. 2018; 67: 1560-1599Crossref PubMed Scopus (2446) Google Scholar The American Association of Clinical Endocrinology NAFLD guideline endorsed both Prati et al's1Prati D. Taioli E. Zanella A. et al.Updated definitions of healthy ranges for serum alanine aminotransferase levels.Ann Intern Med. 2002; 137: 1-10Crossref PubMed Scopus (1191) Google Scholar and the ACG guideline's cutoffs13Kwo P.Y. Cohen S.M. Lim J.K. ACG clinical guideline: evaluation of abnormal liver chemistries.Am J Gastroenterol. 2017; 112: 18-35Crossref PubMed Scopus (620) Google Scholar and recommended further risk stratification in patients with ALT exceeding 30 U/L, regardless of sex.15Cusi K. Isaacs S. Barb D. et al.American Association of Clinical Endocrinology clinical practice guideline for the diagnosis and management of nonalcoholic fatty liver disease in primary care and endocrinology clinical settings: co-sponsored by the American Association for the Study of Liver Diseases (AASLD).Endocr Pract. 2022; 28: 528-562Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar Similarly, the AASLD 2023 NAFLD practice guidance cautioned that "normative values for ALT reported by most laboratories exceed what is considered a true normal" and advised "As a general rule, ALT >30 U/L should be considered abnormal."14Rinella M.E. Neuschwander-Tetri B.A. Siddiqui M.S. et al.AASLD practice guidance on the clinical assessment and management of nonalcoholic fatty liver disease.Hepatology. 2023; 77: 1797-1835Crossref PubMed Scopus (240) Google Scholar With an increasing number of guidelines recommending fixed normal ALT cutoffs (including the ACG clinical guideline on the evaluation of abnormal liver chemistries13Kwo P.Y. Cohen S.M. Lim J.K. ACG clinical guideline: evaluation of abnormal liver chemistries.Am J Gastroenterol. 2017; 112: 18-35Crossref PubMed Scopus (620) Google Scholar), multiple researchers have followed these guidelines and analyzed ALT data using fixed ALT cutoffs.16Takyar V. Nath A. Beri A. et al.How healthy are the "healthy volunteers"? Penetrance of NAFLD in the biomedical research volunteer pool.Hepatology. 2017; 66: 825-833Crossref PubMed Scopus (25) Google Scholar,17Green D.M. Wang M. Krasin M.J. et al.Serum alanine aminotransferase elevations in survivors of childhood cancer: a report from the St. Jude Lifetime Cohort Study.Hepatology. 2019; 69: 94-106Crossref PubMed Scopus (10) Google Scholar With the use of a fixed ALT cutoff and disregard of the laboratory reference interval in research studies, it is challenging to interpret, replicate, or apply research findings to diverse clinical and laboratory settings. With fixed ALT cutoffs recommended in multiple US guidelines, Panteghini et al18Panteghini M. Adeli K. Ceriotti F. et al.American liver guidelines and cutoffs for "normal" ALT: a potential for overdiagnosis.Clin Chem. 2017; 63: 1196-1198Crossref PubMed Scopus (23) Google Scholar cautioned "The mentioned guidelines recommend the use of universal cutoffs for ALT without considering any differences between laboratory assays" and "highlight the critical need for laboratory expertise when drafting clinical guidelines involving the use of laboratory tests." Without the use of laboratory reference intervals despite well-established analytical variation, they concluded "We … are concerned that the implementation of these recommendations may lead to overdiagnosis and unnecessary further testing."18Panteghini M. Adeli K. Ceriotti F. et al.American liver guidelines and cutoffs for "normal" ALT: a potential for overdiagnosis.Clin Chem. 2017; 63: 1196-1198Crossref PubMed Scopus (23) Google Scholar As highlighted by laboratory professionals, a large national US study reported statistically and clinically meaningful ALT measurement differences between analyzers, particularly within the normal range.5Beste L.A. Icardi M. Hunt C.M. et al.Alanine aminotransferase results differ by analyzer manufacturer in a national integrated health setting, 2012-2017.Arch Pathol Lab Med. 2020; 144: 748-754Crossref PubMed Scopus (6) Google Scholar This study of 22,950 samples tested in 5 analyzers reported that mean ALT varied 17 U/L between the highest- and lowest-reading analyzers with ALT < 29 U/L, with more than 1 in 3 ALT analyzers exhibiting notably higher ALT values.5Beste L.A. Icardi M. Hunt C.M. et al.Alanine aminotransferase results differ by analyzer manufacturer in a national integrated health setting, 2012-2017.Arch Pathol Lab Med. 2020; 144: 748-754Crossref PubMed Scopus (6) Google Scholar For example, the same sample within the normal ALT range divided and measured in a low- vs high-reading analyzer could yield an ALT of 28 or 45 U/L, respectively. Beste et al5Beste L.A. Icardi M. Hunt C.M. et al.Alanine aminotransferase results differ by analyzer manufacturer in a national integrated health setting, 2012-2017.Arch Pathol Lab Med. 2020; 144: 748-754Crossref PubMed Scopus (6) Google Scholar cautioned "With guidelines recommending the evaluation of unexplained ALT elevations, our findings suggest that many patients are at risk for misclassification as having 'abnormal' ALT simply as a result of analyzer characteristics." In this US study,5Beste L.A. Icardi M. Hunt C.M. et al.Alanine aminotransferase results differ by analyzer manufacturer in a national integrated health setting, 2012-2017.Arch Pathol Lab Med. 2020; 144: 748-754Crossref PubMed Scopus (6) Google Scholar defining ALT 30 U/L as normal would overdiagnose liver disease in approximately 1 in 5 patients nationwide, which can result in needless anxiety for patients and costly additional referrals or testing. With estimated costs of $448–$502 per patient to evaluate elevated liver enzymes,19Tapper E.B. Saini S.D. Sengupta N. Extensive testing or focused testing of patients with elevated liver enzymes.J Hepatol. 