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56 BASIC SKILLS IN INTERPRETING LABORATORY DATA
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However, technological advances such as the advent of reverse
transcription isothermal amplication (ie, RT- loop- mediated
isothermal amplication [RT-LAMP]), in which amplication
reaction occurs at a constant temperature, have enabled molecular diagnostic tests to be applied to a POC testing platform.19
Molecular tests are typically highly sensitive, provide a qualitative result or a semiquantitative measure of pathogen burden,
and are useful for detecting active infections.
Serological methods detect the presence of immunoglobulin M (IgM) or immunoglobulin G (IgG) antibodies directed
against the virus in a whole blood, plasma, or serum sample.
ese methods typically use enzyme- linked immunosorbent
assays (ELISA) techniques. Performing serological tests involve
applying a small sample of blood from a nger stick (ie, drops) to
a cartridge containing the immunoassay, followed by a couple of
drops of a buer solution. e qualitative results should then be
readily displayed within minutes. e initial antibody response
to an infection varies for each pathogen and among individuals.
e response is comprised of IgM antibodies followed, in time,
by IgG antibodies. us, a test that detects IgM antibodies would
indicate a recently acquired infection, whereas one detecting
IgG antibodies would signify that some time had elapsed since
acquisition of infection. Serologic methods do not detect active
acute infection, and are typically used for diagnosis of chronic
infections or public health disease surveillance and epidemiology eorts (ie, HIV, HCV, and COVID-19).
USES AND APPLICATION OF
COMMON CLINICAL LABORATORY
IMPROVEMENT AMENDMENTS–
WAIVED POINT- OF-CARE TESTS
HgbA1c
Use in Pharmacy
An estimated 34.2 million Americans have been diagnosed
with diabetes mellitus, with an additional 7.3 million remaining undiagnosed.21 In 2015, it was estimated that 88 million
Americans age 18 or older had prediabetes.21 Measurement of
the percent concentration of glycated hemoglobin (HgbA1c) in
blood is a useful CLIA- waived POC test for identifying patients
with prediabetes and monitoring patients with diabetes during
routine follow- up visits. Pharmacists can perform screening for
diabetes as part of large community or corporate health and
wellness eorts. Individuals identied as being at risk can then
be oered counseling on nonpharmacologic lifestyle changes
(eg, exercise, dietary adjustments, and smoking cessation) or
referred to their provider for additional follow- up. It is important that pharmacists reference national diabetes guidelines
when discussing results and determining the appropriate time
to refer patients to their primary care provider.
Determining Appropriate Testing Candidates
Patients at risk for diabetes that do not have current diagnostic
testing for diabetes should obtain an initial laboratory- based
HgbA1c to determine glycemic status; however, if a validated
and regularly monitored CLIA- waived POC test is used for the
HgbA1c, it may be acceptable to use that test for diagnosis when
associated signs and symptoms are present.22 For patients with
a current diagnosis, CLIA- waived POCT of HgbA1c for monitoring allows for more timely disease management.23 Immediate
feedback from CLIA- waived POCT has demonstrated increased
likelihood of medical or pharmaceutical intervention, as well as
greater HgbA1c lowering as compared with commercial laboratory testing.
24
e use of CLIA- waived POC tests provides another tool for
pharmacists practicing in patient- centered, team- based environments to contribute to the appropriate management of
chronic diseases. CLIA- waived POCT services are also used in
outpatient pharmacy settings to monitor the safety and ecacy
of medications as well as provide measurable clinical outcome
data consistent with evidence- based guidelines. CLIA- waived
POC tests are used in the screening of at- risk patients for certain
disease states (eg, diabetes, dyslipidemia) and in their long- term
management. Direct pharmacist involvement using CLIA- waived
POCT in conjunction with medication therapy services, collaborative practice agreements (CPAs), or collaborative drug therapy
management (CDTM) agreements can assist patients in reaching
their chronic disease management goals as well as build strong
patient and pharmacist relationships demonstrating positive
clinical outcomes and return on investment.
perform CLIA- waived POC tests to screen for infections of public
health interest (eg, HCV, SARS-CoV-2, and inuenza), or to aid
in the diagnosis and management of an acute infection in an
individual patient (eg, inuenza, GAS). is section explores
common CLIA- waived POCT services provided by pharmacists
in the outpatient setting; however, it is not an all- inclusive representation of the pharmacist’s role in POCT.
1,20
Pharmacists also
Application of HgbA1c Point- of-Care Testing in Practice
As part of enhanced pharmacy services, pharmacists in an
outpatient setting can build CLIA- waived POCT services into
their workow. Depending on the state board of pharmacy’s
statutes, the pharmacist engaged in a CPA/CDTM agreement
can then follow the protocol to adjust medication dosages,
recommend nonpharmacological therapies, or schedule additional testing or physician follow- up (Minicase 1).
Performance Characteristics
Prior to the early 1990s, measurement of HgbA1c was not standardized, so it was used only as a surrogate marker of glycemic
control. In the early 1990s, the landmark Diabetes Control
and Complications Trial (DCCT) established the correlation
between HgbA1c measurement and the risk of developing
complications from diabetes; subsequently, target values were
created to lower patients’ risk of poor outcomes.
standardization was needed because in the DCCT a very small
dierence, such as 2%, in mean HgbA1c values between treatment groups translated into a signicant decrease in the risk
for a variety of complications from diabetes.25 e National
Glycohemoglobin Standardization Program (NGSP) was initiated to standardize HgbA1c test results so laboratory results
25-27
Rigorous
CHAPTER 4 • PoinT- of-CARE TEsTing 57
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MINICASE 1
Type 2 Diabetes Mellitus and HgbA1C
Stuart M., a 60- year- old man with a 5- year history of type 2 diabetes
mellitus, presents to his primary care clinic for a follow- up visit.
Although he was diagnosed 5 years earlier, he exhibited symptoms
of diabetes for at least 2 years before diagnosis, including nocturia.
He reports increased physical activity but has gained 10 lb over the
past year with little success in weight loss (weight 190 lb; height
5′10″; BMI 27.3 kg/m2). He reports eating a high- carbohydrate
diet with pasta or bread at every dinner. StuartM.’s medications
for diabetes include metformin 500- mg tablets, one tablet twice
a day for the past 4 years, and various nutritional supplements
that he has tried with no noticeable improvement. His personal
blood glucose logs over the past 3 months indicate values ranging
throughout the day from 108 to 264 mg/dL. His previous A1C level,
tested with the POCT device 3 months ago at the clinic, was 7.8%.
