Sweat testing for the diagnosis of cystic
fibrosis: Practical considerations
Vicky A LeGrys,
DrA
From the Division of Clinical Laboratory Science, University of North Carolina at Chapel Hill
School of Medicine
Most pediatricians eventually encounter a patient with a clinical presentation that
warrants the consideration of a sweat test to rule out or confirm the diagnosis of
cystic fibrosis. This article discusses, in a series of questions and answers, the currently available sweat testing methods and describes the various methods' reliability, limitations, and frequency of use. In addition, sweat testing utilization and
the interpretation and evaluation of test results are discussed so that the clinician
can critically analyze the laboratory data. (J Pediatr 1996; 129:892-7)
The understanding of the genetics and pathophysiology of
cystic fibrosis has grown tremendously in the past decade.
In an era of gene sequencing and gene transfer using viral
vectors, it may seem like an anachronism to rely on the phenotypic diagnostic tool of the sweat test. However, because
of the large number of mutations of the CFTR gene, confirmation of diagnosis by genetic testing is limited and the
mainstay of diagnosis is the sweat test. There are several
critical issues associated with sweat testing that can make the
evaluation of a sweat test result challenging. Physicians need
to be aware of the kind of sweat testing being performed on
their patients because many of these methods have limitations. The following series of questions and answers can be
helpful to the clinician faced with ordering and evaluating a
sweat test result. These questions are based on those received
from the practitioners referred to the author by the Cystic
Fibrosis Foundation and are an outgrowth of a workshop
presented at the 1995 North American Cystic Fibrosis Conference.
1. What does a sweat test encompass?
The term sweat testing is a general term referring to the
quantitative or. qualitative analysis of sweat to determine
electrolyte concentration, conductivity, or osmolality for the
Submitted for publication Jan. 19, 1996; accepted July 5, 1996.
Reprint requests: Vicky A. LeGrys, DrA, Professor, Division of
Clinical Laboratory Science, School of Medicine, CB No. 7145,
University of North Carolina at Chapel Hill, Chapel Hill, NC
27599-7145.
Copyright © 1996 by Mosby-Y:ear Book, Inc.
0022-3476/96/$5.00 + 0 9/21176363
892
confirmation of a CF diagnosis. Regardless of the method
involved, a sweat test generally has three parts: sweat stimulation by pilocarpine iontophoresis; collection of the sweat
onto gauze, filter paper, coil, patch, or capillary tube; and
qualitative or quantitative analysis of the sweat for the chloride concentration, the sodium concentration, conductivity,
or osmolality.
2. What is the difference between a qualitative and a
quantitative sweat test?
A qualitative sweat test is a screening test for CF, and a
patient with a positive or borderline result should have a
quantitative sweat test. Screening tests may or may not
measure the amount of sweat collected and may report aresult as positive, negative, or borderline or give an actual
concentration of sweat analytes. Examples of qualitative
screening sweat tests are the Wescor Sweat Chek conducCF
QNS
QPIT
Cystic fibrosis
Quantity not sufficient
Quantitative pilocarpine iontophoresis test
tivity analyzer (Wescor, Logan, Utah), the Advanced Instruments conductivity analyzer (Advanced Instruments,
Norwood, Mass.), the Orion skin electrode for chloride
(Orion Research, Cambridge, Mass.), the Scandipharm CF
Indicator System chloride patch (Scandipharm, Birmingham, Ala.), and sweat osmolality measurements. Some of
these methods have documented problems, which will be
described later.
In a quantitative sweat test, the amount of sweat collected
is measured and then the chloride or sodium concentration
in the sample is quantified.
The Journal of Pediatrics
Volume 129, Number 6
3. According to the U.S. CF Foundation, what kind of
sweat test is approved for diagnosis?
For diagnostic purposes, a sweat test consists of the quantitative analysis of sweat chloride, with or without sodium,
using reliable methods. 1• 2 This procedure, often referred to
as the quantitative pilocarpine iontophoresis test, involves
the collection and quantitation of sweat after pilocarpine
iontophoresis with the use of gauze, filter paper, or Macroduct coils and the quantitative analysis of sweat chloride with
or without sodium. 3 Chloride provides greater discrimination in diagnosis compared with sodium. 4 The diagnosis of
CF is based on at least two positive QPIT results, together
with an appropriate clinical presentation.
4. What clinical sites are appropriate locations for
screening tests?
According to the U.S. CF Foundation, screening tests are
appropriate for clinical sites such as community hospitals,
but they are not appropriate for use at accredited CF care
centers. 5 These care centers should be performing QPIT
testing only.
5. What are the reference values for sweat chloride?
Less than 40 mmol!L: negative
A range of 40 to 60 mmol!L: borderline
Greater than 60 mmol!L: consistent with CF
The inteq>retation of the chloride concentration is made
with regard to the patient's clinical presentation, family history, and age, and the knowledge that some rare mutations
of the CFTR gene are associated with a borderline or negative sweat chloride concentration.6 Sweat electrolyte concentration increases with age, and healthy adults can have
sweat chloride concentrations greater than 60 mmol!L.7
6. What is the distribution of CF patients within the
chloride reference values?
Approximately 98% of patients with CF have sweat chloride concen1rations greater than 60 mmol!L, and approximately l % to 2% have sweat chloride concentrations less
than 60 mmol!L. 8 CF in patients whose sweat chloride concentrations are less than 60 mmol!L can be diagnosed on the
basis of genotype, nasal potential difference studies, or clinical presentation. 8
7. What are the sweat conductivity reference values?
Sweat conductivity is a qualitative screening test. The U.S.
CF Foundation has approved the use of the Wescor Macroduct Sweat Chek as a screening test for use at sites other
than CF care centers. According to the Foundation, a patient
having a sweat conductivity greater than or equal to 50
mmol!L should be referred to an accredited CF care center
for a QPIT. 9 The Sweat Chek manufacturer's decision levels are higher than those of the CF Foundation, which can
lead to confusion between the laboratory and the physician
as to the appropriate decision level. The Foundation's medical advisory committee, in deciding to set the decision limit
LeGrys
893
at 50 mmol!L, did so cautiously, realizing that the goal of
screening tests is to tolerate some false-positive results and
minimize or avoid false-negative results. False-positive test
results will be resolved on further testing, but it would be
unacceptable to miss CF in a patient. When evaluating sweat
conductivity results, physicians should be aware that sweat
conductivity is approximately 15 mmol!L higher than the
sweat chloride concentration because of the presence of unmeasured anions such as lactate and bicarbonate. 10
8. What about the analysis of both sodium and chloride concentrations on the same sample?
Some laboratories analyze both chloride and sodium in the
patient's sweat samples. The determination of both electrolytes can be a useful technique to monitor quality control but
may have limited usefulness in diagnosis. For quality control purposes, a significant discordance between the two
electrolyte concentrations can indicate technical error in
collection, analysis, or both. Diagnostically, several studies
have evaluated the use of sweat Cl/Na ratios in discriminating patients with and those without CF. Because of analytic
variation in the procedures, individual chloride and sodium
concentrations can overlap, thereby limiting the diagnostic
usefulness of a Cl!Na ratio.ll-13
9. What factors affect sweat test accuracy?
Unreliable methods, technical errors, and errors in interpretation can all lead to false sweat test results. There are
problems reported with some of the methods used for sweat
testing. The Orion electrode does not quantitate the amount
of sweat collected and is subject to sample evaporation, and
the electrode may be pressure sensitive, whereas older conductivity analyzers using unheated .collection cups do not
quantitate the amount of sweat collected and are subject to
sample evaporation, condensation, or both. 14- 16 Methods that
do not quantitate sweat collected or do not have an
established minimum sample volume or weight are subject
to false-negative results because an adequate sweat rate cannot be ensured.
