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46 BASIC SKILLS IN INTERPRETING LABORATORY DATA
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MINICASE 1
How can a vitamin cause any problems?
Annie J., a 30- year- old female patient, developed multiple sclerosis
and began taking a biotin nutritional supplement in a dose of
300mg by mouth daily. The patient has heard that biotin can slow
disease progression. Two months later, during an annual physical
examination, a full set of clinical laboratory tests was obtained
that showed significantly elevated serum free thyroxine (FT
elevated free triiodothyronine (FT
hormone (TSH). Upon reviewing these laboratory test results, the
physician scheduled the patient for a follow- up clinic visit. A physical
examination showed a normal size thyroid gland with no nodules
on palpation, a normal heart rate, no tachycardia, and normal
blood pressure. The patient did not have exophthalmos. In review
of systems, the patient had no reports of weight loss, palpitations,
hyperactivity, nervousness, or mood swings. A medication history
showed that the only new medication started prior to the blood
drawing was biotin. Because the efficacy of biotin for multiple
sclerosis has not been proven, the physician asked the patient to
discontinue biotin and to have thyroid function tests repeated in
1week.
), and low thyroid stimulating
3
),
4
is a direct extension of the drug’s testosterone- lowering eect.
Such a patient may seek medical treatment of sexual dysfunction, and he may be inappropriately prescribed depot testosterone injections. us, in this case, depot testosterone injections
will cause a change in serum testosterone levels in the wrong
direction. If serum testosterone levels increase, this should be
a signal that the patient has serial test results, which are inconsistent with expected results of leuprolide, and an investigation
should be done as to the cause (Minicase 1).
22
MANAGING DRUG INTERFERENCES
When a drug is suspected to interfere with a laboratory test,
the clinician should collect appropriate evidence to conrm the
interaction by taking the following steps:
1. Establishing a temporal relationship between the change in
the laboratory test and drug use and ensuring that the change
in the laboratory test occurred aer the drug was started or
aer the drug dose was changed
2.
Ruling out other drugs as causes of the laboratory test change
3.
Ruling out concurrent diseases as causes of the laboratory
test change
4. If possible, discontinuing the causative agent and repeating
the test to see if dechallenge results in a correction of the
abnormal laboratory test
5.
Choosing another laboratory test that will provide assessment
of the same organ’s function, but is unlikely to be aected by
the drug (the clinician can compare the new results against
the original laboratory test result, and check for dissimilarity
or similarity of results)
QUESTION: Assume that biotin caused a drug- laboratory test
interference. Was the interference an in vitro or an in vivo
interference? What is the mechanism by which biotin most likely
caused the interference?
DISCUSSION: Biotin causes an in vitro drug- laboratory test
interaction with thyroid function tests. FT
are commonly performed by radioimmunoassay, which employs a
streptavidin- biotin complex. Exogenous biotin in the patient’s blood
sample, which resulted from oral administration of biotin, interfered
with the streptavidin- biotin complex’s binding with thyroid hormones
and led to false assay measurements.
Although the patient’s FT4 and FT3 suggest that patient has
hyperthyroidism, the patient has no symptoms consistent with
the disease. Moreover, the onset of the abnormal laboratory
tests appears to be temporally related to the start of biotin, and
normalization of thyroid function tests should occur after biotin is
discontinued. These all suggest that the patient has a biotin- induced
laboratory test interference.
6.
Finding evidence in the medical literature that documents
, FT3, and TSH testing
4
3,7-9
the suspected drug–laboratory test interference
7.
Contacting the head of diagnostic labs who maintains or
has access to computerized lists of drugs that interfere with
laboratory tests (the person would also provide assistance in
interpreting aberrant laboratory test results)
13
For any particular patient case, it is oen not possible
to obtain information on all seven of the previously listed
items. e rst four items are crucial in any suspected drug–
laboratory test interference. With the availability of highly
accessible, electronic databases— which can scour the literature quickly for drug–laboratory test interactions— and more
electronic cross- talk between databases for clinical laboratory
tests and those for medications, clinicians can easily nd published information about drug interferences with laboratory
tests; consult with a clinical laboratory specialist, if necessary,
and then take the appropriate steps in managing the patient
( Minicase 2).
23,24
LITERATURE RESOURCES
A systematic search of the medical literature is essential for
providing the appropriate evidence to confirm the drug–
laboratory test interaction. This search will ensure that a
complete and comprehensive review— necessary in making
an accurate assessment— has been done. When searching the
literature, it is recommended to use the method originally
described by Watanabe et al and, subsequently, modied by C.
F. Kirkwood.
tertiary, secondary, and then primary literature. Although there
25,26
Using this technique, the clinician would search
CHAPTER 3 • PRimER on DRug inTERfEREnCEs wiTH TEsT REsulTs 47
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MINICASE 2
Trimethoprim–Sulfamethoxazole-Induced Hypoprothrombinemia
Sally S., a 65- year- old female patient, is started on trimethoprim–
sulfamethoxazole 800/160 mg by mouth twice daily for an upper
urinary tract infection due to
will continue for 14 days. She has atrial fibrillation and is also
taking digoxin 0.125 mg by mouth daily and warfarin 2.5 mg by
mouth daily. She has been on warfarin for years and says that she
is fully aware of all the DOs and DON’Ts of taking warfarin. Her
International Normalized Ratio (INR) regularly and consistently is 2.5,
which is therapeutic. She has no history of liver disease and appears
healthy and well nourished. Prior to the start of the trimethoprimsulfamethoxazole, her serum sodium was 137 mEq/L, potassium
4 mEq/L, BUN 10 mg/dL, creatinine 1 mg/dL, and INR 2.5. After
3days of trimethoprim-sulfamethoxazole, a repeat INR is 5.2, and
she reports persistent nose bleeding, which stops for a few hours
but then restarts again.