The pharmacist performs POC A1C testing based on a CPA.
StuartM.’s vital signs include blood pressure (BP), 128/78mm Hg;
were comparable to those in the DCCT.27 As part of the NGSP,
a network of laboratories works with test manufacturers to standardize their methods.27 Over the years, the rigorous standardization eorts have facilitated the monitoring of HgbA1c with
rapid reporting of results, which has demonstrated improved
glycemic control in type 1 and insulin- treated type 2 patients
with diabetes.
28,29
e American Diabetes Association recommends that the
HgbA1c methods used be NGSP certied.30 NGSP requires
annual manufacturer certication of POC instruments against
a secondary reference laboratory with a HgbA1c range of
4% to 10%. e HgbA1c reporting range for certain devices
may exceed the NGSP certication of accuracy up to 10%,
thus requiring the end user to assess a manufacturer’s documentation of calibration at the upper limit of their reportable
range.24 Although the same quality standards apply for laboratory and POC HgbA1c systems, a concern regarding the
lack of required prociency testing for end users performing
CLIA- waived POC HgbA1c tests exists.
25,26
Few data characterize how these methods truly perform when conducted in the
setting of a CLIA- waived laboratory; thus, their real analytical performance is not known.
25,26
Nonetheless, data indicate
that CLIA- waived POC methods for HgbA1c perform no worse
than many laboratory- based HgbA1c methods.25 Moreover, in
a series of studies, investigators have demonstrated that the
analytical performance of POC instruments for HgbA1c have
improved considerably in the last decade.
31,32
Measurement of
HgbA1c via CLIA- waived POC tests are based on structural
dierences among the various types of hemoglobin (Hgb) molecules, using either anity separation or more specic immunoassays.26 Anity separation methods use a boronate matrix
to measure “total” glycation and distinguish glycated Hgb from
nonglycated Hgb.26 Based on anity separation, the analyzers of
the CLIA- waived POC tests measure the percentage of HgbA1c.
heart rate (HR), 84 beats/min; respiration rate (RR), 20 breaths/
min; and HgbA1C, 8.3%.
QUESTION: What does this A1C level indicate?
DISCUSSION: The rise in A1C level of 0.5% over 3 months indicates
that the patient’s average blood glucose level is increased, and he is
at increased risk for diabetes complications. In addition to the A1C
level, the patient’s weight gain and report of a high- carbohydrate
diet would contribute to the pharmacist’s decision to modify therapy.
According to the CPA and following therapeutic guidelines, the
pharmacist may decide to maximize the metformin therapy and
educate the patient on dietary strategies to reduce the amount
of carbohydrates consumed and increase physical activity with
the goal of weight loss. The pharmacist would also recommend a
follow- up visit with a repeat A1C level in 3 months.
An advantage to anity separation methods is a lack of interference by nearly all Hgb variants or derivatives.26 Immunoassay
methods use specic antibodies directed toward the rst several
amino acids and the glucose molecule of the N- terminal of the
β- chain of the Hgb molecule.26 ese methods measure total
Hgb through methods including turbidimetric measurement
and latex agglutination inhibition.26 Although most immunoassays do not interfere with common Hgb variants (eg, HbAS,
HbAC, HbAD, and HbAE), they are subject to interference with
rare Hgb variants resulting from amino acid substitutions.25
Overestimation of HgbA1c due to variants could result in overly
aggressive treatment; thus, it is important for the user to factor
in this potential inuence.
24
In evaluating the performance characteristics of CLIAwaived POC, HgbA1c tests bias and measures of imprecision
are important.25 Acceptable levels of accuracy and precision for
HgbA1c POCT devices have been suggested by some authors
at within 0.2 points of true value and a coecient of variation
<3%.32 As the measurement of HgbA1c can result in therapy
adjustments, consistency between POCT devices, TAT, and
methods are important components of a laboratory’s policies
and procedures. erefore, using devices meeting NGSP quality measures that are subject to regular monitoring for accuracy
will help ensure accurate and standardized results.
Hemoglobin
Use in Pharmacy
Anemia is caused by the impaired production or increased
destruction of red blood cells, blood loss, or uid overload.
Several CLIA- waived POC tests for Hgb and hematocrit (Hct)
using capillary blood samples have been used in critical care
settings as well as in outpatient settings to assist with the diagnosis of anemia or its associated morbidities.
58 BASIC SKILLS IN INTERPRETING LABORATORY DATA
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Determining Appropriate Testing Candidates
Patients at risk for anemia include those who have deciencies
in their diet, intestinal disorders, chronic conditions, or genetic
disorders as well as those who are menstruating or pregnant.
Pharmacists using POC tests for Hgb in outpatient settings can
screen for anemia as well as monitor therapies.
Application of Hemoglobin Point- of-Care Testing in
Practice
Hemoglobin POCT devices use relatively small amounts of
nger stick blood, allowing for ease of use for trained pharmacists, and quick results. Pharmacists may use results to manage
or monitor anemia, providing recommendations to the patient
and communicating results or recommendations to the provider.
Sickle cell disease is a common genetic disorder worldwide that
has used POCT devices for the screening and early diagnosis
of the disease. However, a detailed discussion of application to
sickle cell disease is outside the scope of this chapter.
Performance Characteristics
e CLIA- waived POC tests to determine an Hgb level are typically based on either the conductometric method or the spectrophotometric method.33 e commonly used spectrophotometric
method measures the azide- methemoglobin formed by the test
reagent mixed with a drop- size sample of capillary, venous, or
arterial blood. e conductometric POCT device uses optical
absorption photometry to obtain Hgb and Hct from a single
drop of blood in less than 1 minute.
In addition to the POCT devices described previously, a noninvasive, multi- wavelength sensor exists that uses a spectrophotometric method to determine Hgb concentration.34 Another
device also uses a sensor that emits wavelengths of light to measure Hgb concentration data based on light absorption through
the nger. In a similar manner as conventional pulse oximetry,
it uses signal processing algorithms and adaptive lters to translate the absorption data. e proposed advantages of a noninvasive testing device would be no risk of exposure to bloodborne
pathogens for the pharmacist and a painless process for the
patient.