Other problems with sweat testing include technical errors
of evaporation and contamination, and errors in dilution, instrument calibration, and result reporting. These errors occur
more often in institutions doing relatively few tests. 16 Interpretation errors in sweat testing include lack of knowledge
of the laboratory method, failure to repeat tests with borderline or positive results, failure to repeat tests with negative
results when inconsistent with the clinical picture, and failure to repeat testing in patients with a diagnosis of CF that
does not follow the expected clinical course. 17
10. What sweat test methods are laboratories currently using?
The results of a recent survey designed to assess sweat test
methodology of laboratories in North America appear in
Table I. Chloride is the most popular analyte for sweat test-
894
LeGrys
The Journal of Pediatrics
December 1996
Table I. Method of analysis
Frequency
Methods
Chloride methods (n =574)
Chloridometer
Direct skin electrode
ISEs
Manual titration
Test patch
Other
Conductivity (n =325)
Wescor Sweat-Chek test
Advanced instruments
Other
Sodium methods (n = 77)
Harne photometer
ISEs
Other
Osmolality (n = 64)
Vapor pressure osmometer
Freezing point depression osmometer
No.
(%)
199
197
59
46
17
36
(34.7)
(34.3)
(10.3)
(8.0)
(3.0)
(6.3)
206
60
59
(63.4)
(18.5)
(18.1)
41
29
7
(53.2)
(37.7)
(9.1)
47
17
(73.4)
(26.6)
From LeGrys VL, Burnett RW. Arch Pathol Lab Med 1994;118:865-7.
Copyright 1994, American Medical Association. Used by pennission.
ISEs, Ion-selective electrodes.
ing. Even though studies have documented the problems
with the direct skin electrode, its use remains popular. One
cannot draw conclusions from Table I concerning the number of tests performed by a given method because of the wide
range in the number of tests performed annually at each institution.
11. Why is it important to establish a minimum
acceptable sweat volume or weight?
Sweat electrolyte concentration is related to sweat rate. At
low sweat rates, sweat electrolyte concentration decreases. 18
The average sweat rate should exceed 1 grnlm2 per minute.
The minimum acceptable sample for analysis from a single
site, with a 2 x 2-inch gauze or filter paper used for stimulation and collection, is 75 mg collected in 30 minutes. With
the use of the Wescor Macroduct coil system, the minimum
acceptable sample is 15 f11 collected in 30 minutes. 3 The
minimum acceptable volume or weight will depend of the
size of the electrode and stimulation area, the type and size
of collecting media, and the duration of the sweat collection
period.
Table II. Diseases other than CF associated with an
elevated sweat electrolyte concentration
Anorexia nervosa
Atopic dermatitis
Autonomic dysfunction
Ectodermal dysplasia
Environmental deprivation
Familial cholestasis
Fucosidosis
Glucose-6-phosphate dehydrogenase deficiency
Glycogen storage disease: type 1
Hypogammaglobulinemia
Klinefelter syndrome
Long-term PGEl infusion
Mauriac's syndrome
Mucopolysaccharidosis type I
Nephrogenic diabetes insipidus
Nephrosis
Protein calorie malnutrition
Pseudohypoaldosteronism
Psychosocial failure to thrive
Untreated adrenal insufficiency
Untreated hypothyroidism
Reproduced with pennission from Sweat testing: sample collection and
quantitative analysis-approved guideline [document C34-A]. National
Committee for Clinical Laboratory Standards (NCCLS), 940 W. Valley Rd.,
Suite 1400, Wayne, PA 19087.
PGEl, Prostaglandin El.
the appropriate methods of sweat collection and analysis,
quality control, and the evaluation and reporting of the test
results.
13. Are there national programs available for assessing accuracy in sweat testing?
The College of American Pathologists, a professional association involved in promoting accuracy in clinical laboratory testing, established proficiency testing for sweat analysis in 1994. The goal of the program is to provide participants with an external evaluation of sweat analysis accuracy,
along with education concerning collection, interpretation,
and testing limitations.
14. What other disorders besides CF can cause sweat
electrolytes to be elevated?
There are a variety of disorders in addition to CF that can
cause elevations in sweat electrolyte concentrations. Most of
these disorders are distinguishable from CF on the basis of
clinical presentation and are listed in Table II.
12. Are there standard procedures established for
sweat testing?
15. How common are false-positive and false-negative
sweat test results?