QUESTION: What do you think is causing the laboratory abnormality?
How should this patient’s condition be managed?
DISCUSSION: Trimethoprim–sulfamethoxazole inhibits cytochrome
2C9, the principal hepatic enzyme that catabolizes warfarin,
Escherichia coli
. Antibiotic treatment
are slight variations in the types of publications included in each
category, a brief description of each literature category follows.
Tertiary literature includes reference texts, monograph databases, and review articles which provide appropriate foundational
content and background material essential for understanding
basic concepts and historical data relevant to the topic. Second-
ary literature is a gateway to primary literature, and it includes
indexing and abstracting services (eg, PubMed). Primary litera-
ture includes case reports, experimental studies, and other nonreview types of articles in journals about the topic. ese represent
the most current literature on the topic. By systematically scanning the literature in this order, the clinician can be sure to have
identied and analyzed all relevant literature, which is crucial in
developing appropriate conclusions for these types of situations.
Tertiary Literature
Tertiary literature, which contains useful information about
drug–laboratory test interferences, includes the Physicians’
Desk Reference. Each complete package insert included in
this book contains a precautions section that includes information on drug–laboratory test interferences. However, it
is important to note that the Physicians’ Desk Reference does
not include package inserts on all commercially available
drugs, nor does it include complete package inserts for all of
the products included in the text. Also, manufacturers oen
do not update package insets with ndings from current literature.27 us, additional resources will need to be checked
(eg, DailyMed by the National Institutes of Health [http://
dailymed.nlm.nih.gov/dailymed/]). DailyMed includes more
than 95,000 package inserts. Also, the drug monographs in the
AHFS Drug Information, published by the American Society
decreases vitamin K–producing bacteria in the gastrointestinal
tract, and displaces warfarin from its plasma protein- binding sites.
A search of the medical literature documents multiple cases of
enhanced warfarin effect when trimethoprim–sulfamethoxazole is
taken concurrently.
In this patient, the drug interaction occurred after trimethoprim–
sulfamethoxazole was started. She is not taking any other
medications that could cause the drug–laboratory test interaction
and has no history of vitamin K deficiency or liver disease,
which could be causing hypoprothrombinemia. To confirm that
trimethoprim–sulfamethoxazole is causing the drug interaction,
the physician could discontinue the drug and then see if her INR
returns to the range of 2 to 3. However, because the trimethoprim–
sulfamethoxazole–warfarin interaction is well known, a better
approach might be to continue antibiotic treatment, hold warfarin
until the INR has decreased to 2.5, and then resume warfarin at a
reduced daily dose while the patient is taking antibiotic.
29,30
of Health-System Pharmacists, include a section on laboratory test interferences. Although the information provided is
brief, it can be used as an initial screen. is resource is available electronically by subscription from the American Society
of Health-System Pharmacists (www.ahfsdruginformation
.com) or from other online databases including First Databank
(www.fdbhealth.com) or Lexicomp (www.wolterskluwer.com
/en/solutions/lexicomp).
A variety of other books about clinical laboratory tests are
provided (List 1). Some are comprehensive references while others are handbooks. All of them provide information about drug–
laboratory test interferences. However, the reference texts are
more complete than the handbooks. In addition, several comprehensive review articles include current information about
drug–laboratory test interferences.
Micromedex Solutions, DynaMed Plus, Drugs.com, Facts and
Comparisons, and Lexicomp, are all online searchable databases
(List 2). For every drug included in the system, information
is available in a drug monograph format, and any information about drug–laboratory test interferences is included in the
monograph. Although not always listed separately as a laboratory test interference, the information may be included in the
adverse reaction, warning, or monitoring section of the monograph. In addition, for some drugs, drug information questions
and answers are included. To access relevant information, the clinician can search information using the name of the drug or the
laboratory test. Oen, the drug–laboratory test interference is
assigned a severity rating (eg, major or minor interference) as an
indication of its clinical signicance, and references to primary
literature are available so that the reader can learn more. ese
online databases vary in content completeness and ease of use.28
48 BASIC SKILLS IN INTERPRETING LABORATORY DATA
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LIST 1. Tertiary Resources
Books and Handbooks
Rifai N, Horvath AR, Wittwer CT. Tietz Fundamentals of
Clinical Chemistry and Molecular Diagnostics. 8th ed.
St.Louis, MO: Elsevier; 2019.
DasGupta A, Hammett-Stabler CA, eds. Herbal Supplements:
Ecacy, Toxicity, Interactions with Western Drugs and Eects
on Lab Tests. Hoboken, NJ: Wiley; 2011.
Laposata M, ed. Laboratory Medicine: e Diagnosis of Disease
in the Clinical Laboratory. New York, NY: McGraw Hill
Medical; 2018.
McPherson RA, Pincus MR, eds. Henry’s Clinical Diagnosis
and Management by Laboratory Methods. 23rd ed.
Philadelphia, PA: Elsevier WB Saunders; 2017.
Rao LV, Snyder LM. Wallach’s Interpretation of Diagnostic
Tests: Pathways to Arriving at a Clinical Diagnosis. 11th ed.
Philadelphia, PA: Wolters Kluwer; 2021.
Young DS. Eects of Preanalytic Variables on Clinical
Laboratory Tests. 3rd ed. Washington, DC: American
Association for Clinical Chemistry; 2007.
Young DS. Eects of Drugs on Clinical Laboratory Tests.
5th ed. Washington, DC: American Association for Clinical
Chemistry; 2000.