2017; 66: 313-319Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar substantive numbers of patients could be tested unnecessarily if clinicians apply the fixed ALT cutoffs in US guidelines (see the case presentation below). Beste et al5Beste L.A. Icardi M. Hunt C.M. et al.Alanine aminotransferase results differ by analyzer manufacturer in a national integrated health setting, 2012-2017.Arch Pathol Lab Med. 2020; 144: 748-754Crossref PubMed Scopus (6) Google Scholar "highlight the need for provider awareness of the ALT reference range when assessing ALT test results" and concluded that "Universal ALT thresholds should be avoided as a trigger for clinical action until differences between analyzers can be resolved." To address these issues, ALT reference intervals could be harmonized, as recommended by members of the American Association for Clinical Chemistry and Practice Guidelines Committee of the AASLD20Dufour D.R. Lott J.A. Nolte F.S. et al.Diagnosis and monitoring of hepatic injury. I. Performance characteristics of laboratory tests.Clin Chem. 2000; 46: 2027-2049Crossref PubMed Scopus (420) Google Scholar as well as by Canadian laboratory professionals.21Parker M.L. Adeli K. CSCC Working Group on Reference Interval HarmonizationPediatric and adult reference interval harmonization in Canada: an update.Clin Chem Lab Med. 2018; 57: 57-60Crossref PubMed Scopus (9) Google Scholar To harmonize ALT reference intervals, ALT measurements must be comparable across laboratories using agreed on standards for quality assurance and consistency. To accomplish this goal, the International Federation of Clinical Chemistry and Laboratory Medicine has made available global standards for ALT and other analytes in more than 100 countries.22The International Federation of Clinical Chemistry and Laboratory Medicine.https://www.ifcc.org/about/Google Scholar The International Federation of Clinical Chemistry and Laboratory Medicine's standard ALT method defines reaction conditions and specifies the use of coenzyme pyridoxal 5′-phosphate to yield consistent ALT values.3Schumann G. Bonora R. Ceriotti F. et al.IFCC primary reference procedures for the measurement of catalytic activity concentrations of enzymes at 37 degrees C. International Federation of Clinical Chemistry and Laboratory Medicine. Part 4. Reference procedure for the measurement of catalytic concentration of alanine aminotransferase.Clin Chem Lab Med. 2002; 40: 718-724Crossref PubMed Google Scholar For more than 20 years, the European Union has legally required laboratory result traceability to reference management systems to ensure accuracy.23Directive 98/79/EC of the European Parliament and of the Council of 27 October 1998 on in vitro diagnostic medical devices.OJEC. 1998; L331: 1-37Google Scholar In the United States, because pyridoxal 5′-phosphate is frequently not included in ALT assays, spuriously low ALT values may be observed in some patients.7Diehl A.M. Potter J. Boitnott J. et al.Relationship between pyridoxal 5′-phosphate deficiency and aminotransferase levels in alcoholic hepatitis.Gastroenterology. 1984; 86: 632-636Abstract Full Text PDF PubMed Scopus (107) Google Scholar ALT assays from the same analyzer manufacturer provide reagents with and without pyridoxal 5′-phosphate to US laboratories. In the United States, analyzer manufacturers complete clinical testing to define the assay reference interval, which is not harmonized with other ALT assays. Individual laboratories using an assay mostly use manufacturer's reference intervals; select well-resourced laboratories may perform clinical studies to refine their own reference interval. However, if US ALT measurements were harmonized to produce closely comparable values across laboratories, specific ALT values could be incorporated in evidence-based guidances for diagnosis and treatment.24American Association for Clinical Chemistry The need to harmonize clinical laboratory test results—a white paper of the American Association for Clinical Chemistry, July 2015.https://www.aacc.org/-/media/Files/Global-Health-Outreach/Harmonization_White_Paper_715.pdf?la=en&hash=7942761541E048BF6C340243A60762775C683BCEGoogle Scholar As an example, harmonizing widely varying prothrombin time coagulation tests to the international normalized ratio (INR) system improved clinical care.25Dorgalaleh A. Favaloro E.J. Bahraini M. et al.Standardization of prothrombin time/international normalized ratio (PT/INR).Int J Lab Hematol. 2021; 43: 21-28Crossref PubMed Scopus (37) Google Scholar In a 2015 white paper, American Association for Clinical Chemistry laboratory professionals supported harmonization of high-priority laboratory tests through broad collaboration with stakeholders and large funded multicenter studies; ALT was not listed as a high priority.24American Association for Clinical Chemistry The need to harmonize clinical laboratory test results—a white paper of the American Association for Clinical Chemistry, July 2015.https://www.aacc.org/-/media/Files/Global-Health-Outreach/Harmonization_White_Paper_715.pdf?la=en&hash=7942761541E048BF6C340243A60762775C683BCEGoogle Scholar With the likely delay of ALT harmonization in the United States, clinician's concerns can be addressed with a series of actions. US manufacturers can be advised on the selection of subjects for the manufacturer's ALT reference interval testing. ALT reference intervals are most valid when determined among diverse populations with limited biologic variation (eg, healthy subjects at low risk of liver disease identified by negative hepatitis B and C tests; body mass index ≤ 25 kg/m2; normal glucose, triglycerides, and cholesterol; without illicit drug or regular alcohol use).4Adeli K. Higgins V. Seccombe D. et al.National survey of adult and pediatric reference intervals in clinical laboratories across Canada: a report of the CSCC Working Group on Reference Interval Harmonization.Clin Biochem. 2017; 50: 925-935Crossref PubMed Scopus (27) Google Scholar,10Valenti L. Pelusi S. Bianco C. et al.Definition of healthy ranges for alanine aminotransferase levels: a 2021 update.Hepatol Commun. 2021; 5: 1824-1832Crossref PubMed Scopus (33) Google Scholar,20Dufour D.R. Lott J.A. Nolte F.S. et al.Diagnosis and monitoring of hepatic injury. I. Performance characteristics of laboratory tests.Clin Chem. 2000; 46: 2027-2049Crossref PubMed Scopus (420) Google Scholar,21Parker M.L. Adeli K. CSCC Working Group on Reference Interval HarmonizationPediatric and adult reference interval harmonization in Canada: an update.Clin Chem Lab Med. 2018; 57: 57-60Crossref PubMed Scopus (9) Google Scholar Regulatory agencies can require the inclusion of pyridoxal-5′-phosphate in ALT assays, whereas laboratory standardization efforts can promote its inclusion to increase ALT consistency. Until US laboratories move toward harmonized ALT methods, interim valid method-specific reference intervals can be advanced to enhance clinicians' confidence in their laboratory's reference interval. With similar concerns about reference intervals, the Canadian Society of Clinical Chemists Working Group on Reference Interval Harmonization seeks to harmonize ALT reference intervals.21Parker M.L. Adeli K. CSCC Working Group on Reference Interval HarmonizationPediatric and adult reference interval harmonization in Canada: an update.Clin Chem Lab Med. 2018; 57: 57-60Crossref PubMed Scopus (9) Google Scholar These clinical chemists intend to both align methods and develop reference intervals from large healthy populations with the collaboration of clinicians, diagnostics manufacturers, informaticians, and accreditation and quality specialists. Because ALT analyzers are similar throughout North America, Canada's harmonization of laboratory reference intervals may facilitate US efforts. Laboratory professionals collaborate increasingly with clinicians to identify healthy subjects without liver disease risk factors for ALT reference interval testing. Among 40 such screened healthy US volunteers selected for ALT reference interval testing, nearly half (45%) exhibited ALT values exceeding 30 U/L, yet all were within the manufacturer-recommended reference interval of the Siemens analyzer (Dr John G. Toffaletti, Duke University Professor in Pathology, personal communication). This study and larger datasets5Beste L.A. Icardi M. Hunt C.M. et al.Alanine aminotransferase results differ by analyzer manufacturer in a national integrated health setting, 2012-2017.Arch Pathol Lab Med. 2020; 144: 748-754Crossref PubMed Scopus (6) Google Scholar attest to the clinically significant ALT measurement differences that preclude the use of clinical guidance cutoffs based on unrepresentative assays. In summary, the broad variation in US ALT analyzer and assay measurements suggests the use of a reference interval in clinical care and research rather than a fixed ALT cutoff. Guidelines defining normal ALT as a fixed ALT cutoff, rather than the reference interval, are premature. Because NAFLD and viral hepatitis guidelines suggest evaluation of ALT elevations above a fixed cutoff, up to 1 in 5 patients can be misclassified as "abnormal" and suffer needless anxiety, costly additional testing, and unnecessary referrals or treatment. This unfortunate cascade of events can be addressed by informing clinicians and researchers of ALT analytical differences, including laboratory experts in guideline panels and research, and enhancing ALT measurement with interim US measures as the laboratory community moves toward internationally harmonized ALT methods. A primary care physician referred an asymptomatic, 42-year-old, overweight, nondrinking man with hypertension, an ALT of 42–45 U/L (14–54 U/L reference interval), an aspartate aminotransferase of 31–34 U/L (15–41 IU/L reference interval), and normal bilirubin, alkaline phosphatase, and albumin on repeated measure over 6 months. His recent testing revealed negative hepatitis B surface antigen and core antibody, hepatitis C antibody, antinuclear and anti–smooth muscle antibodies; and normal transferrin saturation, α1-antitrypsin, ceruloplasmin, and liver ultrasound. The physician told the patient he had ongoing liver injury because his liver tests were staying above the so-called true healthy normal ALT level of 33 U/L, and he would benefit from seeing a liver specialist to discuss a liver biopsy. At your clinic, the patient expressed concern about his liver injury; his uncle was told recently that he had serious liver disease. The patient has required time off work and had out-of-pocket testing costs; he expressed concern about the liver biopsy and the costs of any potential treatment. You explain to the patient that you have carefully reviewed his liver tests. You are pleased that his testing does not show liver disease (ie, as his ALT values are within the normal ALT reference interval of the laboratory), and he does not need a liver biopsy or further evaluation at this time. You explain that current medical guidelines have caused confusion about normal liver test values, which you'll clarify with his doctor. However, as a liver specialist, you are confident that he does not have liver injury and needs no further follow-up with you. Not All "Normal" Liver Enzymes Are Normal!GastroenterologyVol. 165Issue 6PreviewHunt et al1 suggest that owing to variations in alanine transaminase (ALT) measurements in the United States, reference intervals should be used in interpretation of liver enzymes, instead of fixed cutoffs. Although the laboratory reference intervals should be considered in interpretation of liver enzymes, it is worth noting that normal-range transaminases don't always rule out the presence of liver disease.2–5 Full-Text PDF

