Advancements in Sweat Testing Techniques for Cystic Fibrosis: From Classical to Novel Methods

Sweat testing remains a fundamental diagnostic tool for cystic fibrosis (CF), with the classic sweat chloride test (SCT) established as the gold standard since 1959. Despite its wide use, SCT presents challenges including limited accessibility in low- and middle-income countries, difficulties in obtaining adequate sweat samples, especially from infants, and ambiguous borderline results that require further functional or genetic analysis. Newer diagnostic methods, such as nasal potential difference (NPD) and intestinal current measurement (ICM), provide sensitive and specific assessments of CFTR function, but are technically complex and require specialized expertise, restricting their use in resource-limited settings. The beta-adrenergic sweat test (BAST) emerges as a promising, less invasive alternative, directly measuring CFTR-mediated sweat production using evaporimetry or sweat bubble imaging techniques. BAST shows advantages including ease of use, rapid results, and the ability to distinguish between CF, CFTR-related disorders, heterozygotes, and unaffected individuals. Furthermore, recent advances in wearable sensor technologies and microneedle patches indicate future potential for continuous, real-time, and noninvasive sweat monitoring, which could revolutionize CF diagnostics and patient management. This review summarizes the strengths and limitations of current and emerging sweat test modalities, highlighting BAST and wearable sensors as impactful tools for improving CF diagnosis and monitoring, especially in settings with limited resources.

Sweat testing remains a cornerstone in the diagnosis of cystic fibrosis (CF)(1). The classic sweat chloride testing (SCT), also known as the quantitative pilocarpine iontophoresis test, was first introduced by Gibson and Cooke in 1959 and remains the gold standard for CF diagnosis(2, 3). Its principle is based on the observation that individuals with CF have elevated concentrations of chloride in their sweat due to dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) proteins. In low- and middle-income countries, access to SCT is limited and increasingly cost-prohibitive. In these contexts, CF may be clinically indistinguishable from other more prevalent pediatric conditions, such as non-CF bronchiectasis, malnutrition, tuberculosis, and HIV infection(4). Although SCT, particularly when combined with confirmatory genotyping, reliably diagnoses most cases of CF, intermediate values (30–59 mmol/L) without supportive genetic findings may not effectively differentiate CF from CFTR-related disorders (CFTR-RD), which are characterized by partial CFTR function, or from unaffected individuals(5). In addition, genetic testing by itself may not provide a definitive confirmation or exclusion of CF diagnosis when variants with uncertain or variable clinical significance are identified. In these instances, further evaluation of CFTR function may be necessary to either confirm or dismiss a diagnosis of CF or CFTR-RD(5). In addition, the SCT is limited by its dependence on technical precision and operator expertise; calibration errors, inadequate sample collection, or reporting inaccuracies can yield unreliable results (6). Obtaining sufficient sweat, particularly in infants, is often difficult and may require repeat testing, causing delays and added stress(2, 7). Genetic variability further complicates interpretation—while F508del is predominant in Europeans; non-European populations more often carry rare variants, frequently associated with normal or borderline values that increase underdiagnosis risk (8-10). Borderline results (30–59 mmol/L) remain diagnostically ambiguous, necessitating additional genetic or functional testing(2). Various techniques have been developed to measure CFTR activity, including electrophysiological tests such as nasal potential difference (NPD) and intestinal current measurement (ICM), as well as the β‐adrenergic sweat test (BAST) (4, 11). The NPD test is used to analyze ion transport across the nasal epithelium by assessing changes in electrical potential(12). In patients with CF, the potential is more negative than in healthy individuals, which is due to increased sodium absorption linked to CFTR dysfunction(12). Research indicates that NPD testing demonstrates a sensitivity range of 94.8–100% and 96.5–100% when compared to individuals without health issues(13). The ICM evaluates variations in the transepithelial ion current, referred to as short circuit current, within a rectal biopsy sample(14). The assessment of CFTR function involves analyzing the transepithelial movement of ions such as Cl-, HCO3-, and K +(14). ICM is regarded as having greater sensitivity compared to NPD(14). NPD and ICM