Review Articles
• DasGupta A, Bernard DW. Herbal remedies: eects on
clinical laboratory tests. Arch Pathol Lab Med. 2006;
130(4):521-528.
is review summarizes literature from 1980 to 2005 on
herbal drug interactions with laboratory tests. Mechanisms
include (1) herbal agent- induced in vivo toxic eects,
(2) direct assay interference by the herbal agent, or
(3) contaminant in the herbal agent produces in vivo or in
vitro eects that produce changes in laboratory test results.
e eect of Chan su on digoxin blood levels and St. John’s
wort on blood levels of cyclosporine, digoxin, theophylline,
and protease inhibitors are just some of the herbal agent–
laboratory test interactions discussed. is is a follow- up to
the author’s rst article on the topic, which was published in
the American Journal of Clinical Pathology in 2003. As of
2021, this review has not been updated.
• Kroll MH, Elin RJ. Interference with clinical laboratory
analyses. Clin Chem 1994; 40(11 Pt 1):1996-2005.
is is an excellent overview of drug–laboratory test inter-
actions. e article describes how drugs, metabolites, and
additives (eg, heparin and ethylenediamine tetra- acetic
acid) can produce signicant interactions and discrepancies
during in vitro analytic procedures. It also provides a summary of useful references (although outdated) on the topic.
In addition, a suggested approach to drug–laboratory test
interactions is described.
• Lopez A, Fraissinet F, Lefebvre H, etal. Pharmacological
and analytical interference in hormone assays for diagnosis
of adrenal incidentaloma. Ann Endocrinol 2019;
80(4):250-258.
is is an excellent overview of patient- related factors, medications, and analytical factors that can interfere with laboratory tests for metanephrines, aldosterone, renin, cortisol,
or corticosteroid binding globulin.
• Montanelli L, Benvenga S, Hegedus L, etal. Drugs and other
substances interfering with thyroid function. In: Vitti P,
Hegedus L, eds. yroid Diseases. Chaim, Switzerland:
Springer International Publishing; 2018:733-761.
10.1007/978-3-319-45013-1_27.
is review discusses drugs that interfere with regulation of
the hypothalamic- pituitary- thyroid axis and drugs that
interfere with thyroid function. For each medication class
included, the mechanism of the drug- laboratory test interaction is provided and, when available, the frequency of the
interaction in treated patients, whether the interaction
appears to be dose related, and the timeline for the
interaction.
• Sher PP. Drug interferences with clinical laboratory tests.
Drugs 1982; 24(1):24-63.
is useful reference provides many tables of drugs known
to interfere with various laboratory tests. e data are
arranged by laboratory test. For many common laboratory
tests, summary tables of drugs known to interfere with the
particular laboratory tests are provided. Also, mechanisms
for the in vivo and in vitro interactions are described.
Although this reference is dated and is not useful for newer
drugs, it is an excellent resource for older drugs.
• Sonntag O, Scholer A. Drug interference in clinical chemis-
try: recommendation of drugs and their concentrations to
be used in drug interference studies. Ann Clin Biochem.
2001;38(Pt 4):376-385.
In 1995, 18 clinical laboratory test experts identied
24commonly used drugs known to interfere with laboratory tests. Usual therapeutic and toxic drug concentrations
were identied. Both concentrations of each drug were
added in vitro to blood and urine specimens and then various laboratory tests were run on the specimens. Laboratory
testing was duplicated in three dierent laboratories. is
review article summarizes drug–laboratory test interactions
for more than 70 dierent laboratory tests.
• Yao H, Rayburn ER, Shi Q, etal. FDA- approved drugs that
interfere with laboratory tests: a systematic search of U.S.
drug labels. Crit Rev Clin Lab Sci 2017;54(1):1-17.
is includes two extensive listings of medications that
aect urine and blood- based assays along with the authors’
review of the package labeling of more than 65,000 single
ingredient medications. It is a useful reference.
CHAPTER 3 • PRimER on DRug inTERfEREnCEs wiTH TEsT REsulTs 49
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LIST 2. Databases and Websites to Access Databases*
American Hospital Formulary Service Drug Information www.ahfsdruginformation.com
DailyMed https://dailymed/nlm.nih.gov/
DynaMed Plus www.dynamed.com
Facts and Comparisons www.factsandcomparisons.com
Lexicomp www.wolterskluwer.com/en/solutions/lexicomp
Micromedex Solutions http://www.micromedex.com
Prescribers’ Digital Reference http://www.pdr.net
*A subscription may be required to access the resource.
List 1 includes websites of commonly used databases for drug
laboratory test interactions. In addition, some local clinical laboratory websites (eg, http://www.mayocliniclabs.com
/test- info) may be convenient to access and use.
25
Secondary and Primary Literature
For secondary literature, the main indexing or abstracting
service that should be used is PubMed. is allows the clinician to check the literature from thousands of biomedical
journals from 1946 to the present. Due to improvements in
search capabilities, clinicians can search using text words (ie,
words as they might appear in the title or abstract of a journal
article). e database will automatically convert that text word
to ocial medical subject headings or accepted indexing terms.
As a result, search output is optimized despite the lack of prociency or experience of the searcher. In addition, the database
provides links enabling clinicians to locate related articles or
order articles online, which enhance search capabilities and
convenience in obtaining relevant primary literature articles.
is chapter does not allow a complete tutorial on developing search strategies, conducting PubMed searches, and evaluating primary literature. However, the reader is encouraged to
develop expertise in this area so that he or she can identify current, relevant literature eciently. A wide variety of tutorials and
webcasts are available free of charge (https://www.ncbi.nlm.nih
.gov/pubmed/).