OBJECTIVES:Peripheral blood smear (PBS) interpretation represents a cornerstone of pathology practice and resident training but has remained largely static for decades. Here, we describe a novel PBS interpretation support tool.METHODS:In a mixed-methods quality improvement study, a web-based clinical decision support (CDS) tool to assist pathologists in PBS interpretation, PROSER, was deployed in an academic hospital over a 2-month period in 2022. PROSER interfaced with the hospital system's electronic health record and data warehouse to obtain and display relevant demographic, laboratory, and medication information for patients with pending PBS consults. PROSER used these data along with morphologic findings entered by the pathologist to draft a PBS interpretation using rule-based logic. We evaluated users' perceptions of PROSER with a Likert-type survey.RESULTS:PROSER displayed 46 laboratory values with corresponding reference ranges and abnormal flags, allowed for entry of 14 microscopy findings, and computed 2 calculations based on laboratory values; it composed automated PBS reports using a library of 92 prewritten phrases. Overall, PROSER was well received by residents.CONCLUSIONS:In this quality improvement study, we successfully deployed a web-based CDS tool for PBS interpretation. Future work is needed to quantitatively evaluate this intervention's effects on clinical outcomes and resident training.

Septicemia from bloodstream infections (BSI) is the second largest cause of inpatient mortality and the single most expensive condition for US hospitals to manage. There has been an explosive development of commercial diagnostic systems to accelerate the identification and antimicrobial susceptibility testing (AST) of causative pathogens. Despite adoption of advanced technologies like matrix-assisted laser desorption imaging–time-of-flight mass spectrometry and multiplex polymerase chain reaction for rapid identification, clinical impact has been variable, in part due to the persistent need for conventional AST as well as prescriber understanding of these rapidly evolving platforms. Newer technologies are expanding on rapid detection of genotypic determinants of resistance, but only recently has rapid phenotypic AST been available. Yet, improved outcomes with rapid diagnostic platforms are still most evident in conjunction with active antimicrobial stewardship. This review will outline key advancements in rapid diagnostics for BSI and the role of antimicrobial stewardship in this new era.