The National Committee for Clinical Laboratory Standards, a voluntary organization that develops and promotes
the use of national and international standards for performing clinical laboratory tests, has published document C34-A,
entitled Sweat Testing: Sample Collection and Quantitative
Analysis-Approved Guideline. 3 The document describes
The answer depends on the method used. False-positive
results have been reported to be as high as 15% and falsenegative results as high as 12%. 14, 19
16. What are the causes of false-positive and falsenegative sweat test results?
False-positive results can arise because of disorders caus-
The Journal of Pediatrics
Volume 129, Number 6
ing elevations of sweat electrolyte concentrations (see Table
II), eczema, methods that allow sample evaporation to occur,
and other methodologic and technical errors. 17
False-negative results can occur if the patient is edematous, if an inadequate quantity of sweat is collected and analyzed, and because of other methodologic and technical errorsP
17. What patient conditions can affect sweat test
results?
The patient's nutritional status, hydration status, use of
mineralocorticoids, skin condition (eczema, rash), and age
can all affect the sweat electrolyte concentration. Malnutrition, dehydration, eczema, and rash can increase sweat electrolyte concentrations, whereas edema and the administration of mineralocorticoids can decrease sweat electrolyte
concentrations.
18. How should a sweat test result of 213 be interpreted?
Physiologically, the maximum sweat chloride concentration is around 160 mmoJJL. 20 When evaluating a result significantly higher than 160 mmoJJL, one should consider the
following:
a. The units associated with the number. Perhaps 213 is
the weight of the sweat sample in milligrams.
b. The analyte being measured. Perhaps the laboratory is
analyzing the sweat for osmolality. The reference
ranges for sweat osmolality are 50 to 150 mmol!kg
(normal), 150 to 200 mmol!kg (borderline), and greater
than 200 mmol!kg (consistent with CF). 3
c. Laboratory error.
d. Munchausen syndrome by proxy. 21 Order a second
collection and analysis, asking the laboratory to observe the patient during the entire collection process.
19. Why do some patients fail to produce an adequate
sweat volume/weight?
Insufficient sweat samples, also referred to as "quantity
not sufficient" samples, can be due to several factors such
as age, race, skin condition, and collection system. 22 Though
it may seem to be more difficult to obtain an adequate sweat
sample in very young infants, studies have shown no statistically significant difference in the proportion of QNS results
in patients younger than 6 weeks of age in comparison with
patients older than 6 weeks of age. 22• 23 Differences in skin
resistance because of ethnicity or individual patient variability may lead to QNS samples. For example, in the United
States a higher prevalence of QNS samples have been
reported with black patients than with white patients. 24 Collection systems vary with regard to insufficient samples; for
example, there is a 0.7% failure rate associated with collection onto gauze or filter paper compared with a 6.1% failure
rate associated with the use of the Wescor Macroduct coils. 10
20. Can sweat collection be extended if the patient
LeGrys
895
does not provide sufficient amounts of sweat in 30 minutes?
No, the amount of sweat required is derived from a rate
equation using 30 minutes as a variable. Extending the collection beyond 30 minutes will increase the amount of sweat
required. In addition, extending the collection time can allow additional opportunity for sample evaporation and, in
practice, does not significantly add to the sample quantity.
21. Why cannot two insufficient sweat samples be
combined for analysis?
The average sweat rate of 1 gm/m2 per minute is
determined independently for each site. The requirement is
a physiologic one, not an analytic one, because sweat electrolyte concentration increases with increased sweat rate. 18
Samples below the average sweat rate can cause false-negative sweat electrolyte results.
22. How old does a patient have to be to undergo a
sweat test?
Because of a report of transient elevations in sweat electrolyte concentrations in the first 24 hours after birth, it is
recommended that patients be at least 48 hours old before
undergoing a sweat test. 3· 25
23. When can a sweat test be repeated?
Anytime, preferably when the patient is physiologically
and nutritionally stable.
24. What body sites are appropriate for sweat collection?
Arms or legs. The skin should be free of rash or inflammation. The stimulation site should be selected so that the
iontophoresis current will not cross the heart.
25. Is there any difference in sweat electrolyte concentration collected from different body sites?
No.
26. Should laboratories be performing the sweat test
in duplicate on each patient (i.e., collection and analysis
from two different sites)? In this situation, what is the
acceptable variation between the results?
Because of the potential for significant preanalytic variation with the sweat test, it is suggested that the test be performed in duplicate from two sites for quality assurance. 3
This should not be misconstrued as representing multiple,
independent sweat tests for diagnosis. For diagnostic purposes, patients with a positive sweat test result should be retested on a separate occasion for confirmation.
