Sweat Testing


Article Author:
Henry Schmidt


Article Editor:
Girish Sharma


Editors In Chief:
Ishwarlal Jialal


Managing Editors:
Avais Raja
Orawan Chaigasame
Khalid Alsayouri
Kyle Blair
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beenish Sohail
Hajira Basit
Phillip Hynes
Sandeep Sekhon


Updated:
9/19/2019 10:38:27 PM

Introduction

Cystic fibrosis (CF), a rare genetic disorder, characterized by multisystem involvement including progressive, potentially fatal pulmonary disease, has been described as being the most prevalent inherited fatal disorder in the White population of Northern European origin. However, this autosomal recessive disorder also presents in other populations, including African-Americans, Hispanics, and Asians. In patients with CF,  Researchers first noted sweat chloride abnormality in CF patients in 1953; this spawned the development of the sweat test in 1959. Since the discovery of the CF gene in 1989, which codes for the protein cystic fibrosis transmembrane regulator (CFTR), there are reports of more than 2000 mutations.  The cystic fibrosis transmembrane regulator is at the apical surface of the epithelial cells in the airways, gastrointestinal tract, pancreas, genitourinary system, and the sweat glands in the skin. The defective, deficient or absent CFTR function results in abnormal chloride transport across the chloride channels and abnormal sodium transport along with the secondary effect on water movement across the cell membrane. Decreased chloride secretion along with increased sodium reabsorption (along with water as a secondary effect) across the apical surface of the epithelial cells results in increased viscosity of secretions in the organs involved and in the case of skin, elevated levels of chloride in the sweat. Detection of elevated values of sweat chloride, in a suspected patient, by quantitative pilocarpine iontophoresis test (QPIT) is considered to be the gold standard for the diagnosis of cystic fibrosis.[1]

Specimen Collection

The Cystic Fibrosis Foundation (CFF) recommends that a sweat test be done at a CFF-accredited care center by a trained technician. The sweat test is typically performed on the patient’s arm or leg. The test involves iontophoresis of pilocarpine to stimulate sweat production by sweat glands. Collection modalities include gauze, filter paper, or macroduct coil.[2] Since the sweat chloride can present as transiently elevated in the first 24 hours of life, the CFF clinical care guidelines recommend that sweat testing should be done after 48 hours of birth or later. Two samples are collected due to the underlying variability of the test and the potential for an insufficient sample. Pilocarpine iontophoresis is done for 5 minutes, followed by sweat collection for not more than 30 min. For the gauze or filter paper method, the stimulated area must be 2 x 2 inches. The minimum quantity of sweat collected for the gauze method is 75 mg, and a minimum sample volume of 15 microliters is necessary for the macroduct method.[2]

Procedures

The clinician conducts iontophoresis of pilocarpine on the patient's skin. In the original Gibson-Cooke method, two electrodes, one covered in gauze soaked with pilocarpine and the other with deionized water, are placed on the patient's arm or leg. A small, painless, electrical current is then applied for 5 minutes; referred to as iontophoresis. Afterward, a collecting source, such as gauze, filter paper, or a Macroduct coil is used to collect the sweat. The allotted time for sweat collection should not exceed 30 minutes. Using the Gibson-Cooke method for QPIT, a minimum of 75mg of sweat is required adequate testing. However, most centers in the US utilize collection via macroduct coil, which requires only 15 microliters of sweat for analysis. Sweat should not be collected from multiple sites for the same test as the rate of sweating determines the chloride content. The collected source then goes to the lab for quantification of chloride.[2][3]

Indications

Indications for the sweat test include individuals suspected of having cystic fibrosis, either through a positive newborn screening test or if clinical features suggestive of CF are present. The sweat test is considered to be the gold standard as a confirmatory test. CF genotyping is recommended to help decide CF mutation-specific therapy, in case the sweat test results are borderline or sweat test is not technically possible (e.g., severe eczema). The CFF recommends CF genotyping in all patients. In the United States, the newborn screen tests for an elevated level of IRT (immunoreactive trypsinogen) and if positive may reflex to a DNA test for known mutations of the CFTR gene, depending on the each state’s protocol. A child demonstrating a positive newborn screen will subsequently require confirmatory sweat testing at a CF center.[3]