SUMMARY
Although the number of drug–laboratory test interferences
increases as the number of commercially available drugs
increases, improved literature resources that compile information on this topic and improved assay methodologies
have helped clinicians in dealing with suspected cases of this
problem. Most drug–laboratory test interferences are due to in
vivo eects of drugs; that is, the drug’s pharmacological or toxic
eects produce specic alterations in laboratory values. A drug–
laboratory test interference should be suspected whenever a
laboratory test result does not match the signs and symptoms in
a patient, when the results of dierent tests that assess the same
organ function or drug eect conict with each other, or when
serial laboratory test values vary greatly over a short period of
time or are inconsistent with expected results.
To determine if a drug is interfering with a drug–laboratory
test, the clinician should, at a minimum, establish a temporal
relationship between the change in the laboratory test and drug
use; rule out other drugs and diseases as the cause; and discontinue the drug and repeat the laboratory test to see if dechallenge
corrects the abnormal laboratory test. e literature should be
checked to see if documentation of the drug–laboratory test
interference can be found. e literature search should be systematic to ensure retrieval of the most comprehensive and current information. erefore, the clinician should proceed from
the tertiary to the secondary and then to the primary literature
and use a variety of resources to arrive at a conclusion.
LEARNING POINTS
1.
What are the differences between an in vivo and an in vitro
drug interference with a laboratory test?
ANSWER: An in vivo interaction is characterized by an actual
change in measured analyte concentration or activity prior to
specimen collection and analysis. That is, the change in the measured analyte occurred in the patient and the laboratory test
abnormality is true. An in vitro interaction is characterized by a
drug’s physical presence in a body uid or tissue specimen, which
interferes with clinical laboratory testing during the analytical
process. The interference occurs outside the patient’s body and
after the specimen is collected from the patient.
2.
What type of laboratory test is prone to in vitro drug
interferences? If a drug laboratory tes t interaction is suspected, what options are available?
ANSWER: Radioimmunoassays are prone to in vitro drug interfer-
ences when cross reactions occur between the measured analyte
and other substances in the specimen, wh ich could include a drug’s
metabolites, other chemically similar drugs, or heterophilic antibodies. If a drug- laboratory test interference is suspected, the clinician
can explore the option of performing the laboratory tes t using a dif
ferent assay method (eg, high performance liquid chromatography).
-
50 BASIC SKILLS IN INTERPRETING LABORATORY DATA
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3.
What key information should a clinician collect to con-
rm that a drug is causing a laboratory test interaction?
ANSWER: The four key criteria in conrming the presence of a
drug–laboratory test interaction include the following:
Ensuring that the change in the laboratory test occurred after
the drug was started
Ruling out other drugs as causes of the laboratory test change
Ruling out concurrent medical illness(es) as causes of the labo-
ratory test change
Stopping the drug and seeing if the laboratory test result returns
to the predrug value
4.
What type of literature resource should a clinician access
first to review foundational information on a drug’s
adverse reaction prole and the likelihood that it could
be causing an in vivo laboratory tes t abnormality?
ANSWER: Tertiary literature, which includes reference texts,
review articles, and searchable databases, will provide good
background information on medications. This information is
helpful in understanding the primary literature on the topic.
REFERENCES
1. Sher PP. Drug interferences with clinical laboratory tests. Drugs.
1982;24(1):24-63.PubMed
2. Funder JW, Carey RM, Mantero F, et al. e management of primary
aldosteronism: case detection, diagnosis, and treatment: An Endocrine
Society clinical practice guidelines. J Clin Endocrinol Metab.
2016;101(5):1889-1916.PubMed
3. Odhaib SA, Mansour AA, Haddad NS. How biotin induces misleading
results in thyroid bioassays: case series. Cureus. 2019;11(5):e4727.
PubMed
4. Tsoi V, Bhayana V, Bombassaro AM, et al. Falsely elevated vancomycin
concentrations in a patient not receiving vancomycin. Pharmacotherapy.
2019;39(7):778-782.PubMed
5. Yao H, Rayburn ER, Shi Q, et al. FDA- approved drugs that interfere with
laboratory tests: a systematic search of US drug labels. Crit Rev Clin Lab
Sci. 2017;54(1):1-17.PubMed
6. Steimer W, Müller C, Eber B. Digoxin assays: frequent, substantial, and
potentially dangerous interference by spironolactone, canrenone, and
other steroids. Clin Chem. 2002;48(3):507-516.PubMed
7. Giord JL, de Koning L, Sadrzadeh SMH. Strategies for mitigating risk
posed by biotin interference on clinical immunoassays. Clin Biochem.
2019;65:61-63.PubMed
8. Avery G. Biotin interference in immunoassay: a review for the laboratory
scientist. Ann Clin Biochem. 2019;56(4):424-430.PubMed
9. Bowen R, Benavides R, Colón-Franco JM, et al. Best practices in
mitigating the risk of biotin interference with laboratory testing. Clin
Biochem. 2019;74:1-11.PubMed
10. Smith SE, Rumbaugh KA. False prolongation of International
Normalized Ratio associated with daptomycin. Am J Health Syst Pharm.
2018;75(5):269-274.PubMed
11. Saito M, Hatakeyama S, Hashimoto H, et al. Dose- dependent articial
prolongation of prothrombin time by interaction between daptomycin
and test reagents in patients receiving warfarin: a prospective in vivo
clinical study. Ann Clin Microbiol Antimicrob. 2017;16(1):27.PubMed
12. Steimer W. Performance and specicity of monoclonal immunoassays
for cyclosporine monitoring: how specic is specic? Clin Chem.
1999;45(3):371-381.PubMed
13. Dimeski G. Interference testing. Clin Biochem Rev. 2008;29(suppl 1):
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routine clinical chemistry testing. Clin Chem Lab Med. 2006;44(3):
311-316.PubMed
15. Punja M, Neill SG, Wong S. Caution with interpreting laboratory results
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clinical laboratory tests. Clin Chem. 1972;18(10):1041-1303.PubMed
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August 12, 2020.