Most patients' sweat chloride concentrations on duplicate
testing agree within 1 to 5 mmoJJL. The laboratory can set
an appropriate range based on the standard deviation in their
laboratory. One suggestion is that for patients with chloride
concentrations less than 60 mmol!L the duplicate results
must agree within 10 mmol!L, and for patients with chloride
concentrations greater than 60 mmoJJL agreement must be
within 15 mmol!L. 3
896
LeGrys
27. Is there any risk to the patient undergoing a sweat
test?
There is a very slight (probably <1%) risk of a bum or urticaria.
28. Why would a patient get burned, and how should
the burn be treated?
A skin bum can occur if the iontophoresis current is
greater than 4 rnA, if the bare metal of the electrode touches
the skin, if the reagent interface is not sufficiently moist, or
if the electrode surface is damaged or oxidized. In addition,
patients vary with regard to their skin resistance and their
sensitivity to the iontophoresis procedure, which may account for the occurrence of bums despite appropriate techniques. Depending on the severity of the bum, either no
treatment or an antibiotic ointment is sufficient. The sweat
should not be collected over the bum site.
29. Why does localized urticaria occur, and how frequent is it? How should the urticaria be treated?
The occurrence of localized urticaria is rare. The patient
may react to the pilocarpine or to the phenomenon of electrical stimulation. 26 If it is the latter, urticaria will appear
under both electrodes.
The test should be discontinued, and sweat should not be
collected over the site of urticaria. Depending on the severity of the reaction, antihistamines can be administered.
30. Can a sweat test be performed on a patient receiving oxygen?
Yes, if the oxygen is delivered by nasal cannula or face
mask. Because of the remote risk of electrical sparking, patients should not undergo sweat testing while receiving oxygen by an open delivery system. 3
31. Can a sweat test be performed on a patient receiving fluid intravenously?
Yes, as long as the infusion does not interfere with good
skin-pad-electrode contact and the iontophoresis does not
interfere with venous flow. In addition, care should be taken
to ensure that there is no contamination of the collection site
by the fluid. 3
32. Can the sweat test be performed on either the left
or right limb?
·
Yes, particularly if the iontophoresis unit is battery powered. The original caution concerning sweat testing on the
right arm was in reference to iontophoresis units operating
from house current. 3
33. What kind of quality control should the laboratory
be performing?
Laboratories should document competency testing of all
personnel performing sweat test collection or analysis. Analytically, laboratories should be running a positive and a
negative control with every patient sample, using procedures
described in the National Committee for Clinical Laboratory
Standards document. 3 The controls can be electrolyte stan-
The Journal of Pediatrics
December 1996
dards, appropriately diluted urine control material, or commercially prepared sweat control material. If electrolyte
standards are used as controls, they should not be the standards used to calibrate the instrument.
34. What kind of information should be on the laboratory report for a sweat test?
Specific information concerning what analyte of sweat is
being measured. For example, does the test measure chloride, sodium, conductivity, or osmolality? The interpretation
of the results depends on the physician's being knowledgeable about the analytic method, because decision levels vary
considerably with each analyte. In addition, the sweat weight
or volume should also be reported to ensure adequate sample collection.
35. What kind of questions should the physician ask
the laboratory concerning sweat testing?
a. Is the sweat test a screening or a definitive (quantitative) test?
b. What does the test measure?
c. What is the minimum sample volume/weight?
d. How many tests are performed annually?
e. Who performs the test? How is competency evaluated?
f. What kind of quality control and quality assurance is
ongoing?
SUMMARY
A reliable sweat test result depends on many factors, including the use of appropriate methods, performance of a
sufficient number of tests to maintain proficiency, performance of the test by competent technologists, active quality
control and quality assurance programs that include the use
of two controls, consistently acceptable performance on
College of American Pathologists proficiency testing, and
knowledgeable interpretation of the test results in light of the
patient's clinical presentation.
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3. National Committee for Clinical Laboratory Standards. Sweat
testing: sample collection and quantitative analysis-approved
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1994. (Address: 940 W. Valley Rd., Suite 1400, Wayne, PA
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4. Gleeson M, Henry RL. Sweat sodium or chloride. Clin Chern
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