Patient care and public health require timely, reliable laboratory testing. However, clinical laboratory professionals rarely know whether patient specimens contain infectious agents, making ensuring biosafety while performing testing procedures challenging. The importance of biosafety in clinical laboratories was highlighted during the 2014 Ebola outbreak, where concerns about biosafety resulted in delayed diagnoses and contributed to patient deaths. This review is a collaboration between subject matter experts from large and small laboratories and the federal government to evaluate the capability of clinical laboratories to manage biosafety risks and safely test patient specimens. We discuss the complexity of clinical laboratories, including anatomic pathology, and describe how applying current biosafety guidance may be difficult as these guidelines, largely based on practices in research laboratories, do not always correspond to the unique clinical laboratory environments and their specialized equipment and processes. We retrospectively describe the biosafety gaps and opportunities for improvement in the areas of risk assessment and management; automated and manual laboratory disciplines; specimen collection, processing, and storage; test utilization; equipment and instrumentation safety; disinfection practices; personal protective equipment; waste management; laboratory personnel training and competency assessment; accreditation processes; and ethical guidance. Also addressed are the unique biosafety challenges successfully handled by a Texas community hospital clinical laboratory that performed testing for patients with Ebola without a formal biocontainment unit. The gaps in knowledge and practices identified in previous and ongoing outbreaks demonstrate the need for collaborative, comprehensive solutions to improve clinical laboratory biosafety and to better combat future emerging infectious disease outbreaks.

The need for accurate antibody testing in patients following symptomatic or asymptomatic infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is well documented. How we best utilize the data obtained from these antibody studies is still a haunting question (1). There are now over 160 serologic kits on the market for the detection of antibodies to this virus (2). Most are not Emergency Use Authorization (EUA)/FDA approved, and due to the poor performance of some of these assays, the FDA has requested more stringent data (2). In any case, a validation study is necessary prior to reporting patient results. One early issue in the validation/evaluation of antibody tests for evidence of SARS-CoV-2 infection is the possibility of cross-reacting antibodies from the plasma of patients who had been infected with one or more of the common cold coronaviruses (coronavirus 229E, HKU1, NL63, and OC43). Antibody testing for SARS-CoV-2 in these patients could result in reduced specificity of the SARS-CoV-2 antibody assays due to false-positive results from cross-reacting antibodies (3). This is a problem for numerous reasons, especially in a low-prevalence population where there could be more false positives than true positives. It also ties in with issues outlined in the Infectious Diseases Society of America (IDSA) guidelines (4) and in a commentary in Lancet (5) on how to best utilize antibody test data, especially when there could be false-positive results, including cross-reacting antibodies to the four common cold coronaviruses.

Background The global pandemic of Severe Acute Respiratory Syndrome-Related Coronavirus 2 (SARS-CoV2) has resulted in unprecedented challenges for healthcare systems. One barrier to widespread testing has been a paucity of traditional respiratory viral swab collection kits relative to the demand. Whether other sample collection kits, such as widely available MRSA nasal swabs can be used to detect SARS-CoV-2 is unknown. Methods We compared simultaneous nasal MRSA swabs (COPAN ESwabs ® 480C flocked nasal swab in 1mL of liquid Amies medium) and virals wabs (BD H192(07) flexible mini-tip flocked nasopharyngeal swabs in 3mL Universal Transport Medium) for SARS-CoV-2 PCR testing using Simplexa COVID-19 Direct assay on patients over a 4-day period. When the results were discordant, the viral swab sample was run again on the Cepheid Xpert Xpress ® SARS-CoV-2 assay. Results Of the 81 included samples, there were 19 positives and 62 negatives in viral media and 18 positives and 63 negative in the MRSA swabs. Amongst all included samples, there was concordance between the COPAN ESwabs ® 480C and the viral swabs in 78 (96.3%). Conclusion We found a high rate of concordance in test results between COPAN ESwabs ® 480C in Amies solution and BD H192(07) nasopharyngeal swabs in in 3 mL of Universal Viral Transport medium viral media. Clinicians and laboratories should feel better informed and assured using COPAN ESwabs ® 480C to help in the diagnosis of COVID-19.

The mammalian immune system deploys complex mechanisms to identify and defeat infections. Innate immunity recognizes molecular patterns associated both with entire classes of pathogens and with cell damage and distress. Adaptive immunity develops target-specific recognition and attack molecules aimed at specific and unique molecular elements of pathogens. A panoply of effector mechanisms directed by the innate and adaptive immune systems delay, damage, expel, contain, or destroy invading microbes. Unfortunately, most pathogenic microbes multiply hundreds of times as rapidly as we; so for every complex and elegant mechanism of immunity, microbes have found ways to subvert or evade. This chapter provides an outline of the components of mammalian immunity and, using five model organisms, explore a few of the astonishing array of mechanisms pathogenic microbes use to maintain themselves and proliferate inside the human body. Additionally, we attempt to describe the regulatory subtlety and discretion of both the immune system and the pathogen; the former to avoid overreaction and self-damage, the latter to utilize the resources of the host for efficient maintenance and transmission. Human infections are the outcome of these intricate, edged molecular conversations between host and pathogen.

Background and Objectives Opioid overdose‐related deaths increased from approximately 18 000 deaths in 2007 to 46 802 deaths in 2018. Fentanyl is primarily responsible for the increase in opioid overdose deaths from 2011 through 2017. The primary aim of this study is to determine the rates of fentanyl in the urine drug screens of all patients who presented to the psychiatric emergency room at VA Connecticut, over 7 months in 2018. Methods Data were collected for all patient presentations between June 2018 and December 2018. There were 746 total patient presentations, with 497 being unique. Collected data included basic demographic information, psychiatric diagnosis, and urine drug screen for various illicit substances, including fentanyl. Results Over 15% of patients screened positive for fentanyl. Patients who tested positive for fentanyl were further classified based on positive urine drug screening results for other opioids, cocaine, or both. Twenty percent of patients who screened positive for fentanyl and cocaine tested negative for other opioids. This category suggests that some veterans might be consuming fentanyl with cocaine. Discussion and Conclusions Fentanyl was found at a high rate, even in the absence of other opioids, which suggests that some veterans might be consuming fentanyl with cocaine. Consequently, harm reduction strategies should be broadened to include all patients at risk of fentanyl overdose, including patients who use substances (eg, cocaine) that are potentially adulterated with fentanyl. Scientific Significance This study is the first one of its kind that looked at rates of fentanyl use in all presentations to a psychiatric emergency room. While it is well‐known that fentanyl is highly prevalent, these findings extend the current state of knowledge by replication in a psychiatric emergency population. (Am J Addict 2021;30:92–95)

The SARS-CoV-2 virus has emerged and rapidly evolved into a current global pandemic. Although bacterial and fungal coinfections have been associated with COVID-19, little is known about parasitic infection. We report a case of a COVID-19 patient who developed disseminated strongyloidiasis following treatment with high-dose corticosteroids and tocilizumab. Screening for Strongyloides infection should be pursued in individuals with COVID-19 who originate from endemic regions before initiating immunosuppressive therapy.