In children clinically suspected to have cystic fibrosis, a referral to a CF center for sweat testing is indicated. Patients with cystic fibrosis may present with a myriad of different presentations. Neonates may present with meconium ileus. Smaller children may present with pulmonary complications such as recurrent pneumonia, upper respiratory infections, wheezing, and coughing. Gastrointestinal manifestations include failure to thrive with malabsorptive stools, recurrent abdominal pain. Given the clinical suspicion, children obtain a referral for testing.[4] Table 1 describes some of the common indications for sweat testing. Sweat testing may also serve as a surrogate biomarker for evaluating CFTR function. The result of a sweat test informs clinicians regarding the effects of CFTR-modulating drugs such as ivacaftor.[4]

Potential Diagnosis

An elevated level of chloride (over 60 mmol/L) in the sweat is diagnostic for cystic fibrosis, sweat chloride levels in less than 29mmol/L is normal. A level between 30 to 60 mmol/L is considered borderline, and repeat sweat test or further testing is required. This range may reflect a heterozygous carrier which cannot be accurately detected with sweat testing. The result of a positive newborn screen needs to be interpreted together with the sweat to test to reliably diagnose CF. Specific known mutations of CF do not cause elevated sweat chloride, and therefore sweat testing does not provide clarity.[1]

Patients with a positive newborn screen and a negative sweat test sometimes receive diagnoses other than CF, such as CF-related metabolic syndrome (CRMS) and CF screen-positive, inconclusive diagnosis (CFSPID). A normal sweat chloride test does not exclude the diagnosis, in which case the clinician should pursue genotyping or other alternative diagnostic studies (such as nasal membrane potential difference, intestinal current measurement, semen analysis, or assessment of pancreatic function), especially if there is a high index of clinical suspicion for cystic fibrosis.[1]

Normal and Critical Findings

Sweat chloride levels:

  •  Less than 30 mmol/L: CF is unlikely
  • 30 to 59 mmol/L: CF is possible, further testing may be required
  • 60 or greater mmol/L: diagnostic of CF

Sweat chloride in patients without cystic fibrosis should be less than 30 mmol/L. Values greater than 60 mmol/L are diagnostic of cystic fibrosis. Intermediate values between 30 to 60 mmol/L are considered to be an elevated but not diagnostic level. Cystic fibrosis is possible in these patients, but repeat or alternative testing is necessary.[1]

For patients with intermediate sweat chloride levels (30 to 60 mmol/L), genetic testing may help to confirm or exclude the diagnosis. In patients with two CF-causing mutations on separate chromosomes, no further diagnostic testing is necessary, and CF diagnosis is confirmed. For patients without CF-causing mutations, no further testing is indicated as CF is unlikely. In patients with undefined CFTR mutations or CFTR mutations of varying clinical consequence, the clinician should pursue further testing if clinical features are present; this may entail NPD (nasal potential difference), ICM (intestinal current measurement), semen analysis, or pancreatic function testing.[1]

Interfering Factors

False positives are rare, but sweat chloride may elevate falsely in other pathologic syndromes and situations, including:

  • Improper testing technique
  • Atopic dermatitis
  • Untreated adrenal insufficiency
  • Glycogen storage disease
  • Panhypopituitarism
  • Hereditary nephrogenic diabetes insipidus
  • Hypothyroidism
  • Pancreatitis
  • Malnutrition
  • Mucopolysaccharidosis
  • Ectodermal dysplasia
  • Prostaglandin E1 infusion

Newborns may not produce enough sweat and may need to wait until later in infancy before an adequate sweat quantity can be collected. Infants with a positive newborn screen can undergo testing as early as 2 days of life. However, the Cystic Fibrosis Foundation recommends waiting until the child is 10 days old. For premature infants, testing should wait until they are 2 kilograms in size and greater than 36 weeks corrected gestational age, if possible.[4][5]

Patient Safety and Education

Sweat testing with QPIT is a quick, painless, safe, and reliable test used for CF diagnosis. The electrical stimulation is painless and does not cause discomfort. For safety reasons, the iontophoretic current source needs to be battery powered. Inspection for current control and leakage must be periodically performed by biomedical engineering according to the manufacturer’s recommendations. After a positive result, either a second testing sample is collected, or genetic testing is performed to confirm the diagnosis. Testing is only performed at CFF accredited cystic fibrosis centers. Other methods of measuring CTFR function, including measuring the total osmolality, conductivity, and sodium or potassium levels of sweat are not recommended for the diagnosis.[2]

Further information about sweat testing for patients and families is available via the Cystic Fibrosis Foundation.