20. Grötsch H, Hajdu P. Interference by the new antibiotic cefpirome and
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4
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Point- of-Care Testing
Lisa M. Cillessen, Heather Lyons-Burney,
and Paul O. Gubbins
OBJECTIVES
After completing this chapter, the
reader should be able to
•
Identify resources for Clinical
Laboratory Improvement
Amendments–waived point- of- care
testing options
•
Interpret the performance
characteristics of common point of- care tests
•
Describe clinical opportunities
for point- of- care testing in an
outpatient pharmacy setting for both
population- and patient-
applications
•
Identify potential resources for
maintaining good laboratory
practices
•
Discuss the limitations for
Clinical Laboratory Improvement
Amendments–waived pointtesting
specic
of- care
e pharmacist’s role in the healthcare system is continually evolving. Over time,
the pharmacist’s role has shied from being product focused to delivering patientoriented pharmaceutical care. Today, pharmacists are on the frontline of providing
patient- centered care and wellness, and their role in delivering care as a member of
the healthcare team is essential. Pharmacists are highly trained, accessible healthcare
professionals who are second only to registered nurses in terms of the number of
practicing professionals. ey are also underutilized in the U.S. healthcare delivery
system.1 However, when working in collaboration with physicians and other healthcare professionals, pharmacists’ roles and their ability can be expanded to deliver
quality patient- centered care and improve public health.
Working in collaboration with other providers and public health ocials, pharmacists can leverage their knowledge and accessibility to oer point- of- care testing (POCT) services that are waived under the Clinical Laboratory Improvement
Amendments of 1988 (CLIA-88) (CLIA- waived POCT).2 Such services are oered
to manage chronic diseases, improve access to healthcare services, rapidly initiate
appropriate therapy, and screen for diseases of public health signicance.2 Chapter1
denes POCT, dierentiates it from home testing, and provides an overview of the
advantages and disadvantages of these testing paradigms. e objective of this chapter
is to describe and illustrate opportunities to perform CLIA- waived POCT in outpatient pharmacy settings. is chapter focuses on POC tests and POCT by expanding
on the overview of common CLIA- waived POC tests provided in Chapter1; in addition, this chapter discusses available tests, reviews their performance measures and
practical limitations, discusses their use in current practice, and identies potential
future applications for their use in practice.
1
FEDERAL AGENCIES INVOLVED WITH CLINICAL
LABORATORY IMPROVEMENT AMENDMENTS–
WAIVED POINT- OF-CARE TESTS AND TESTING
DOI 10.37573/9781585286423.004
e U.S. Food and Drug Administration (FDA) and the Centers for Medicare and
Medicaid Services (CMS) are the federal agencies charged with oversight of CLIA.
e Centers for Disease Control and Prevention (CDC) supports the CLIA program
by serving as a resource for analytical, research, and technical information on CLIA
and POCT.
e FDA regulates test manufacturers and classies their tests by a premarket
authorization process. During this authorization process, the FDA uses criteria in
the CLIA regulations to classify tests according to their level of complexity (high,
moderate, or waived) and potential for risk to public health. Waived tests are lowcomplexity methods that are simple to use, and their risk of producing erroneous
results is negligible or poses no reasonable risk of harm to the patient if performed
incorrectly.3 In public health emergencies, like the COVID-19 pandemic, the FDA
commissioner can authorize the use of medical products, including diagnostic tests,
before they undergo the normal review and classication process using an Emergency Use Authorization (EUA).4 Since an EUA allows use of a diagnostic test before
it has been classied according to its complexity, the authorization must specify the
51
52 BASIC SKILLS IN INTERPRETING LABORATORY DATA
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test can be performed in a patient care setting (ie, at the POC),
or else it must be performed in a laboratory capable of carrying
out moderate to high complexity tests.
4
CMS regulates facilities that conduct laboratory testing,
including all POC tests, on human specimens for health assessment, diagnosis, prevention, or treatment of disease. Waived
Washington from CLIA so some of the processes and regulations to perform CLIA- waived tests are dierent. More information on how to apply for a CLIA Certicate of Waiver can be
found at the CMS website (https://www.cms.gov/Regulations
- and-Guidance/Legislation/CLIA/How_to_Apply_for_a
_CLIA_Certicate_International_Laboratories.html).
laboratories, such as community pharmacies or ambulatory care
clinics, can only perform waived tests and are not subject to regular inspections, personnel requirements, or prociency testing.
To perform such tests, these sites must obtain a CLIA Certicate
of Waiver from CMS, pay applicable fees biannually, and follow the manufacturers’ testing instructions. In most states, the
process is similar; however, CMS has exempted New York and
Resources
e market for CLIA- waived POC tests continually and rapidly
grows and changes. erefore, a pharmacist who has a CLIA
waiver must be aware of the most current information on the
available tests. e FDA, CMS, and CDC websites provide useful
and current information on CLIA- waived tests (Table4-1).
TABLE 4-1. Resources for CLIA-Waived POCT
AGENCY RESOURCE SITE COMMENTS
FDA Searchable list of
analytes used in
waived laboratory
test systems
http://www.accessdata.fda.gov
/scripts/cdrh/cfdocs/cfClia
/analyteswaived.cfm
• Select an analyte to display a list
of waived test systems for it, with
hyperlinks to regulatory information and
documentation
• Updated frequently
• Contains more regulatory information
than clinicians need
5,6
Website with
information on
EUAs issued for
emergencies
(eg, COVID-19,
H1N1)
https://www.fda.gov/medical- devices
/emergency- situations- medical
- devices/emergency- use- authorizations
• Information on EUAs for diagnostic,
nondiagnostic, and therapeutic medical
devices
• Information on diagnostics tests for a
given disease includes date EUA was
issued, manufacturer, hyperlink to
authorizing letter, technology, authorized
setting, hyperlinks to authorizing
documents
CMS A listing of tests
that have been
granted a waived
status under CLIA
https://www.cms.gov/Regulations- and
-Guidance/Legislation/CLIA/Downloads
/waivetbl.pdf
• List is organized by CPT code
• Contains less information than the U.S.
FDA website
• Provides basic information (eg, CPT code,
test name, and manufacturer) in an easyto- read tabular format, which clinicians
may nd useful
CDC CLIA website https://www.cdc.gov/clia/default.aspx • Good resource with professional
information and educational resources
regarding the analytical and technical
aspects of a test for a given analyte
Website for CLIAwaived POC tests
https://www.cdc.gov/labquality
/waived- tests.html
• Contains hyperlinks to documents
that outline good laboratory practices
for sites performing waived tests
and a booklet detailing the practical
considerations for performing CLIAwaived POCT or developing CLIA- waived
POCT services
5,6
CPT = current procedural terminology; FDA = Food and Drug Administration.
CHAPTER 4 • PoinT- of-CARE TEsTing 53
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PERFORMANCE CHARACTERISTICS
OF CLINICAL LABORATORY
IMPROVEMENT AMENDMENTS–
WAIVED POINT-
OF-CARE TESTS
AND THEIR APPLICATION
Like any test, CLIA- waived POC tests have random and systemic
error associated with their use. us, pharmacists should be aware
of the variability of POC tests when interpreting their results.
Agiven test’s performance characteristics will be included in the
manufacturer’s test literature. In addition, such information may
be gleaned from the literature or the manufacturers’ websites.
Most CLIA- waived POC tests for chronic disease management
that are applicable to outpatient pharmacy settings are either qualitative or quantitative. All CLIA- waived POC tests for infectious
diseases that are applicable to outpatient pharmacy settings are
qualitative. CLIA- waived POC tests can be described in terms
of several performance characteristics introduced in Chapter1,
including accuracy/bias, precision, specicity, sensitivity, negative predictive value (NPV), and positive predictive value (PPV).
Accuracy and Bias
e terms accuracy and bias are oen used synonymously.
Accuracy, the percentage of true results, is a performance measure
of qualitative CLIA- waived POC tests. In contrast, bias, how close
the mean test measurement is to the true value, is a performance
measure for quantitative CLIA- waived POC tests. e accuracy
of a qualitative CLIA- waived POC test can be aected by many
variables, including errors in sample collection, environmental
conditions (eg, temperature, humidity), operator error (ie, not
following test manufacturer instructions), improper instrument
operation, and maintenance. Likewise, depending on the analyte,
negative or positive bias associated with a quantitative CLIAwaived POC test may necessitate conrmatory lab- based testing
for values that exceed a certain acceptable threshold.
Precision
For a CLIA- waived POC test, precision characterizes test reproducibility (ie, the degree to which the test performed under
constant conditions produces the same measurement each time).
For qualitative CLIA- waived POC tests, precision is characterized by PPV, which is the proportion of true positive results
relative to all (ie, true and false) positive results. A CLIA- waived
POC qualitative test with high precision regularly returns truly
positive results. For quantitative CLIA- waived POC tests, precision is characterized by values such as standard deviation, relative
standard deviation (coecient of variance), or standard error
of the mean. A CLIA- waived POC quantitative test with high
precision regularly produces results that are in close agreement.
Application of Accuracy/Bias and Precision
Accuracy/bias and precision characterize the quality of a CLIAwaived POC test. ese quality measures help the clinician
choose the test, by comparing the expected performance of a
test across dierent manufacturers. In addition, using these
measures clinicians can evaluate the validity of a test’s result, and
assess whether it is performing within its expected error limits.
ese quality measures are determined in studies for regulatory
approval, the results of which are included in the manufacturer’s
provided package insert for the test.
Specificity and Sensitivity
CLIA- waived POC tests for chronic disease management in an
outpatient pharmacy setting evaluate the need for therapy and
medication adjustments at a certain treatment threshold. In the
case of infectious diseases, they conrm the presence of an infectious disease and aid in its diagnosis. A perfect CLIA- waived
POC test for a chronic disease would return the exact value
above or below the threshold, whereas one for an infectious
disease would produce a positive result in all patients with the
infection and a negative result in all patients without it. Unfortunately, like laboratory- based tests, no CLIA- waived POC test
is perfect.7 us, when choosing a CLIA- waived POC test, clini
cians must consider a test’s specicity and sensitivity, when there
is a referenced laboratory standard for comparison, or the analogous respective terms negative percent agreement and positive
percent agreement, in the absence of one.
e specicity, or negative percent agreement, of a qualitative
CLIA- waived POC test represents its ability to not detect the
analyte when it is indeed absent (ie, a true negative). e specicity of a quantitative test is dependent on a cuto value, which
is also known as the limit of detection.
A qualitative CLIA- waived POC test with 90% specicity will
incorrectly detect the presence of the analyte in 10% of those
tested when they do not have the analyte of interest (ie, false positives). us, when screening for the presence of an infectious
disease, using a CLIA- waived POC test with high specicity is
desired because it means the test is rarely positive in the absence
of the infection. e sensitivity, or positive percent agreement,
of a qualitative CLIA- waived POC test represents its ability to
detect the analyte when it is indeed present (ie, a true positive).
e sensitivity of a quantitative test is dependent on a predened
cuto or threshold value so that a diagnosis or therapeutic management decision can be made. A qualitative CLIA- waived POC
test with 80% sensitivity will positively detect 80% of those tested
who have the analyte of interest, but it will not detect the other
20% who also have it (ie, false negatives). us, when screening
for an infectious disease that carries a poor prognosis or is highly
contagious, using a CLIA- waived POC test with high sensitivity is desired because a false negative result cannot be tolerated.