are the most extensively documented in both research settings and clinical practice. However, both are costly and demand highly specialized technical skills and expertise, which are often unavailable in low and middle-income countries(4) (Table 1). The β-Adrenergic Sweat Test (BAST): The CFTR‐dependent BAST is a novel method for assessing sweat production rates, utilizing either evaporimetry or the sweat bubble imaging (15, 16). In 1984, Sato & Sato found that the eccrine sweat glands in individuals with CF did not respond to β-adrenergic agonists, yet they exhibited seemingly normal reactions to cholinergic stimulation(17). It directly assesses CFTR secretory function in vivo, offering a complementary diagnostic tool to the classic SCT (4, 15). BAST is simpler to perform and less invasive than NPD and ICM, while also showing a greater capacity than SCT to distinguish between CF, CFTR‐RD, CFTR heterozygotes, and individuals without CFTR variants(15, 18). Physiological Basis: Two pathways stimulate sweat secretion: the primary cholinergic pathway, which is mainly responsible for thermal sweating, and the secondary β-adrenergic pathway(17). CFTR-dependent β-adrenergic pathways in sweat electrophysiology and observations of reduced sweat responses in CFTR carriers and absent responses in CF individuals led to developing the BAST as a diagnostic tool(17, 19). Beta-adrenergic stimulation results in sweating, which can be evaluated using two techniques: evaporimetry and sweat bubble imaging(20, 21) (Table 2). Evaporimetry measures water vapor flux but is sensitive to movement, environmental variability, and typically requires intradermal injections(20-22). In contrast, image‐based techniques—using either digital bubble imaging or capacitive sensors—detect sweat responses at lower stimulant concentrations and operate with needle‐free, portable designs(20-22) (Figure 1). Kim et al. determined that the threshold for detecting bubbles through imaging was less than 0.2 nanoliters per square centimeter per minute, while evaporimetry showed response thresholds at about 5% of the total effect(20). Salinas et al. demonstrated that sensors based on imaging identified β-adrenergic responses in all CF patients, in contrast to an 80% detection rate with evaporimetry(21). Reynaerts et al. found that a needle-free image-based method, using the ET50 (time to reach 50% of maximal effect) cutoff, achieved 100% sensitivity and specificity(22,23). These results suggest that image-based sweat rate sensors provide enhanced sensitivity, lower detection thresholds, decreased susceptibility to movement, and greater tolerability compared to evaporimetry, although they occasionally face challenges in measurement standardization. In addition it has a modified iontophoresis approach, which avoids intradermal delivery, could prove advantageous for early care of young children, enhancing the test’s utility in neonatal screening(18). Protocol of Evaporimetry: The process for inducing β-adrenergically mediated sweat secretion consisted of three steps(15): 1- initiating cholinergic secretion with 0,01 mg of carbachol; 2- inhibiting this secretion using 8,8 mg of atropine; and 3- promoting β-adrenergic secretion by administering 8,8 mg of atropine, 4,4 mg of isoproterenol hydrochloride, and 0,93 mg of aminophylline to maximize intracellular cAMP levels(15). The carbachol dose was adjusted accordingly, as the maximum sweating rate achieved through beta-adrenergic stimulation is roughly 10-15% of that obtained via cholinergic stimulation(15, 17, 24). Drugs were intracutaneously injected into the forearm at the same site to form a blanched ”wheal” (z5 mm diameter)(15). After mineral oil coating, sweat secretion was assessed for 10–15 minutes post-injection using an evaporimeter probe. Atropine injection nearby measured background transpiration. The rate of evaporative water loss (kg water/m2/h) is presented without units. The classic SCT was performed on the other arm for comparison. Sweat chloride concentration was determined by chloridometry. Healthy controls exhibit robust β-adrenergic-induced sweat secretion, while individuals with CF show absent or markedly reduced response. Heterozygotes display intermediate values, roughly half that of controls(4, 15). Protocol of Sweat bubble imaging: The assay designed to evaluate CFTR secretory function is composed of two successive phases of stimulated secretion(25). Methacolin injection: The first phase, which lasts for 15 minutes, is dedicated to measuring M-sweating, the reaction to methacholine. An imaging site was selected on the volar surface of the forearm. The surrounding area was swabbed with alcohol, and Methacolin in lactated Ringers was injected intradermally(25). Following the injection, a deep reservoir was secured over the injection