Evaluation of a Novel Automated Allergy Intradermal Skin Test Reader: A Diagnostic Accuracy Study

The intradermal test (IDT) and skin prick test (SPT) represent the primary diagnostic tool [1], and most common used in vivo biomarker in the study of immediate hypersensitive reactions [2]. IDT is used in the study of drug and hymenoptera venom allergy [1], consisting in a manual procedure (MP) that involves different measurement techniques and criteria with the consequent variability between health professionals [3], being the lack of their standardisation still a pending task [4]. The current positive criteria (an increase of 3 or more millimetres in maximum diameter (MD) of the initial wheal and surrounding erythema) [3] depends on a manual measurement, where it is difficult to obtain such a small measurement in a reproducible and reliable way. After all, the final decision on whether a test is positive or negative will depend on the judgement of the professional doing the study.

Nexkin DSPT (Digital Skin Prick Test) is a medical device that automatically assess the wheal size in SPT. This device, based on 3D-laser technology, reconstructs the geometry of the arm of the patient, followed by an algorithm-based methodology that locates the wheals and calculates their shape and size (area in mm², and MD and orthogonal diameters in mm) automatically [5]. In 2021, our group conducted a clinical trial to validate the use of Nexkin DSPT for the measurement of SPT; our results showed higher reliability for the device in comparison to MP, correlations between the MP and Nexkin DSPT showed a relatively strong association (area: r = 0.742, p < 0.001; MD: r = 0.700, p < 0.001; OD: r = 0.644, p < 0.001) and the consistency of Nexkin DSPT readings were greater than those of the MP in the test–retest: reading variations in Nexkin DSPT area (2.02 mm²; SD = 3.42) were lower than those of the MP (4.94 mm²; SD = 4.14) (p < 0.001) [6].

A prospective study, company-sponsored, was conducted at Clínica Universidad de Navarra (PI_2021/155), IDTs were performed in 194 participants with positive (histamine) and negative (saline solution) controls. Two readings were executed (immediate and after 20 min) both automatically, with Nexkin DSPT and by the MP (performed by the same allergology specialist in all cases). We aimed to determine sensitivity and specificity, agreement between both methods as well as a potential cut-off point for diagnosis.

For the estimation of sensitivity, specificity, discrimination capability and the identification of potential cut-off points we randomly selected 97 wheals from each of both groups (histamine and saline solution). The complete sample was used for the evaluation of the agreement between the MP and the device, and for the comparisons between the immediate and second reading of the device. Characteristics of the participants, immediate and 20-min histamine, and saline solution wheal size of each procedure are shown in Table 1.

We are aware that the gold standard diagnostic tool for immediate and delayed hypersensitivity reactions is the provocation test, but due to ethical constraints in many cases it is not performed [7, 8]. For this reason, in an experimental outcome, we designated the positive control (histamine) and negative control (saline solution) as proxies for the gold standard, as they are used as controls in the real-life practice. We anticipated that the histamine wheals would result in an increase in size (3 or more millimetres in MD of the initial wheal) while the saline solutions would not. Our findings indicated that Nexkin DSPT exhibited substantial sensitivity and specificity, 99.0% (95% CI: 94.39–99.97) and 96.9% (95% CI: 91.23–99.36), respectively. In the MP, the sensitivity was 97.9% (95% CI: 92.75–99.75), and the specificity was 100% (95% CI: 96.27–100).

We have verified that the obtained cut-off point for the MD (3.81 mm increase) closely aligns with the established guidelines [3] and for the area was defined as an increase of 32.05 mm². Nexkin DSPT can offer immediate area wheal measure, a task often challenging to perform in routine clinical practice.

The level of agreement between Nexkin DSPT measurements and manual measurements was moderate to low, ranging from 0.40 (95% CI: 0.27–0.51) for the MD in the immediate histamine wheals readings to 0.65 (95% CI: 0.56–0.73) for MD in the second histamine readings. In our opinion, this variability may be attributed to various factors that affect the MP, including the act of outlining the wheal perimeter with a pen and other factors related to human involvement. Additionally, the device provides measurements with decimals, which, though nearly identical, can result in lower intraclass correlation coefficient results when considering the entire sample. In some instances of device readings, approximately 1.8% detected the presence of a blood vessel or artefact, which contributed to the lack of agreement between the two measurement methods.

Related to the discrimination capability of Nexkin DSPT, we can see that it is good to excellent across the three wheal size measurements.

Interestingly, we were able to detect a difference in the size of the saline solution wheals between the immediate and the second readings performed by Nexkin DSPT, this was statistically significant.

Limitations of this study include the lack of a previously fixed volume for test solutions, which may have contributed to the variability in immediate wheal size. Considering the outcomes obtained from our study, we can deduce that Nexkin DSPT has the potential to streamline skin testing procedures, thereby reducing variability, and enhancing the precision and consistency of IDTs. Thus, Nexkin DSPT could represent a significant advancement in the ongoing efforts to standardise this crucial test in the field of allergy clinical practice. Additional information about methods, findings and discussion are available in the following repository: https://doi.org/10.7910/DVN/NG5EOT.

M.P.M.-P., J.M.N.-C., C.M.D.A. and G.G. created the methodology and wrote the original draft. M.P.M.-P., C.M.D.A., E.T., O.M. and G.G. performed the investigation. J.M.N.-C. performed the statistical analysis. All the authors have agreed to be responsible for ensuring the accuracy of the presented data.

G.G. is a member of the Nexkin Medical advisory board and patent's co-author: Measuring Wheals and Detecting Allergies. O.M. and E.T. are Nexkin Medical employees and shareholders. The remaining authors have no conflicts of interests.