8
Application of Specificity and Sensitivity
Specicity and sensitivity are performance characteristics that are
independent of the population of interest being tested and are
considered xed characteristics of the test.7 erefore, without
further improvements in the methodology or analytical techniques, their values do not signicantly change. Choosing the
CLIA- waived POC test with the highest specicity minimizes
the chance that someone without the condition or disease will
be misidentied as having it. us, when using a CLIA- waived
POC test to screen for a condition or disease that many of those
tested will not have, choose the method with the highest sensitivity to optimize the testing eorts. A highly sensitive test does
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54 BASIC SKILLS IN INTERPRETING LABORATORY DATA
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not oen produce a false negative result. By doing so, the chance
that someone with the condition or disease goes undetected will
be minimized. To assess the value of specicity and sensitivity
and relate them to patients in one’s clinical setting, the test’s NPV
and PPV must be considered.7 By calculating either of these
values, clinicians can apply a test’s performance to their own
clinical setting.
Negative Predictive and Positive Predictive Value
For a qualitative CLIA- waived POC test, the NPV addresses the
likelihood that a given patient does not have the condition or
disease of interest when the test result is negative. Similarly, for
a qualitative CLIA- waived POC, the PPV addresses the likelihood that a given patient has the condition or disease of interest
when the test result is positive.
Application of Negative Predictive Values and
Positive Predictive Values
e application of these values provides useful insight into how
to interpret test results. Unlike specicity and sensitivity, NPVs
and PPVs are not xed characteristics of the test, but they are
dependent on the population being tested and are inuenced by
the prevalence of the disease. Understanding how these values
are inuenced by disease prevalence can help clinicians use
strategies to optimize test performance and mitigate overtesting
and thereby improve the usefulness of a CLIA- waived POC test.
e NPV allows the clinician to determine how reassuring
to be when answering the question from the patient who tested
negative (“How likely is it that I do not have this condition?”),
whereas the PPV allows the clinician to answer the question
from the concerned patient who tested positive (“How likely is
it that I have this condition?”).
7
Interferences
Interferences are a performance characteristic that is not statistically based. Rather, interferences are medical conditions, medications, or other substances that might inuence test results
positively or negatively. For qualitative tests, interference can
cause false negative or false positive results, whereas for quantitative tests, it can obscure the limit of detection. Interferences with CLIA- waived POC tests can occur and oen involve
cross- reactivity, microbial, or other interfering substances, such
as chemicals or certain foods. Information on interferences is
included in the manufacturer information included with the
tests, which personnel performing the test must read to ensure
they have the most up- to- date information.
SPECIMENS USED IN CLINICAL
LABORATORY IMPROVEMENT
AMENDMENTS–WAIVED POINT
OF CARE
Waived tests are approved for use only with unprocessed specimens that require no manipulation (eg, centrifugation, precipitation, dilution, and extraction). Serum or plasma specimens
require manipulation during sample preparation or training in
their handling; thus they are not suitable for use in CLIA- waived
POC tests.9 Clinicians should be aware that some test systems
provide instructions for processed and unprocessed specimen
types, but waived use is intended only for the testing of unprocessed specimens.
Specimens Used in Common Clinical
Laboratory Improvement Amendments–
Waived Point-
of-Care Tests for Chronic
Disease State Management
In addition, depending on the type of specimen the test analyzes,
not all CLIA- waived POC tests used for disease state management are suitable or feasible for use in an outpatient pharmacy
setting. e most commonly obtainable specimen types for
POCT in disease state management are urine and whole blood.
Urine
e urine dipstick and tablet reagent urinalysis are common
CLIA- waived POC tests found in many outpatient settings.
Urine testing may involve a tabletop POC testing device or may
be a manually read test kit. e determination of what type of
POC testing device to use may factor in cost, time to test, and
eciency to document results.10 It is important to consider the
specicity and sensitivity, and the NPV and PPV, for the POC
urine test used at the practice site due to variability between
devices.11 Subsequent therapy or treatment recommendations
based on data collected from a POC urine test should be based
on the specic device and analyte sampled. Typically, a sample
is obtained in a clean container and analyzed promptly. If the
time between collection and analysis is delayed more than
4hours, the sample may be able to be refrigerated.12 Depending upon the test, an average of 1 to 2 oz may be needed for an
accurate analysis. In addition, patients may be asked to obtain
a sample in the morning in order for more concentrated urine
to be collected.13 Oen, a clean catch urine is necessary, requiring the patient to clean the genital area before collecting the
sample to avoid contamination. Patients may be asked to alter
sampling technique to obtain a rst- void urine or a midstream
urine sample.11 Menstrual period or vaginal secretion eect on
certain test results may impact the timing of a test or ability to
obtain a clean sample.
Whole Blood
Pharmacists obtain whole blood samples through a nger stick
method for a variety of CLIA- waived POC tests. Blood conservation is one advantage of POC tests; as such, tests analyze whole
blood analytes using volumes typically measured in drops of
blood rather than milliliters. Each testing device may require
varying amounts of a blood sample for a given analyte, making
it critical for pharmacists to follow the manufacturer’s guidelines
for blood sample collection as required by CLIA- waived testing
regulations. e minimal amount of blood required by POC
tests may also reduce the chance of errors that can occur when
using larger volumes. As described in Chapter1, a quick turnaround time (TAT) is also a major advantage to POCT. e TAT
is the time interval from sample collection to test performance,
CHAPTER 4 • PoinT- of-CARE TEsTing 55
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and it is a critical step in ensuring test accuracy for some CLIAwaived POC tests. Outpatient pharmacy settings are oen
very busy; thus, pharmacists performing CLIA- waived POCT
services in these settings must be cognizant of proper sample
collection technique and timing information. is information
is also found in the manufacturer’s guidelines.
Specimens and Types of Tests Used for
Common Clinical Laboratory Improvement
Amendments–Waived Point-
of-Care Tests
for Infectious Diseases Screening and
Management
Currently, there are CLIA- waived tests for 17 infectious diseases
analytes, but not all these tests have POC applications or are
suitable for testing in the outpatient pharmacy setting. e most
common obtainable specimen types for POCT for screening or
management of infectious diseases are swabbed secretions from
nose, nasopharynx, oropharynx, oral mucosal transudate, and
whole blood.
Secretions From the Nose, Nasopharynx, and
Oropharynx
Several infectious disease analytes, such as group A streptococci
(GAS), severe acute respiratory syndrome coronavirus 2 (SARSCoV-2), and inuenza A and B, cause acute respiratory illnesses.
e upper respiratory tract— the nasopharynx, oropharynx, and
laryngopharynx— is easily accessible to airborne microorganisms
and is colonized throughout life by commensal organisms and
potential bacterial pathogens, including GAS, but not by viruses.
Collecting lower respiratory tract specimens, such as sputum for
diagnostic purposes, oen requires invasive procedures, and for
this reason, CLIA- waived POC tests for GAS, SARS-CoV-2, and
inuenza A and B rely on obtaining secretions from the more
readily accessible upper respiratory tract. With minimal training,
pharmacists can perform nasopharyngeal, nasal, or oropharyngeal swabs to collect specimens that would be suitable for the
available CLIA- waived POC tests. Such samples can also be
collected by nasopharyngeal aspiration or nasal wash, but these
collection methods are technically dicult and not practical for
a pharmacist to perform in an outpatient setting.
Oral Mucosal Transudate
To date, human immunodeciency virus (HIV) -1 and -2are
the only infectious disease analytes measured from oral mucosal
transudate specimens for CLIA- waived tests. In 2004, the FDA
approved a rapid HIV antibody–based, CLIA- waived POC
test— which it had initially approved for nger stick, whole
blood, and plasma specimens— for use with specimens of oral
mucosal transudate. In 2012, the FDA approved an identical
version of the test for sale directly to consumers for in- home
use, which cannot be used in clinical outpatient settings. Oral
mucosal transudate is more acceptable to patients because of its
noninvasive, pain- free specimen collection and its rapid TAT.
Moreover, the test enabled the expansion of testing eorts from
laboratory- based facilities to outpatient settings, community
health and nonclinical outreach testing sites, thereby increasing the availability of HIV testing and allowing more people to
14,15
get tested and learn their results in a timely manner. e test
also enables individuals to get tested at least once as part of
routine healthcare.16 With minimal training, pharmacists can
swab a person’s oral cavity to obtain oral mucosal transudate
and perform the professional version of the CLIA- waived test. In
general, POC tests for HIV-1 or HIV-2 using oral mucosal transudate specimens are less technically demanding than methods
using blood and minimize the concern for biohazard disposal.
Methods using oral mucosal transudate have low sensitivity and
may miss more acute HIV infections than CLIA- waived tests
that use whole blood specimens.
Whole Blood
HIV-1, HIV-2, and hepatitis C virus (HCV) are among the
common infectious disease analytes measured from whole
blood for CLIA- waived POC tests. Like POC tests for chronic
disease state management, many pharmacists are comfortable
with obtaining whole blood samples through a nger stick
method for these CLIA- waived POC tests.
waived oral tests for HIV-1 and HIV-2, the CLIA- waived whole
blood tests for HIV-1 and HIV-2 require more equipment (eg,
lancets) and biohazard waste precautions (eg, sharps containers
and gloves). Although a blood sample for HIV-1, HIV-2, and
HCV CLIA- waived tests that use whole blood can be obtained
by venipuncture, it is easier to obtain the sample via nger stick
for POCT purposes in outpatient pharmacy settings. However,
HIV-1 and HIV-2 antibodies and p24 antigen concentrations
are generally lower in whole blood nger stick samples than
from plasma.
17,18
Unlike the CLIA-
Types of Point- of-Care Tests for Infectious Diseases
e types of tests that exist to detect pathogens are antigen,
molecular, and antibody- based methods. ese methods dier
in what is measured and their role in testing for a given pathogen.
Antigen tests detect protein fragments of the pathogen that elicit
an immune response; therefore, they may serve as a marker for
infection. However, the tests do not distinguish between antigen
from a viable pathogen and antigen from a nonviable pathogen,
so a positive antigen test does not necessarily mean the patient
has an active infection. Antigen tests target protein fragments
that are large enough to detect without the use of amplication
reactions, oen through lateral ow chromatographic enzyme
immunoassays or latex agglutination techniques. Such techniques can be performed with little or no training and typically produce a visual readout. However, despite its convenience,
visual readouts may be unreliable; thus, for some pathogens,
many contemporary antigen tests use an automated reader.19
Antigen tests typically have lower sensitivity than molecular
tests and provide a qualitative result.19 ese tests can be used
to detect exposure that may necessitate therapy, and screen for
potential outbreaks in institutions or environments with close
quarters to develop further preventative strategies.
Molecular methods for detecting pathogens amplify nucleic
acids in the viral genome using real- time reverse transcription
polymerase chain reaction (rtRT-PCR) or reverse transcription
isothermal amplication. e amplication reaction in rtRTPCR methods requires a series of alternating temperature cycles,
which makes their application to a POC platform challenging.
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