Clinical Significance

If there is clinical suspicion of a child having cystic fibrosis from newborn genetic screening, or if clinically suspected by a healthcare provider, a sweat test should be performed to confirm the diagnosis. The sweat test is considered to be the gold standard for diagnosing CF and used in conjunction with clinical findings and family history to make the diagnosis. Cystic fibrosis is a  lifelong condition with many healthcare ramifications. Given the evolving therapies for patients with cystic fibrosis, early diagnosis is vital to ensure prompt therapeutic intervention and clinical monitoring. Patients with cystic fibrosis are living longer lives than ever before, with the median age of survival being greater than 40 years in developed countries. Children with diagnosis later in life likely to have better outcome given the likelihood of residual CFTR function and a less severe phenotype.[6]


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Sweat Testing - Questions

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A 4-month-old female presents to the clinic with failure to thrive. She was born in Eastern Europe and was adopted shortly after birth. Results of newborn screening are not available. She has been taking approximately 3 ounces of 19 kilocalories-per-ounce formula every 3 hours. On examination, she is thin-appearing but active and alert. The remainder of the physical exam does not reveal any abnormalities. A complete blood count is within normal limits. A sweat test is conducted, which demonstrates a sweat chloride level of 82 mmol/L. Which of the following diagnoses is associated with normal sweat chloride levels?



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An infant is born at 30 weeks gestation, weighing 1,800 grams. His resuscitation included providing continuous positive airway pressure (CPAP). He is admitted to the NICU for further management. At day 6 of life, the newborn screening results show elevated immunoreactive trypsinogen (IRT). Vital signs show a temperature of 36.8 C, a heart rate of 160 beats per minute, and a respiratory rate of 34 breaths per minute. He is being provided 7 mmHg of CPAP. His exam is notable for coarse breath sounds in both lung fields, but no wheezing or retractions are noted. What steps are indicated for follow-up testing?



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An 11-month old male infant with a past history of severe atopic dermatitis is referred to the local clinic for evaluation. Previous visits have been concerning for failure to thrive, chronic cough, and greasy stools. Examination of the skin reveals diffuse, poorly controlled eczematous lesions affecting the arms and legs. There is very little subcutaneous fat. A 25-hydroxy-vitamin D level measured at a prior visit is 8 ng/ml. Which of the following is the next best step?



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A 16-year-old male with cystic fibrosis presents to the clinic for a follow-up visit. He takes enzyme supplementation with meals, and he has been using chest physiotherapy twice daily. Genetic testing reveals homozygous G551D mutation of cystic fibrosis transmembrane regulator (CFTR) protein. He is started on ivacaftor to improve his CFTR protein function. Which of the following is most helpful in monitoring the disease?



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An infant male is born via spontaneous vaginal delivery to a 30-year-old woman with no significant past medical history. The mother received all routine prenatal care, and the prenatal course was unremarkable. Newborn screening is concerning for cystic fibrosis. He is discharged from the newborn nursery on day 3 of life, and his hospital stay was unremarkable. The patient is brought to the clinic for sweat testing. His weight is at the 45th percentile for age. His exam does not reveal any abnormalities. The result of a sweat test demonstrates a sweat chloride level of 47 mmol/L. CFTR genotyping for this patient shows a homozygous delta-F508 mutation. What is the next best step for diagnosis?



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Sweat Testing - References

References

Elborn JS, Cystic fibrosis. Lancet (London, England). 2016 Nov 19;     [PubMed]
Littlewood JM, The sweat test. Archives of disease in childhood. 1986 Nov;     [PubMed]
Eng W,LeGrys VA,Schechter MS,Laughon MM,Barker PM, Sweat-testing in preterm and full-term infants less than 6 weeks of age. Pediatric pulmonology. 2005 Jul;     [PubMed]
LeGrys VA,Yankaskas JR,Quittell LM,Marshall BC,Mogayzel PJ Jr, Diagnostic sweat testing: the Cystic Fibrosis Foundation guidelines. The Journal of pediatrics. 2007 Jul;     [PubMed]
Davis PB, Cystic fibrosis since 1938. American journal of respiratory and critical care medicine. 2006 Mar 1     [PubMed]
GIBSON LE,COOKE RE, A test for concentration of electrolytes in sweat in cystic fibrosis of the pancreas utilizing pilocarpine by iontophoresis. Pediatrics. 1959 Mar     [PubMed]

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