wheal, the skin was dried using compressed gas, and water-saturated mineral oil was added. Light-emitting diodes positioned 0,5 cm above the skin provided oblique lighting to visualize the unstained M-sweat bubbles(25). The reservoir was fixed in place with a computer-controlled digital camera equipped with a macro lens. Images were captured at 30-second intervals(25). The camera captured an area of 66.5 mm², containing at least 50 measurable glands in our subjects(25). The secreted sweat formed expanding spherical bubbles that remained attached to the sweat column in the sweat duct openings but did not wet the oil-covered surface. After 15 minutes, the sweat and oil were removed, centrifuged, and stored at -220°C, after which the reservoir was removed and the area blotted with an absorbent dressing(25) (Figure 2). Cocktail injection: The second phase, extending over 30 minutes, focuses on assessing C-sweating, the response elicited by the cocktail(25). The site was re-injected within 2 min with atropine, isoproterenol and aminophylline dissolved in lactated Ringers for a 0.1 ml injection volume(25). This cocktail previously stopped sweating from high-dose Methacolin ”instantly” and elicited a pure b-adrenergic sweat response, as indicated by its total block by propranolol(17). Two minutes after the cocktail injection—when M-sweating was blocked by atropine but before C-sweating began—the site was rinsed with distilled water and dried with gas. This was done before adding the oil reservoir/imaging chamber and indicator oil, which occurred three minutes post-injection(25). To visualize the small sweat bubbles in CFTR-compromised subjects, particles of water-soluble dye were dispersed in the oil. When a dye particle comes into contact with a sweat bubble, it integrates into the bubble and stains it blue, making it easily visible against the skin. The imaging chamber for cocktail-stimulated sweating utilized a chamber with the same LED light ring, positioned 1,7 cm above the skin to provide diffuse lighting that effectively highlighted the stained sweat droplets(25). Advantages of the BAST: Compared to the conventional SCT, the BAST offers superior discriminatory power, particularly in cases with inconclusive or borderline SCT results(4, 26, 27). BAST is more accurate in excluding CF among children with ambiguous diagnoses and in identifying individuals with CFTR-related disorders or atypical genotypes that may yield normal or borderline chloride levels(15). Moreover, the BAST verified the presence of CF disease in individuals with mutations such as 3849+10kBC>T and D1152H, which typically show normal or borderline sweat [Cl-] levels(26, 27). This makes BAST especially valuable for clarifying diagnoses in complex or intermediate cases.Conducting the test via evaporimetry ensures it remains minimally invasive and is generally well accepted by patients. This method involves the local application of stimulatory agents and the subsequent measurement of sweat secretion through skin surface sensors, which helps to minimize the risks and discomfort typically associated with more invasive procedures such as NPD or ICM(18, 28).The β-Adrenergic Sweat Test can be completed in a relatively brief timeframe and does not necessitate the specialized technical skills or equipment required for NPD or ICM(4, 28). The implementation of evaporimeters facilitates real-time, consistent measurements of sweat rates, rendering the test suitable for routine clinical application and multicenter research(15, 28). This ease of access is especially advantageous in environments where advanced electrophysiological testing is not an option(4).In addition to its diagnostic utility, the BAST stands out as a significant biomarker for evaluating CFTR function in vivo. Its application in clinical trials is on the rise, as it provides a direct assessment of the effectiveness of CFTR-modulating therapies by measuring functional recovery post-treatment(18). The test’s sensitivity to subtle variations in CFTR activity renders it essential for both the development of new drugs and the tailored management of individual patients(15). Limitations and Challenges: In evaporimetry, repeated intracutaneous injections are essential for both stimulating and inhibiting sweat secretion effectively(18). This make the clinical application of this test particularly challenging in infants and young children. Despite this, all subjects involved in the study handled these injections well(4, 15). Advers event: Studies have reported either no adverse events or mild ones(17, 21, 24). Salinas et al. found the test well tolerated in children, with no serious adverse events and normal physiological monitoring, including electrocardiogram and vital signs, though skin irritation occurred from sequential iontophoresis(21). Behm et