Physiologic factors can aect Hgb measurement, emphasizing the need for consistency in laboratory procedures and
documentation. Identied causes of variation include capillary blood versus venous blood, tourniquet use for longer than
30seconds, patient position (standing, sitting, or supine), time
of day, whether the right or le hand is used, and even which
nger is used for a capillary sample.
35
Cholesterol
Use in Pharmacy
Heart disease has a profound eect on the United States population as the leading cause of death among men and women and
aects all races and ethnic groups.36 In 2018, it was estimated
that atherosclerotic cardiovascular disease (ASCVD) caused
nearly one of every three deaths in the United States.36 Elevated
cholesterol is one of the leading causes of ASCVD. Hyperlipidemia, dened as a total serum cholesterol >200 mg/dL, aects
an estimated 95 million adults, although only an estimated
43million are taking medication(s) to reduce their risk.
Pharmacists perform screening for ASCVD risk as part of
large community or corporate health and wellness eorts. Individuals identied as at risk are oered counseling on nonpharmacologic lifestyle changes (eg, exercise, dietary adjustments,
blood pressure management, and smoking cessation) or referred
to their provider for additional follow- up. Additionally, under
a CPA/CDTM agreement, pharmacists can initiate or modify
medications to minimize a patient’s ASCVD risk.
37
Determining Appropriate Testing Candidates
While many workplace health and wellness plans oer annual
cholesterol screenings, current clinical guidelines recommend
screening adult patients every 4 to 6 years to assess a patient’s
ASCVD risk.38 Patients on therapy are oen monitored on a
routine basis.
38
Application of Cholesterol Point- of-Care Testing in
Practice
Trained pharmacists applying and properly using CLIA- waived
POC tests for the management of chronic diseases provides
signicant benets to community health. Chronic disease
management for cardiovascular disease and hyperlipidemia,
specically, are areas in which pharmacists have demonstrated a
positive impact on outcomes.1 Managing ASCVD and lowering
ASCVD risk oen require prescription medication therapies in
addition to nonpharmacological lifestyle changes. In addition,
clinical management guidelines for ASCVD and the medications
used in its treatment recommend regular monitoring of laboratory values to determine appropriate drug dosing. It is important
for pharmacists to reference national disease state guidelines
when discussing results and determining the appropriate time
to refer patients to their primary care provider.
As part of enhanced pharmacy services, pharmacists in an
outpatient setting can build CLIA- waived POCT services into
their workow. As described previously, common CLIA- waived
POC tests for chronic disease state management require the collection of a small blood sample for the monitoring of cholesterol. Depending on the state board of pharmacy’s statutes, the
pharmacist engaged in a CPA/CDTM agreement could then
follow the protocol to adjust medication dosages, recommend
nonpharmacological therapies, or schedule additional testing
or physician follow- up. e accessibility of pharmacists enables
them to reach large numbers of adults at risk for ASCVD with
appropriate cholesterol testing, which may benet prevention
and treatment eorts in a community.
Performance Characteristics
Historically, the National Cholesterol Education Program’s goal
to reduce morbidity and mortality caused by ASCVD relied
on accurate and precise measurement of the lipid prole. In
response to the need to improve cholesterol measurement, the
CDC created the Cholesterol Reference Method Laboratory
Network to ensure that manufacturers of diagnostic products
in meeting the criteria of the National Reference System for
Cholesterol (NRS/CHOL).39 e NRS/CHOL determines the
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methods and materials for cholesterol testing that are used
by research laboratories, which may determine the American
College of Cardiology and American Heart Association prevention guidelines for healthcare professionals on the treatment and
management of blood cholesterol to reduce ASCVD risk.
Several of the CLIA- waived tests have demonstrated accept
able ranges of specicity and sensitivity when compared with
test methods from the Clinical and Laboratory Standards Institute (CLSI).40 Many waived tests and devices are available for
the testing of cholesterol that report results ranging from only
total cholesterol to an entire standard lipid panel (eg, total
cholesterol, high- density lipoprotein, low- density lipoproteincalculated, and triglycerides). ese tests and devices typically
use nger stick capillary or venous blood samples and produce
results within a few minutes. ere are two common CLIAwaived POC test methodologies, one using combined enzymatic methodology and solid- phase technology and the other
using reectance photometry to produce results in minutes. e
procedure manuals for each test provide guidance on proper
specimen collection, handling, and quality control (QC) measures. Variants, including day- to- day or seasonal variations, can
contribute to the accuracy of a cholesterol level.
41,42
Common
variants to consider in interrupting the POC test results include
age, gender, diet and alcohol, exercise, medications, fasting, and
pregnancy.
41,42
Blood Chemistries
Use in Pharmacy
A wide variety of CLIA- waived POCT devices measure blood
chemistry in an outpatient setting. A blood chemistry analyzer
uses a whole blood sample and can measure analytes, including
ionized calcium, carbon dioxide, chloride, creatinine, glucose,
potassium, sodium, and urea nitrogen. In addition, some CLIAwaived blood chemistry analyzers measure other analytes,
including alanine amino transferase, aspartate amino transferase, albumin, total bilirubin, alkaline phosphatase, and total
protein. Blood chemistry analyzers with these analytical capabilities can be used by a pharmacist practicing under a CPA or
CDTM provisions in state regulations or statutes to determine
liver and renal function values and assist with any appropriate
medication dosing adjustments for chronic conditions, such as
diabetes or cardiovascular disease.
Many medications are used in the management of chronic
diseases that can lead to electrolyte imbalances. Additionally,
most medications’ pharmacokinetics are impacted by renal
and/or liver function. Blood chemistry panels, such as a complete metabolic panel, can assist pharmacists in understanding a
patient’s renal and liver function to adjust or monitor the safety
of these medications. CLIA- waived POC platforms for blood
chemistries have multiple panels, not all of which are CLIAwaived. Measuring blood chemistries in real time can enable the
pharmacist to adjust the medications accordingly. It is important
that pharmacists understand the performance characteristics
of these tests, reference guidelines, and ranges when discussing
results and determining the appropriate time to refer patients
to their primary care provider.
Determining Appropriate Testing Candidates
Patients under the supervision of a pharmacist for chronic
disease management (eg, hypertension, diabetes) require routine
blood chemistry monitoring to ensure the safety and ecacy of
their medications. Pharmacists should consult relevant national
-
guidelines and perform necessary basic assessments to determine when to use these tests in the appropriate patient.
Application of Blood Chemistries Point- of-Care Testing
in Practice
Many medications on the market require renal or hepatic dosing
adjustments as a patient’s renal or liver function declines. Assessing
a patient’s renal and hepatic function at the POC allows a pharmacist with a CPA/CDTM agreement to adjust the medication
dose or modify a patient’s treatment to provide safe pharmacological treatment.43 Several chronic disease medications (eg,diuretics,
angiotensin converting enzyme inhibitors) can impact a patient’s
electrolytes. To safely start and modify these medications, it is
essential to assess the patient’s electrolytes before and aer. Using
POCT to monitor the electrolytes allows the pharmacist to make
real-
time decisions and adjust medications accordingly.
Performance Characteristics
CLIA- waived POC tests for blood chemistries analyze whole
blood samples collected through venipuncture or nger stick,
depending on the analyzer and analytes being tested. Analyzers can provide results within minutes from a few drops of
blood. To produce readable results, the analyzer conducts
chemical reactions between the whole blood and the chemical
reagents provided to produce chromophores, which are then
measured through photometry. Using absorbed wavelengths,
the analyzer can determine the concentration of the desired
analyte. In general CLIA- waived POC tests for blood chemistries meet established thresholds for total allowable error for
most analytes.44 However, in dierent settings, analytes such as
sodium, glucose, calcium, and others may demonstrate signicant bias, compared with reference methods.44 Reasons for the
bias include dierences in analytical methods used by the CLIAwaived POC test and the comparator or improper sample collection technique (eg, failure to properly clean the ngertip prior
to obtaining capillary blood).
44,45
Urinalysis
Use in Pharmacy
e urine dipstick and tablet reagent urinalysis are common
CLIA- waived POC tests found in many outpatient settings.
Urinalysis screens for a variety of dierent diagnostics (eg,
urinary tract infection, pregnancy) and assists in the management of chronic diseases (eg, glucose, ketones, albumin to creatinine ratio). With a CPA/CDTM agreement, pharmacists provide
nonpharmacological treatment and antibiotic treatment for a
urinary tract infection identied through a CLIA- waived POC
urinalysis. Additionally, pharmacists use urinalysis to assess
patients with diabetes through monitoring glucose, albumin,
and ketones in the urine, providing guidance on adherences and
ecacy of medication(s).
60 BASIC SKILLS IN INTERPRETING LABORATORY DATA
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Determining Appropriate Testing Candidates
When considering incorporating urinalysis into the pharmacy
workow, the location for obtaining a urine sample will determine the site’s ability to use these POC tests. e site needs to
ensure a private area to obtain a urine specimen while ensuring
the accuracy of the sample.
Application of Urinalysis Point- of-Care Testing in
Practice
A variety of urinalysis POC tests allow pharmacists to screen
for and manage a variety of conditions and disease states. e
urinalysis test provides pharmacists with values for bilirubin, glucose, Hgb, ketone, leukocytes, nitrite, pH, protein, and
specic gravity. is test can be used to detect an acute urinary
tract infection. Additional POC testing for urine albumin
concentration or albumin to creatinine ratio for identication
of microalbuminuria can assist the pharmacist in the management of diabetes or hypertension.24 Pharmacists involved with
prescribing or administering birth control may benet from
urine human chorionic gonadotropin (hCG) testing to determine a patient’s pregnancy status. Outpatient monitoring for
proteinuria for pregnant patients during routine prenatal care
may aid in identifying patients at risk for preeclampsia.
24,46
e
pharmacist involved in a smoking cessation program might
use a nicotine detection test. is test detects nicotine and its
metabolites in urine and could indicate the smoking status of
an individual as a low or high nicotine consumer. Additionally,
urine POC tests can also be used for a variety of other screening and diagnostic purposes; however, these uses are beyond
the scope of this chapter. It is important that pharmacists reference national disease state guidelines when discussing results
and determining the appropriate time to refer patients to their
primary care provider.
Performance Characteristics
Urine POCT studies are limited and, of those available, there
is considerable variation in how the urine screening tests are
performed: such testing is oen in conjunction with other
physical assessments, the review of symptoms, and laboratory
testing. e interpretation of results depends on proper collection procedures and testing methods. Additionally, it is important to consider specicity and sensitivity and the NPV and PPV
for the POC urine test used at the practice site because of variability between devices.
11
Hepatitis C Virus
Use in Pharmacy
An estimated 2.4 million people in the United States are infected
with HCV, and nearly half of infected individuals are unaware
of their infection because they are asymptomatic.
estimates suggest there were nearly 44,700 new infections in
2017.50 Studies demonstrate that testing adults for HCV is cost
eective in a variety of outpatient pharmacy settings and can
facilitate linkage to care.
51
Clinic models that are led by pharmacists or models in which
they assist in care provide accessible and eective alternatives
47-49
e CDC
for providing outpatient HCV care.52 Given the accessibility of
pharmacists, training pharmacists on the application and proper
use of screening for HCV with CLIA- waived POC tests can have
a signicant impact on public health eorts, increasing the number of people getting tested, especially those at high risk (eg,
younger patients using illicit intravenous drugs) who are not
receiving care.
17,53
Pharmacist- directed CLIA- waived POCT
eorts can increase the linkage to care (eg, follow- up assessment
with providers, medicine distribution, and access to medication
assistance programs) and expand access to appropriate counseling services and community resources.
17,53
Such eorts can also
enhance collection of prevalence and surveillance data to help
resources reach targeted at- risk populations.
Determining Appropriate Testing Candidates
Guidelines for HCV testing have evolved as HCV shied from
a chronic infection to a curable disease. Current guidelines
recommend routine, one- time testing for all adults and riskbased testing for patients younger than 18 years. Periodic repeat
testing can be performed in all individuals who are at increased
risk of or have been exposed to HCV. Pharmacists can identify
individuals for testing based upon risk behaviors or exposures
and other conditions or circumstances outlined in the national
guidelines.
54
Application of Hepatitis C Virus Point- of-Care Testing in
Practice
In 2013, the CDC recommended that the testing sequence for
current active hepatitis C infection begin with testing for the
HCV antibody, including use of the rapid POC assay prior to
further HCV RNA testing and linkage to care. A positive HCV
antibody test does not distinguish whether the patient currently
has acute or chronic active HCV infection or a past infection
that has resolved. erefore, to conrm active infection, individuals testing positive must have a follow- up HCV RNA PCR test
to detect HCV viremia, which informs management and treatment decisions.54 Persons with a negative screening are considered not infected and do not need further evaluation unless
they have a known risk factor.54 us, CLIA- waived POCT for
HCV oers potential savings in healthcare expense as well as the
opportunity to educate patients on risk factors.
Performance Characteristics
Currently, there is one FDA- approved CLIA- waived POC
rapid immunoassay test that detects antibodies to HCV from
whole blood samples obtained either by venipuncture or nger
stick.55 e results from it can be read between 20 to 40 minutes
aer the analysis is started, which enables a patient to receive
pretest and posttest counseling within a single visit. is test
is a noninstrumented, indirect lateral ow immunoassay, and
its performance characteristics are summarized in Table4-2.
It has excellent sensitivity and specicity using whole blood
from a nger stick.56 In a multicenter study of individuals at
risk for HCV infection, the test demonstrated a clinical performance equivalent to laboratory- based tests across all specimen
types.57 In addition, several studies have observed that the specicity of the HCV rapid test with all specimen types is similar to
CHAPTER 4 • PoinT- of-CARE TEsTing 61
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b
OVERALL
CLINICAL
SPECIFICITY (%)
b
OVERALL
CLINICAL
SENSITIVITY (%)
TIME TO
RESULTS
(MIN)
99.8 (OMT)
100 (VPWB)
HIV-1 Abs
99.3 (OMT)
99.6 (FSWB)
20
HIV-1 Abs = 99.9
HIV-1 Abs = 99.7
HIV-2 Abs = 100
99.9
HIV-1 Abs = 99.7
99.9 (OMT)
98.9 (OMT)
HIV-2 Abs = 100
25–40 (OMT)
100 (FSWB)
99.9 (VPWB)
Low risk 100
High risk 98.9
99.8 (FSWB)
99.9 (VPWB)
HIV-1 Abs = 99.9
HIV-2 Abs = 100
10–25 (FSWB)
10–25 (VPWB)
Overall 99.6
99.5
c
99.8
<2
20–40 100 100
SPECIMEN
TYPE
a
ANALYTE(S)
(TYPE OF ABS)
CLIA WAIVER
GRANTED METHOD
OMT, FSWB,
VPWB
(IgG)
June 2004 Lateral ow HIV-1/2 Abs
FSWB, VPWB 10 100 99.7
(IgG + IgM)
FSWB, VPWB 15
FSWB, VPWB 15
(IgG)
(IgG)
OMT
FSWB
(IgG)
VPWB
FSWB 20
HIV-1/2 Abs
(IgG + IgM)
FSWB
(IgG + IgM)
July 2012 Flow through HIV-1/2 Abs
VPWB
February 2011 Lateral ow HCV Abs FSWB
43,44
TEST MANUFACTURER
TABLE 4-2. Summary of CLIA-Waived POC Tests for HIV and HCV
HIV
OraSure
Technologies
OraQuick
Advance
Rapid HIV-1/2
antibody test
Trinity Biotech November 2004 Sandwich HIV-1/2 Abs
Uni-Gold
Recombigen
HIV test
1/2 Stat-Pak
Chembio March 2011 Lateral ow HIV-1/2 Abs
Sure Check
Chembio May 2006 Lateral ow HIV-1/2 Abs
Clearview HIV-
HIV-1/2
DPP HIV-1/2 Chembio December 2012 Dual path ow HIV-1/2 Abs
Abbott Laboratories December 2014 Lateral ow HIV-1 p24 Ag
43
Determine
HIV-1/2 Ag/Ab
combo test
bioLytical
Laboratories
44
INSTI HIV-1/2
antibody test
HCV
OraSure
Technologies
OraQuick rapid
antibody HCV
test
Abs = antibodies; Ag = antigen; FSWB = whole blood via nger stick; OMT = Oral mucosa transudate; VPWB = whole blood via venipuncture.
Values obtained from product package inserts and/or from manufacturers websites, except where noted.
a
Data for whole blood via nger stick unless otherwise noted, data for whole blood via venipuncture not provided.
Only HIV-1 Abs data provided.
c
b
62 BASIC SKILLS IN INTERPRETING LABORATORY DATA
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that reported for anti-HCV enzyme immunoassay (EIA).58 e
CLIA- waived POC test to detect antibodies to HCV also has a
high degree of interoperator agreement in result interpretation.59
For these reasons, the initial testing for HCV antibody screening
with POC rapid immunoassay is an eective alternative to the
third- generation EIA methods.
56
Human Immunodeficiency Virus
Use in Pharmacy
Estimates suggest that nearly 1.2 million individuals in the
United States are living with an HIV infection, of whom 161,800,
or one in eight (13%), are unaware of their infection.60 Testing
is important because individuals who are unaware of their HIV
infection status cannot take advantage of treatments to reduce
viral loads and maintain their health; thus, they pose a risk of
transmitting the infection to others.
Given the accessibility of pharmacists and a less stigmatizing setting, pharmacies can be eective for the delivery of
HIV testing, even though they are underutilized. Data demonstrate that by training pharmacists to perform CLIA- waived
POC tests for the screening of HIV, pharmacies can be an eective setting for those who have not previously been tested and
increase access to testing, particularly in underserved areas.61
HIV screening in pharmacies can have signicant impact on
public health eorts to increase the number of people getting tested, especially those who engage in high- risk behaviors. Pharmacist- directed CLIA- waived POCT eorts could
increase the linkage to medical treatment (eg, facilitate medicine distribution and access to medication assistance programs); expand access to appropriate counseling services,
community resources, and care; and aid in risk- mitigation
eorts (eg, needle exchange programs). Such eorts can also
enhance the collection of prevalence and surveillance data to
help resources reach targeted at- risk populations quicker. Recognizing these public health benets, the CDC oers a training program on HIV testing in community pharmacies (https://
www.cdc.gov/hiv/eective-interventions/diagnose/hiv-testing
-in-retail-pharmacies?Sort=Title%3A%3Aasc&Intervention%20
Name=HIV%20Testing%20in%20Retail%20Pharmacies).
Determining Appropriate Testing Candidates
e CDC recommends that individuals aged 13 to 64 years be
tested for HIV at least once as part of routine care and that individuals with risk factors be tested annually.16 When performing CLIA- waived POCT for HIV, refer to national guidelines to
determine who should be tested.
Application of Human Immunodeficiency Virus Pointof-Care Testing in Practice
Studies show that the accessibility of community pharmacies can
be leveraged to successfully oer CLIA- waived POCT services
for HIV infection.
POCT services for HIV in a pharmacy practice setting requires
a modest amount of sta training, and the costs are similar
to other services oered in these settings.
studies indicate pharmacies can serve as an alternate, highly
18,61-66
Moreover, establishing CLIA- waived
16
16
18,63,64,66
Collectively,
accessible, and less stigmatizing healthcare facility to perform
HIV testing services.
18,62-66
Approximately 1 week is needed for
viral infection and replication to produce detectable p24 antigen,
which is the rst viral protein that can be measured aer HIV
infection. is antigen is then detectable for approximately 1
to 8 weeks (average within 2 weeks), until there is sucient
antibody production to bind and neutralize it. On average, the
onset of symptoms occurs within 1 to 3 weeks of infection and
corresponds to seroconversion (ie, the development of antibodies). Seroconversion occurs in most individuals within 4 weeks
of potential exposure (ie, infection). Individuals who have not
seroconverted by 4 weeks should do so by 12 weeks postexposure. At that point, if seroconversion has not occurred (ie, the
test result is negative), the individual is considered HIV negative.
Performance Characteristics
ere are several CLIA- waived POC tests to detect antibodies
to HIV-1 and HIV-2 and one test that detects those antibodies
plus HIV-1 p24 antigens. Following specimen collection, the
time to test results for HIV POC tests ranges from 1 minute
to 20 minutes, which enables a patient to receive pretest and
posttest counseling within a single visit. ese test devices are
typically based on a capillary lateral ow design and use whole
blood from a nger stick or oral mucosal transudate. e performance characteristics of these tests are summarized in Table4-2.
e performance characteristics of the CLIA- waived POC
tests for HIV are sucient to detect HIV infection or its absence.
In general, the CLIA- waived POC tests for HIV have specicity and sensitivity equivalent to nonwaived HIV screening test
kits (eg, ELISA) approved for laboratory use.67 e performance
characteristics of CLIA- waived POC tests for HIV vary depending on the type of test (eg, antigen or antibody- based), whether
it detects only one type of immunoglobulin (ie, IgG) or more
(ie, IgM and IgG) antibodies, the stage of infection, whether the
analyte has achieved measurable concentrations to give a positive result (ie, the window period), and the type of specimen (eg,
whole blood or oral mucosal transudate) being analyzed. Acute
HIV infection (ie, the period from infection to seroconversion)
is dicult to detect with CLIA- waived POC tests because HIV
antibody titers are typically low in this stage of HIV infection.
us, these tests have lower sensitivity than the nonwaived
laboratory- based ELISAs and automated systems for detecting
seroconversion.67 is means the window period may be longer for CLIA- waived POC tests for HIV compared with a nonwaived test performed in a laboratory. According to the CDC,
laboratory- based antigen/antibody tests can detect HIV infection from venous blood within 18 to 45 days postexposure; the
CLIA- waived POC counterpart does so within 18 to 90 days.68
Tests using oral mucosal transudate are highly accurate but have
even lower sensitivity for detecting seroconversion than those
using serum, plasma from venous blood, or whole blood from
a nger stick because the antibody concentration found in oral
mucosal transudate is lower.
that measure HIV antibody in oral mucosal transudate oen
fail to detect acute HIV.
tion to antibodies for HIV-1 and HIV-2, the marketed combination CLIA- waived POC test should allow for the detection of
69,70
us, CLIA- waived POC tests
67,70
By measuring p24 antigen in addi-
CHAPTER 4 • PoinT- of-CARE TEsTing 63
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acute infection.71 However, to date, the test does not detect p24
antigen with a high sensitivity; thus its accuracy for detecting
acute infection is poor as well.
72,73
In addition to stage of infection, HIV prevalence in the population being tested can impact
the oral tests.69 In high- prevalence settings, the PPVs for either
whole blood or oral mucosal transudate are similar; however, in
low- prevalence settings, PPVs are much higher for whole blood
than oral mucosal transudate specimens.70 CLIA- waived POC
HIV testing will involve an initial HIV test and, if it is reactive, a
follow- up HIV test in a moderate to high complexity laboratory.
A negative test result in someone aer a potential HIV exposure should be repeated aer the window period, approximately
12weeks aer the potential exposure.
68
Influenza A and B
Use in Pharmacy
e annual burden of inuenza in the United States uctuates
markedly depending on a variety of variables. According to
CDC estimates, each year since 2010, inuenza infects between
9 and 45 million individuals and results in 140,000 to 810,000
hospitalizations and up to 61,000 deaths.74 Inuenza occurs
seasonally and produces symptoms that are oen indistinguishable from bacterial respiratory infections. Moreover, the
prompt initiation of appropriate cost- eective antiviral therapy
is key to hastening the resolution of the infection and limiting
its severity.
Using CLIA- waived POC tests to screen for inuenza represents a collaborative opportunity for pharmacy and local health
departments to improve data sharing that informs disease surveillance eorts.75 In some cases, such eorts can be combined
with technological solutions to improve vaccine and antiviral
distribution and perhaps even curtail inappropriate antibacterial use. In addition, POCT for inuenza can assist with eorts
to distinguish between inuenza and COVID-19.
Determining Appropriate Testing Candidates
e CDC has published useful algorithms to guide interpretation of CLIA- waived POC tests for inuenza and clinical
decision- making when influenza activity in the community is high (https://www.cdc.gov/u/professionals/diagnosis
/algorithm- results- circulating.htm) or low (https://www
.cdc.gov/flu/professionals/diagnosis/algorithm- results- not
- circulating.htm).76 To determine if a patient is an appropriate
candidate for testing, pharmacists should perform an appropriate physical assessment to determine if the patient has symptoms
consistent with an acute respiratory disease that began within
several days of patient presentation. Accordingly, CLIA- waived
POCT for inuenza should be performed using a highly sensitive and specic test during the inuenza season when the
disease prevalence is high.76 Pharmacy researchers developed
a physician–pharmacist collaborative management model for
inuenza based largely on the CDC principles.77 In that model,
pharmacists in a community practice setting provided CLIAwaived POCT services for inuenza by screening adult patients
for symptoms of an inuenza- like illness and using proper
nasal swab specimen collection technique to obtain a sample.77
ePPV of the tests was maximized by performing these activities only when local inuenza activity had been documented by
state or federal surveillance and by performing a physical assessment and assessing vital signs (eg, heart rate, blood pressure,
respiratory rate, temperature, and oxygen saturation).77 Only
11% of patients with an inuenza- like illness had a positive
result. Moreover, because the CPA prevented pharmacists from
dispensing oseltamivir or antibacterial therapy to patients who
tested negative, the study demonstrated that this practice model
can lead to rational use of antivirals and avoid the overuse of
unnecessary antimicrobial therapy.
77
To determine whether inuenza is present in a specic
patient population and assist providers in diagnosing and treating acute respiratory illnesses, the CDC also recommends that
CLIA- waived POCT be done during an acute outbreak of a
respiratory disease and in patients with clinical signs and symptoms of inuenza during the inuenza season.
76
Application of Influenza A and B Point- of-Care Testing
in Practice
Studies demonstrate that protocol driven CLIA- waived POCT
for inuenza using antigen or molecular tests can be successfully implemented in the outpatient setting, particularly in
community pharmacies.
77-80
ese services increase access to
care outside of normal clinic hours for patients regardless of
their insurance status or whether they have a primary care
provider.
77-80
In addition, such services provide patients appropriate therapy without promoting the overuse of antibiotics.78
By oering CLIA- waived POCT services for inuenza in the
outpatient setting, pharmacists can also collaborate with public
health agencies to improve seasonal surveillance eorts and
reduce inappropriate antibacterial use in respiratory illnesses
during the inuenza season.
2,75,81
Performance Characteristics
e results of antigen or molecular CLIA- waived POC tests for
inuenza depend on viral load, which is inuenced by several
variables, including patient age and the timing of sample collection relative to symptom onset. Pharmacists should recognize
that viral loads are higher in samples obtained from infected
children than those obtained from infected adults. us, when
evaluating literature to select a test with appropriate performance data for their patients, pharmacists should be aware
that performance data are typically better when the tests are
performed using samples from infected children than samples
from infected adults.19 In addition, viral shedding peaks 24 to
72 hours aer symptoms begin. is time interval represents the
ideal window to achieve optimal test performance. erefore,
when assessing whether a patient is an appropriate test candidate, pharmacists should establish when symptom onset began.
Other variables that pharmacists cannot mitigate that inuence
viral load (and therefore may aect test performance) include
the viral strain, materials used to collect the sample, type of
specimen, and, in the case of antigen tests, the volume of viral
transport media used in test.19 In addition, regardless of method,
the performance characteristics of these tests can be aected by
annual genomic dris or a shi when it occurs.
82,83
64 BASIC SKILLS IN INTERPRETING LABORATORY DATA
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Historically, CLIA- waived POC tests for inuenza virus
nucleoprotein antigen have been chromatographic lateral ow
immunoassays. Such tests oen lacked sensitivity for a variety of
reasons, including being based upon immunochromatographic
methodology that did not amplify the target antigen and relying
on visual detection.19 However, since 2015, several technological and regulatory developments have led to improvements in
the sensitivity of CLIA- waived POC tests for inuenza in general. First, with the advent of isothermal nucleic acid amplication methods that enable rapid detection of DNA/RNA, the
rst molecular test for inuenza was authorized by the FDA
in 2015.84 en, in 2017, the FDA reclassied these tests from
classI to class II devices.85 is reclassication enabled the FDA
to impose more rigorous performance thresholds for the antigen
tests in 2018. According to the new thresholds, existing and new
antigen tests must achieve sensitivity of at least 80% compared
with a molecular test and 80% to 90% when compared with viral
culture.85 Tests that could not meet the performance standards
are no longer available in the United States.
e performance characteristics of marketed antigen and
molecular CLIA- waived POC inuenza tests are summarized
in Table4-3. e antigen CLIA- waived POC inuenza tests are
simple to use and provide results within 15 minutes. e tests
dier in terms of simple sample processing prior to test, incubation and run times, and throughput capacity.86 Most tests now
use automated, rather than visual, detection to improve sensitivity and performance to meet the FDA thresholds. As stated previously, antigen tests have lower sensitivities to detect inuenza
viruses in respiratory specimens than molecular tests.
82,83
us,
negative results of antigen CLIA- waived POC inuenza tests
should not be used to exclude a diagnosis of inuenza.
82,83
For
this reason, the Infectious Diseases Society of America (IDSA)
recommends the use of molecular CLIA- waived POC inuenza
tests rather than antigen CLIA- waived POC inuenza tests for
the detection of inuenza viruses in respiratory specimens of
outpatients.
Molecular CLIA- waived POC inuenza tests use dierent amplication methods, including isothermic nucleic acid
amplication, RT-PCR, and one that uses RT-PCR followed
by hybridization to allow for qualitative to be read visually.19
Unlike antigen CLIA- waived POC inuenza tests, molecular
tests use samples that require no manipulation (ie, addition of
buers). Molecular tests produce results within 15 to 30 minutes
depending on the amplication method. In general, sensitivities of available molecular CLIA- waived POC tests range from
66% to 100%.
82
Group A Streptococci
Use in Pharmacy
Pharmacists can use POC tests for GAS to assist in the acute
management of infected patients.
of adult acute pharyngitis and 15% to 30% of acute pharyngitis
among children.90 Epidemiologically, GAS pharyngitis occurs
primarily in the winter and early spring and aicts individuals
in a narrow age range. Clinically, GAS pharyngitis has a wellrecognized presentation and rarely requires conrmation by
78-80,87-89
GAS causes 5% to 10%
culture, but its symptoms are oen indistinguishable from viral
respiratory tract infections. Data from the United States, Canada,
and the United Kingdom demonstrate that CLIA- waived POC
tests for GAS improve access to care and help ensure that appropriate antibiotic therapy is initiated if warranted, which could
hasten infection resolution by 1 to 2 days.
78-80,87-89
Determining Appropriate Testing Candidates
GAS is the most common bacterial cause of acute sore throat, but
it is dicult to accurately diagnose it as a cause of pharyngitis.91
On the basis of clinical manifestations alone, GAS pharyngitis is
oen indistinguishable from viral respiratory tract infections.
91,92
In contrast, to adults, GAS pharyngitis is more common than
viral etiologies among children and adolescents (Minicase 2).
erefore, to aid in the identication of patients with pharyngitis
who have a high likelihood of GAS infection, additional strategies are needed. Performing an appropriate physical exam and
applying its results using a validated, age- based clinical prediction rule, such as the Modied Centor Criteria Score, can further
assist in identifying patients with pharyngitis who would benet
most from CLIA- waived POCT for GAS.93 Originally developed
in 1981, the Modied Centor Criteria Score was based on the
presence of tonsillar exudates, swollen tender anterior cervical
nodes, fever, and the lack of cough and was used to estimate
the probability of acute GAS pharyngitis in adults with a sore
throat.93 e score was later modied by adding age to the
criteria and validated in a large study of adults and children.94
e Modied Centor Criteria Score ranges from −1 to 5, with
testing for GAS recommended in patients with a score of 2 or
higher.92 However, even when using this clinical prediction rule,
there is limited success in accurately diagnosing GAS pharyngitis because at the highest Modied Centor Criteria Scores
(eg, ≥4), it only helps identify 53% of patients with GAS phar-
91-95
yngitis.
e Modied Centor Criteria and their interpretation are summarized in Table4-4. In a pilot study, pharmacy
researchers developed a physician–pharmacist collaborative
management model for GAS based largely on these principles.87
In that model, pharmacists in a community practice setting used
the Modied Centor Criteria to screen 316 patients, of whom
273 were eligible for testing. Only 48 patients (17.5%) had a
positive test result and received amoxicillin or azithromycin per
their CPA. is pilot project demonstrated that such a practice
model can dramatically reduce inappropriate antimicrobial
use in the community practice setting.87 Like inuenza, these
results were validated by several studies, including one that used
a molecular test, in a variety of community pharmacy settings,
in multiple states, and several countries.
78-80,87-89
Application of Group A Streptococci Point- of-Care in
Practice
Performance characteristics of current CLIA- waived POC tests
for GAS are suciently robust: the current guidelines do not
recommend any additional conrmatory tests for adults when
results are negative. Although conrmatory testing is currently
recommended when CLIA- waived POC test results are negative
in children and adolescents, data suggest that such follow- up
testing may not be necessary.
91,96
CHAPTER 4 • PoinT- of-CARE TEsTing 65
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a,b
i
h,i
h
OVERALL
ACCURACY (%)
A/B
NPV (%)
A/B
PPV (%)
A/B
OVERALL
CLINICAL
SPECIFICITY (%)
A/B
91/99
h
91.7/99.0
h
89.7/100
g
95.6/100
92.2/98.2
i
95.1/98.9
i
83/94.4
i
94.7/99.4
94.5/97.3
h,i
95.6/98.0
h,i
90/89.9
g,i
NPSh95/96
NSh94/95
NPSh99/98
NSh97/98
NPSh75/84
h
NS
82/81
NPS
95/97
h,i
96.1/95.6
h,i
77.7/84.2
h,i
87.4/89.0
i
96.0/98.1
h,i
97.0//97.9
h,j
97.6/100
h,i
95.3/81.5
Data not provided
NPS
i
98.5/97.7
NS
98.2/
99.6
97.6/
99.3
i
NS, NPS 15 84.3/89.5
f,i
81.5/80.9
≤10
NS, NPS
d
f
OVERALL
CLINICAL
SENSITIVITY (%)
A/B
TIME TO
RESULTS
(MIN)
SPECIMEN
TYPE
NPS 10 81.3/77.8
c
NPS
NS, NPS 3–15 NS
97/90
90/89
c,e
i
NPS, NS 15 96.4/82.3
NPS
i
92.8/100
<15
97.6/
97.3
98.9/
98.4
97/94 94/99 83/90 76.3/89.3 95/98
<30
100/100 96.8/94.1 Data not provided
<30
97/94 94/99 82/90 99/99 94.5/98.2
<30
NS
TABLE 4-3. Summary of Performance Characteristics for CLIA-Waived POC Tests for Inuenza A and/or B
TEST (MANUFACTURER)
Antigen-Based Tests
BD Veritor System for Rapid Detection
of Flu A+B (Becton Dickinson)
BinaxNOW Inuenza A&B Card with
QuickVue Inuenza A+B Test
Digival 2 (Abbott Laboratories)
(Quidel Corporation)
Soa Inuenza A+B
(Quidel Corporation)
Acucy Inuenza A&B Test
(Sekisui Diagnostics, LLC)
Molecular TestsjID NOW Inuenza A & B 2 (Abbott) NPS, NS
Xpert Xpress Flu (Cephid) NPS, NS 20–30 NS
AcculaTM Flu (Mesa Biotech) NS
Cobas RInuenza A/B Assay (Roche) NPS
Silaris Inuenza A/B
(Sekisui Diagnostics, LLC)
Data for nasal aspirate/nasal wash not included.
Values obtained from product package inserts and/or from manufacturers websites.
A = inuenza virus A; B = inuenza virus B; NPS = nasopharyngeal swab; NS = nasal swab.
a
b
Does not distinguish between inuenza A and B virus infections when used alone.
Requires separate analyzer or reader device.
c
d
e
Values taken from 2 × 2 table of results in package insert.
Values represent negative percent agreement.
Immunouorescence assay.
Values represent positive percent agreement.
f
Clinical study included both specimen types.
g
h
i
j
Includes only tests that detect inuenza A and/or B, not other respiratory pathogens.
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