On 24 August 2020, the Centers for Disease Control and Prevention (CDC) updated its website to highlight that asymptomatic individuals, even those with exposure to a COVID-19-positive contact, do not necessarily need to be tested unless they have medical conditions associated with increased risk of severe illness from COVID-19. The CDC subsequently updated its guidance on 19 September 2020 to support testing of asymptomatic persons, including close contacts of persons with documented SARS-CoV-2 infection. In this editorial, the American Society for Microbiology Clinical and Public Health Microbiology Committee's Subcommittee on Laboratory Practices comments on testing of asymptomatic individuals relative to current medical knowledge of the virus and mitigation measures. Specific points are provided concerning such testing when undertaking contact tracing and routine surveillance. Limitations to consider when testing asymptomatic persons are covered, including the need to prioritize testing of contacts of positive COVID-19 cases. We urge the CDC to consult with primary stakeholders of COVID-19 testing when making such impactful changes in testing guidance.

We present a case of a 20-year-old male who had ambiguous HIV test results after entering new provider care and whose status was later complicated by undetectable viral RNA off antiretroviral therapy (ART). Verifying HIV infection status may occasionally require sensitive DNA testing that might need to be considered in diagnostic guidelines to resolve diagnosis and ensure appropriate ART management.

Background: Stethoscope hygiene is rarely done despite guideline recommendations. We wanted to determine whether demonstrating what is growing on the stethoscopes of providers via culture or bioluminescence technology alters perceptions and improves compliance. Methods: Providers were given the opportunity to (1) culture their stethoscopes before and after disinfection with alcohol pads, alcohol-based hand rub, or hydrogen peroxide disinfectant wipes and (2) swab stethoscopes for bioluminescence-based adenosine triphosphate testing before and after disinfection. Outcomes were observed for hand and stethoscope hygiene rates and before and after intervention survey responses. The bacteria that were isolated, colony-forming units (CFU), and bioluminescence scores were tracked. Results: A total of 1,245 observed hand hygiene opportunities showed that compliance improved from 72.5%-82.3% (P < .001). In addition, 590 observed patient-provider encounters revealed no significant change in stethoscope hygiene rates of 10% initially and 5% afterward (P = .08), although self-reported rates trended from 56%-67% postintervention (P = .06). Perceptions regarding stethoscope hygiene importance improved (8.5/10 to 9.3/10; P = .04). Disinfection with alcohol pads, alcohol-based hand rub, and hydrogen peroxide disinfectant wipes were equivalent in CFU reduction (P = .21). Conclusions: Showing providers what is growing on their stethoscopes via cultures and bioluminescence technology before and after disinfection improved "buy in" regarding stethoscope hygiene importance. Both methods were rated as having an equal impact, however, objective observations failed to show improvement. (C) 2019 Published by Elsevier Inc. on behalf of Association for Professionals in Infection Control and Epidemiology, Inc.

Interest continues to grow regarding the role of serologic assays for the detection of prior infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The U.S. Food and Drug Administration (FDA) has granted emergency use authorization (EUA) status to many SARS-CoV-2 serologic assays. In this document, expert recommendations from clinical microbiologist members of the American Society for Microbiology (ASM) concerning detailed verification strategies for SARS-CoV-2 serologic assays with FDA EUA are provided, as are insights into assay limitations and reporting considerations for laboratories. Assessments concerning single-antibody and multiantibody isotype detection assays, which may provide either differentiated or nondifferentiated (i.e., total antibody) antibody class results, are addressed. Additional considerations prior to assay implementation are also discussed, including biosafety, quality control, and proficiency testing strategies. As the landscape of SARS-CoV-2 serologic testing is rapidly changing, this document provides updated guidance for laboratorians on application of these assays.

We discuss the current practice of point-of-care diagnostics in infectious diseases as methods transition from antigen-based to molecular, and beyond simple molecular to the next generations of point-of-care testing methods. We evaluate the role of point-of-care at different sites of care and describe and evaluate trends likely to be driven by advances in molecular methodology, emerging biomarkers, and informatics. We describe strengths, weaknesses, opportunities, and threats to the development of point-of-care diagnostics in the near (1-10 years) and more distant (10-20 years) future.