al. (1987) reported mild delayed hypersensitivity skin reactions in two control subjects, managed with topical corticosteroids(24). Sato and Sato (1984) noted palpitations in some subjects at high isoproterenol doses(17). FUTURE DIRECTIONS: Wearable Sensor-Based Sweat Tests: Recent advances in wearable and flexible sweat sensors are revolutionizing sweat testing by enabling continuous, real-time, and noninvasive monitoring of sweat biomarkers(29). These platforms integrate microfluidics, electrochemical sensing, and wireless data transmission, allowing for multiplexed analysis of electrolytes, metabolites, and other analytes directly on the skin(30). Such systems can autonomously induce sweat via iontophoresis and provide rapid, quantitative results, potentially replacing or augmenting traditional laboratory-based methods(29).Wearable sweat sensors have demonstrated excellent agreement with SCT for chloride measurement and offer additional benefits such as ease of use, reduced sample volume requirements, and suitability for remote or ambulatory monitoring(2, 29). These innovations are poised to expand the clinical utility of sweat testing beyond CF to include metabolic, endocrine, and pharmacological applications(29). Microneedle patch: The sweat test for newborns involves stimulating the sweat glands on both forearms using pilocarpine nitrate, administered through iontophoresis(31). The goal is to collect a small sweat sample, typically ranging from 15 to 100 µl(31). However, inadequate collection is common, particularly in infants under three months old, due to factors such as gestational age, ethnicity, or skin characteristics(32). This often necessitates repeat testing, leading to diagnostic delays and parental anxiety. As an alternative, microneedle (MN) patches are proposed for pilocarpine delivery(33). These patches, composed of tiny, drug-loaded needles that dissolve in the skin, are minimally invasive, painless, and easy to use(34). MN technology has already been proven effective for various drug and vaccine deliveries and is cost-effective, with patches costing less than $1 each(35) (Table 3). This approach could streamline sweat induction and collection, enhancing early and accurate CF diagnosis in infants(33).Microneedle patches consist of a two-dimensional array of solid conical formations composed of pilocarpine nitrate and water-soluble excipients(36). The height of these MNs is kept below 1 mm to prevent pain and bleeding(36). When applied, MNs penetrate the stratum corneum barrier and dissolve into the interstitial fluid of the epidermis and dermis, thereby releasing their payload. The patches resulted in sweat concentrations similar to those produced by iontophoresis, along with increased Cl− levels(36). Further clinical research is needed to evaluate the effectiveness of MN patches across various subpopulations, including individuals suspected of having CF. Saliva: Collecting saliva samples is a non-invasive, fast, cost-effective, and simpler method compared to SCT(37) (Table 3). In the study by Gonçalves et al., it was found that chloride and sodium levels were elevated in patients with CF compared to healthy individuals(37). The study determined that the method employed for ion concentration measurement rendered saliva unsuitable(37). Nevertheless, the authors acknowledged the potential of saliva as a future alternative to SCT(37). Given that CF influences the potassium levels, pH, and volume of saliva, future research should focus on identifying diagnostic markers and developing precise measurement techniques. CONCLUSION: In many low- and middle-income countries, the burden of CF remains underestimated due to limited diagnostic capacity and absence of universal newborn screening programs. To address this gap, there is a need for low-cost, user-friendly, accurate sweat testing methods that can be implemented in resource-limited settings. Such innovations—whether simplified chloride measurement techniques, portable devices, or alternative point-of-care tools—would enable earlier diagnosis, improve patient outcomes, and provide better epidemiological data. Even in countries with newborn screening programs, there remains a subset of patients with intermediate results or cases missed by classic SCT, highlighting the need for faster, accessible diagnostic tools. 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Authors Metrics & Citations Metrics Article Usage 276views 142downloads Citations Download citation Mine Kalyoncu, Yasemin Gokdemir (Guest Editor). Advancements in Sweat Testing Techniques for Cystic Fibrosis: From Classical to Novel Methods. Authorea. 25 August 2025. DOI: https://doi.org/10.22541/au.175614490.05057088/v1 DOI: https://doi.org/10.22541/au.175614490.05057088/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu.